Improved clinical effectiveness of adalimumab when initiated with clindamycin and rifampicin in hidradenitis suppurativa.

BACKGROUND: Adalimumab monotherapy for hidradenitis suppurativa (HS) is often insufficient with a maximum clinical efficacy of 60% in Hidradenitis Suppurativa Clinical Response (HiSCR) and limited effect on draining tunnels. Data suggest that adalimumab therapy could be improved by concomitant antibiotics. OBJECTIVE: To compare the clinical effectiveness of adalimumab with clindamycin and rifampicin versus adalimumab monotherapy after 12 weeks. METHODS: This retrospective study included patients who started adalimumab with additional clindamycin and rifampicin and patients treated with adalimumab monotherapy, matched on sex and refined Hurley score. The primary outcome measure was the difference in change in the International Hidradenitis Suppurativa Severity Score System (IHS4) at 12 weeks. RESULTS: In total, 62 patients were included in the combination therapy group (n = 31) and adalimumab monotherapy group (n = 31), showing comparable IHS4 scores; 32.5 versus 29, p = 0.87 at baseline respectively. The combination therapy demonstrated greater clinical effectiveness expressed in median IHS4 improvement (-20 vs. -9, p < 0.001), IHS4-55 (74% vs. 36%, p = 0.002), median draining tunnel reduction (-4 vs. -2, p < 0.001) and pain response (47% vs. 27%, p = 0.02). CONCLUSION: Adalimumab initiated with clindamycin and rifampicin shows greater clinical effectiveness than adalimumab monotherapy. An important difference in effect was observed in the decrease of draining tunnels, addressing a serious limitation of adalimumab monotherapy.

Complement activation in Hidradenitis suppurativa: Covert low-grade inflammation or innocent bystander?

Hidradenitis suppurativa (HS) is a chronic auto-inflammatory skin disease with a complex and multifactorial pathogenesis involving both the innate and adaptive immune system. Despite limited evidence for local complement activation, conflicting results have been published on the role of systemic complement activation in HS. It was hypothesized that complement was consumed in highly inflamed HS skin, trapping complement from the circulation. Therefore, the aim of this study was to evaluate this local complement deposition in HS skin lesions using routine and commonly used complement antibodies.Direct immunofluorescence for C1q, C3c, C4d, C5b-9, and properdin was performed on frozen tissue sections of 19 HS patients and 6 controls. C5a receptor 1 (C5aR1) was visualized using immunohistochemistry. Overall, we found no significant local complement deposition in HS patients versus controls regarding C1q, C3c, C4d, C5b-9, or properdin on either vessels or immune cells. C5aR1 expression was exclusively found on immune cells, predominantly neutrophilic granulocytes, but not significantly different relatively to the total infiltrate in HS lesions compared with controls. In conclusion, despite not being able to confirm local complement depositions of C1q, C3c, C4d, or properdin using highly sensitive and widely accepted techniques, the increased presence of C5aR1 positive immune cells in HS suggests the importance of complement in the pathogenesis of HS and supports emerging therapies targeting this pathway.

Adalimumab and infliximab survival in patients with hidradenitis suppurativa: a daily practice cohort study.

BACKGROUND: Biologics are often required for the treatment of hidradenitis suppurativa (HS). However, data on the drug survival of biologics in daily practice are currently lacking. OBJECTIVES: To assess the drug survival of antitumour necrosis factor biologics in a daily practice cohort of patients with HS and to identify predictors for drug survival. METHODS: A retrospective multicentre study was performed in two academic dermatology centres in the Netherlands. Adult patients with HS using biologics between 2008 and 2020 were included. Drug survival was analysed with Kaplan-Meier survival curves and predictors of survival with univariate Cox regression analysis. RESULTS: The overall drug survival of adalimumab (n = 104) at 12 and 24 months was 56·3% and 30·5%, respectively, which was predominantly determined by infectiveness. Older age (P = 0·02) and longer disease duration (P < 0·01) were associated with longer survival time. For infliximab (n = 44), overall drug survival was 58·3% and 48·6% at 12 and 24 months, respectively, and was predominantly determined by infectiveness and side-effects. Surgery during treatment was associated with a longer survival time (P = 0·01). CONCLUSIONS: Survival rates were comparable for adalimumab and infliximab at 12 months, and were mainly determined by ineffectiveness. Age, disease duration (adalimumab) and surgery (infliximab) are predictors for longer survival.

Barriers to recruitment of children with cerebral palsy in a trial of home-based training.

Many trials fail to include the targeted number of participants, causing scientific and ethical problems. The COAD trial of home-based training programs (HBTPs) for children with unilateral cerebral palsy (CP) encountered recruitment problems, even though the parent-delivered home-based approach complies with recent health-care developments in the Netherlands. The current project aimed to identify the barriers to recruitment in the COAD trial. This summative, multidimensional evaluation comprised informal conversational interviews in which stakeholders who had been involved reflected on the factors that impeded successful recruitment of participants into the COAD trial. Barriers to implementation and recruitment were clustered according to the constructs of the Consolidated Framework for Implementation Research (CFIR). Member checking validated the findings. A total of 41 stakeholders contributed to the evaluation. Barriers to the implementation of the HBTPs were identified within every domain of the CFIR (intervention characteristics, outer setting, inner setting, characteristics of individuals, and process). Parent-delivered home-based training was perceived as highly complex and in conflict with the pressures on and the needs of parents. Many parents preferred the alternative center-based group interventions. The involvement of a resonance group was highly valued, and opportunities for further enhancements emerged. Additionally, the importance of research consortia was emphasized. The appropriateness of the RCT as the study design was criticized. The findings of this study are summarized in a tool which provides a dozen directions for the successful recruitment of participants in pediatric rehabilitation research.

[The relationship between traumatic experiences and dissociative phenomena]. / Het verband tussen belastende ervaringen en dissociatieve verschijnselen.

BACKGROUND: Intuitively we are convinced that there must be a causal relationship between traumatic experiences and dissociation. However, although the theory is both elegant and attractive, the existence of a direct causal link between trauma and dissociation is open to question. Available studies on this theme have methodological shortcomings. AIM: To obtain more insight into the frequency with which psychiatric patients have undergone traumatic experiences and to find out more about the relationship between theses experiences and dissociative phenomena. METHOD: Over a period of two years new outpatients attending psychiatric clinics completed questionnaires about their past life and mental health; in these questionnaires they gave information about traumatic experiences, dissociative phenomena, psychological symptoms and psychological functioning. RESULTS: Only 38 of the 351 patients who completed the questionnaire stated that they had never had any traumatic experiences. A relatively large number of patients mentioned that they had experienced emotional deprivation in their family of origin. The correlation coefficient between traumatic experiences and the scores for dissociative phenomena was 0.30. CONCLUSION: In view of the weak positive correlation between traumatic experiences and dissociative phenomena the hypothesis of a linear causal relationship seems unlikely. It is possible that the relationship is based partly on the poorer general psychological functioning that follows exposure to traumatic experiences.

Identification of genes potentially involved in rupture of human atherosclerotic plaques.

Although rupture of an atherosclerotic plaque is the major cause of acute vascular occlusion, the exact molecular mechanisms underlying this process are still poorly understood. In this study, we used suppression subtractive hybridization to make an inventory of genes that are differentially expressed in whole-mount human stable and ruptured plaques. Two libraries were generated, one containing 3000 clones upregulated and one containing 2000 clones downregulated in ruptured plaques. Macroarray analysis of 500 randomly chosen clones showed differential expression of 45 clones. Among the 25 clones that showed at least a 2-fold difference in expression was the gene of perilipin, upregulated in ruptured plaques, and the genes coding for fibronectin and immunoglobulin lambda chain, which were downregulated in ruptured plaques. Reverse transcriptase-polymerase chain reaction analysis on 10 individual ruptured and 10 individual stable plaques showed a striking consistency of expression for the clones SSH6, present in 8 ruptured and 2 stable plaques, and perilipin, expressed in 8 ruptured plaques and completely absent in stable plaques. Localization studies of both perilipin mRNA and protein revealed expression in cells surrounding the cholesterol clefts and in foam cells of ruptured atherosclerotic plaques. No expression was observed in nondiseased artery, and only a few cells in the shoulder region of stable plaques tested positive for perilipin. In conclusion, this study shows that it is possible to identify genes that are differentially expressed in whole-mount stable or ruptured atherosclerotic plaques. This approach may yield several potential regulators of plaque destabilization.

A cross-national study of posttraumatic stress disorder in Dutch-Australian immigrants.

OBJECTIVE: Studying the rates of posttraumatic stress disorder (PTSD) in people who experienced World War II, but who have subsequently lived in different environments is a way of looking at the impact of recovery environment on PTSD. Immigrants had less support in terms of the social cohesion in their home country, but were not subjected to the same triggers of war-related intrusions. METHOD: Posttraumatic stress disorder was investigated in citizens from the Netherlands who emigrated to Australia in the post-World War II years (n = 251). Immigrants born between 1920 and 1930 (n = 171) were compared with a same-aged group living in Holland (n = 1461) for stressful war experiences and the extent of PTSD. RESULTS: Those who had been exposed to the most severe war stress were overrepresented in the immigrant group. Immigrants with current PTSD more often stated that motives for migration were threat of a third world war, disappointment with Dutch society and personal problems. We were unable to demonstrate specific effects of emigration on the prevalence of current PTSD. CONCLUSIONS: This study suggests that exposure to severe war stress promoted the need to emigrate. The comparable PTSD scores of the groups of war victims living in Australia and the Netherlands support the notion that extreme war stress may be considered the primary determining factor in the development of PTSD, and that actual post-war living circumstances are, in the long term, of subordinate importance.

Reported physical health in resistance veterans from World War II.

Male Dutch Resistance veterans from World War II who reported on chronic diseases were compared with subjects from a population survey. Resistance veterans in general reported significantly more disease. Veterans with symptoms of posttraumatic stress disorder reported more disease than those who had none. Furthermore, 13 specific disease categories were more prevalent in the Resistance veterans than in the general population. In the Resistance veterans total number of reported diseases was significantly correlated with anxiety, depression, and posttraumatic stress disorder. In Resistance veterans weekly tobacco use was comparable to that of the control subjects, but alcohol consumption was significantly less.

Prevalence and course of posttraumatic stress disorder in Dutch veterans of the civilian resistance during World War II: an overview.

This study concerns the prevalence of current and lifetime Posttraumatic Stress Disorder (PTSD) in various groups of officially recognized Veterans of the Dutch civilian Resistance against the Nazi occupation during World War II. In total, 1046 Resistance veterans living in The Netherlands and 52 who immigrated to the United States after the war were examined. Between four and five decades after the end of WW II, between 25 and 50% were suffering from current PTSD. The life-time prevalence is estimated to be substantially higher. The course of PTSD proved highly variable. There had often been a delay of several decades between the end of the war and reoccurrence or first onset of posttraumatic symptoms. The prevalence of PTSD in Resistance veterans who emigrated to the United States was hardly different from that of the veterans still living in The Netherlands.

Peripheral vascular alterations during experimental heart failure in the rat. Do they exist?

Structural changes of the peripheral vascular component as seen during hypertension and atherosclerosis have been suggested during heart failure but have never been reported. Therefore, we studied possible structural alterations in the peripheral vasculature in an experimental model of heart failure, induced by ligation of the left coronary artery in rats. Large conduit and resistance-type arteries were excised at 1, 3, 5, and 12 weeks after myocardial infarct induction (MI) or sham surgery. Vessel dimensions (medial cross-sectional area [CSA], internal and external diameters, and media-to-lumen ratios) as well as medial collagen and elastin volume fractions were measured by computerized morphometry. The hydroxyproline assay was used to determine collagen and elastin content biochemically. In separate groups of animals, peripheral tissue flows were measured by using radioactive microspheres 5 and 12 weeks after MI. To evaluate the effects of the degree of heart failure, the animals of the 12-week group (n = 10) were subdivided into groups of moderate (< 45% infarct size) and large (> 45% infarct size) infarction. At all time points, body weights of sham-operated and MI rats were comparable. Lung weights of infarcted animals were increased proportionally to infarct size. No major changes in vessel dimensions were seen at the earlier time points. Twelve weeks after coronary artery ligation, significantly smaller CSAs were observed in several large conduit arteries such as the thoracic aorta, carotid artery, and superior mesenteric artery. These changes coincided with reductions in both internal and external diameters. In contrast, internal and external diameters of mesenteric and pulmonary resistance arteries were increased after 12 weeks of coronary artery ligation.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between pathological findings and values of haematological and blood-chemistry variables in apparently healthy finishing pigs at slaughter.

The present study was performed to study possibilities of early decision making for appropriate conveyor-line at future slaughtering of normal, clinically healthy finishing pigs. Blood was collected at slaughter from barrows (n = 112). A meticulous examination for subclinical pathological lesions was performed, revealing 5 groups of subjects listed in order of increasing disease-activity: 1--no real disease-activity; 2--with mild subchronic lesions; 3--with subacute lesions; 4--with abscesses; and 5--with fibrinous-necrotic lesions. Significant differences for values of erythrocyte sedimentation rate (ESR), protein, albumin, globulins, and plasma viscosity appeared to occur in this series. It is suggested that measuring acute phase reactants in blood of slaughtered pigs in the near future may reveal appropriate modern tools for meat inspection and predicting slaughtered animal quality.

Blood platelets are concentrated near the wall and red blood cells, in the center in flowing blood.

Hematocrit and vessel wall shear rate are important factors in the transport and subsequent adherence of platelets to vessel wall subendothelium. When mass transport theory is applied to platelets in flowing blood, the blood is usually considered to be a fluid with platelet and red cell wall concentrations similar to the average tube concentration. With the laser-Doppler technique, we found how red blood cell ghosts and platelets were distributed radially for various hematocrits and wall shear rates. Red cell ghosts are crowded near the axis of the tube, with a local hematocrit higher than the average tube hematocrit, and they decrease steadily toward the wall. In the absence of ghosts, platelets exhibit the 'tubular pinch' effect (rigid particles crowding at 0.6 x tube radius). In the presence of ghosts, the platelets are expelled toward the wall region. This high concentration at the wall increases with higher average tube hematocrit and wall shear rates. Increasing the average tube platelet concentration 10 times causes the wall concentration to increase only three times. The increase in platelet adherence observed with increasing hematocrit and increasing wall shear rate can be partially ascribed to increased platelet concentration near the wall. The observation that the increased platelet concentration does not fully explain the platelet adherence data suggests that platelet transport may also be enhanced by a shear rate-dependent rotary motion.

An in vitro study of the adhesion of blood platelets onto vascular catheters. Part I.

The adhesion of human blood platelets onto vascular catheters was studied using a specially designed perfusion chamber. Polyurethane catheters were exposed to citrated human blood for different periods (up to 20 min) and at different wall shear rates (190, 260, 330 sec-1). The rate of platelet adhesion was determined using 111In-labeled platelets, while the morphology of adhering platelets was investigated using scanning electron microscopy. A linear increase in platelet adhesion was found within the first 10 min of perfusion, after which a plateau value was reached. The number of adhering platelets did not vary significantly with the shear rates applied, which may indicate that within the range of shear rates studied, the adhesion of platelets onto the catheter surface is mainly determined by the rate of the reaction between the platelets and the material surface. Catheters coated with a conjugate of heparin and albumin showed a four- to five-fold reduction in platelet adhesion as compared to uncoated catheters. This reduction in platelet adhesion was not only due to the presence of albumin moieties at the surface but also to the presence of heparin residues in the adsorbed albumin-heparin conjugate.

Increased red blood cell deformability due to isoxsuprine administration decreases platelet adherence in a perfusion chamber: a double-blind cross-over study in patients with intermittent claudication.

Platelet transport towards the vessel wall is influenced by the hematocrit, red blood cell (RBC) size, and shape. Recent in vitro studies have indicated that RBC deformability may also influence platelet transport. The observation that isoxsuprine, a known vasodilating drug, caused increased RBC deformability in vitro and decreased platelet transport in vitro prompted us to study the effects of this drug in vivo. The study was performed in a double-blind cross-over study of isoxsuprine v placebo in ten patients with peripheral arterial insufficiency. RBC deformability was estimated from viscosity measurements using the blood viscosity equation of Dintenfass and expressed as T value. Platelet transport was studied in an annular perfusion chamber according to Baumgartner. Human umbilical arteries were used as blood vessels. Perfusion studies were performed with whole blood or with RBCs of the patients mixed with normal platelets and plasma at a standardized hematocrit and platelet count. An increase in RBC deformability concomitant with a decrease in platelet adherence was observed in patients on isoxsuprine with a drop in T value of approximately 0.06 (from 0.91 toward 0.86), and a concomitant decrease in platelet adherence of 20% to 40%. These observations differed significantly from the results in the placebo group and showed a significant group-period interaction at the cross-over of medication (analysis of variance). The effects on platelet adherence were observed at high vessel wall shear rate (1,800 s-1) with perfusates consisting of patients' RBCs and donor plasma and platelets at standardized hematocrit and platelet count. No differences were observed under these conditions at a shear rate of 300 s-1. When whole blood of patients was used, nonsignificant effect was observed at shear rates of 300 s-1 and 1,800 s-1. This was probably caused by the added noise due to variations in hematocrit and platelet number. These data demonstrate that isoxsuprine increases RBC deformability, and they suggest the possibility of decreasing platelet-vessel wall interaction in vivo by manipulation of RBC deformability.

Fluid shear as a possible mechanism for platelet diffusivity in flowing blood.

Platelet transport theory is based on convection diffusion and describes adequately the influence of wall shear rate, platelet concentration and axial (down stream) position. Until now, the influence of the predominant factors affecting platelet adherence, the hematocrit and the red cell size, was not included in this theory. Their role remained hidden in the platelet diffusivity (Dw), which was assumed to be related to the shear rate (gamma) expressed in s-1 by a power law function Dw = m gamma n, in which m and n were thought to be constants. We have determined platelet diffusivity directly from platelet adherence to subendothelium as a function of axial distance in an in vitro perfusion system. Our results indicate that m is a constant with a value of (1.05 +/- 0.05) 10(-9) cm2 s-1 and that n is a function of the hematocrit (h) which is best approximated by a quadratic equation n = 0.297 + 1.29 h - 0.90 h2. The effect of red cell size was introduced by correcting the hematocrit containing factors in this quadratic equation for the square of the red cell diameter. This correction was made on the basis of theoretical considerations. The theoretically derived platelet adherence correlated closely with the previous experimental data regarding the effect of red cell size in which we found that the hemodynamic effect of red cells on platelet adherence decreases with decreasing red cell diameter.

Red blood cell deformability influences platelets--vessel wall interaction in flowing blood.

Hematocrit and red cell size are important factors for the transport of blood platelets toward subendothelium in flowing blood. We report that red cell deformability also influences platelet transport. Red cell deformability was estimated with Couette-flow viscosimetry at a shear rate of 130 s-1 and expressed as a 'T' factor--a dimensionless parameter relating the relative viscosity and the hematocrit derived from the relationship: T = (1 - mu -0.4 rel)/H, where mu rel is the relative viscosity and H is the hematocrit. The normal value of T was within a narrow range (0.91 +/- 0.02). Treatment of normal red cells with isoxsuprine and chlorpromazine caused decreased rigidity and decreased T. Cholesterol loading and treatment with diamide increased rigidity and increased T. In vitro perfusion experiments in an annular perfusion system with everted human umbilical arteries were performed with perfusates to which such treated red blood cells were added to investigate their influence on platelet adherence to artery subendothelium. Platelet adherence was well correlated with red cell rigidity, with increased adherence at increased rigidity and vice versa. A change in T of 0.10 corresponded to a change in platelet adherence of approximately 50%. These effects were more pronounced at a wall shear rate of 1,800 s-1 than at 300 s-1.

Velocity profiles in annular perfusion chamber measured by laser-Doppler velocimetry.

p6e fluid flow in the annular perfusion chamber of Baumgartner developed to study platelet vessel wall interaction was examined with laser-Doppler velocimetry. A laminar and stable flow with a Reynolds number of less than or equal to 50 was measured at flow rates up to 3 ml s-1. No turbulence was found. The wall shear rate directly determined from measured velocity profiles agreed well with theory. The experiments underlined the necessity to work with vessels of uniform thickness and a smooth surface.

A perfusion chamber developed to investigate platelet interaction in flowing blood with human vessel wall cells, their extracellular matrix, and purified components.

A flat perfusion chamber was developed to study the interaction of blood platelets in flowing blood with cultured human vessel wall cells, their connective tissue matrix, and isolated connective tissue components at defined shear rate conditions. A cover slip covered with endothelial cells or extracellular matrix components was introduced into the chamber. Laser-Doppler velocimetry showed a symmetrical flow profile at flow rates between 50 and 150 ml/min (wall shear rate 300 to 1100 sec-1). Platelet deposition was estimated by using blood platelets labeled with indium-111 or by a morphometric method. Blood platelets did not adhere to endothelial cells at wall shear rates of 765 sec-1 and the endothelial cells remained attached for at least 10 min of perfusion. In preconfluent cultures of endothelial cells, blood platelets adhered to extracellular material in areas between the cells. Removal of endothelial cells by treatment with 0.5% Triton X-100 induced increased platelet adherence with a preference for certain, as yet unidentified, fibrillar structures of the extracellular matrix. Platelet adherence to equine collagen was also studied after coating the cover slips by spraying of small collagen droplets followed by air drying. Platelet adherence and the subsequent platelet aggregate formation occurred predominantly along visible collagen fibers. These studies showed that this perfusion chamber has a laminar and symmetrical flow allowing qualitative and quantitative investigation of platelet interaction with endothelial cells, their extracellular matrix, and pure connective tissue components. A variety of wall shear rates and exposure times can be applied at controlled conditions without removing cells or extracellular material.

Red blood cell size is important for adherence of blood platelets to artery subendothelium.

The hematocrit is one of the main factors influencing platelet adherence to the vessel wall. Raising the hematocrit causes an increase of platelet accumulation of about an order of magnitude. Our studies concern the role of red cell size. We have studied this effect using an annular perfusion chamber, according to Baumgartner, with human umbilical arteries and a steady-flow system. Normal human red blood cells (MCV 95 cu mu) increased platelet adherence sevenfold, as the hematocrit increases from 0 to 0.6. Small erythrocytes from goats (MCV 25 cu mu) caused no increment in adherence in the same hematocrit range. Rabbit erythrocytes (MCV 70 cu mu) caused an intermediate increase in adherence. Red blood cells from newborns (MCV 110-130 cu mu) caused a larger increase in platelet adherence than normal red cells at hematocrit 0.4. These results were further confirmed with large red blood cells from two patients. Experiments with small red cells (MCV 70 cu mu) of patients with iron deficiency showed that platelet adherence was similar to normal red cells, provided the red cell diameter was normal. Small red blood cells of a patient with sideroblastic anemia caused decreased adherence. These data indicate that red cell size is of major importance for platelet adherence. Red cell diameter is more important than average volume. However, for size differences in the human range, the hematocrit remains the dominant parameter.