Ron Wolterbeek

Do Biofilm Formation and Interactions with Human Cells Explain the Clinical Success of Acinetobacter baumannii

Background The dramatic increase in antibiotic resistance and the recent manifestation in war trauma patients underscore the threat of Acinetobacter baumannii as a nosocomial pathogen. Despite numerous reports documenting its epidemicity, little is known about the pathogenicity of A. baumannii. The aim of this study was to obtain insight into the factors that might explain the clinical success of A. baumannii. Methodology/Principal Findings We compared biofilm formation, adherence to and inflammatory cytokine induction by human cells for a large panel of well-described strains of A. baumannii and compared these features to that of other, clinically less relevant Acinetobacter species. Results revealed that biofilm formation and adherence to airway epithelial cells varied widely within the various species, but did not differ among the species. However, airway epithelial cells and cultured human macrophages produced significantly less inflammatory cytokines upon exposure to A. baumannii strains than to strains of A. junii, a species infrequently causing infection. Conclusion/Significance The induction of a weak inflammatory response may provide a clue to the persistence of A. baumannii in patients.

Neurosensory disturbances one year after bilateral sagittal split osteotomy of the mandibula performed with separators: A multi-centre prospective study

Bilateral sagittal split osteotomy (BSSO) is an effective and commonly used treatment to correct mandibular hypo- and hyperplasia. Hypoesthesia of the inferior alveolar nerve (IAN) is a common complication of this surgical procedure. This prospective multi-centre study aimed to determine the incidence of neurosensory disturbances of the IAN after BSSO procedures performed without the use of chisels. Our study group comprised 158 patients, with a follow-up period of 1 year, who underwent BSSO (with or without Le Fort I) that incorporated the use of sagittal split separators and splitters but no chisels. The percentage of BSSO split procedures that resulted in IAN damage was 5.1%. The percentage of patients (without genioplasty) who experienced IAN damage was 8.9%. The concomitant genioplasty in combination with BSSO was significantly associated with hypoesthesia. Peri-operative removal of the wisdom tooth or a Le Fort I procedure did not influence post-operative hypoesthesia. We believe that the use of splitting forceps and elevators without chisels leads to a lower incidence of persistent post-operative hypoesthesia 1 year after BSSO of the mandible, without increasing the risk of a bad split.

Significant lead-induced tricuspid regurgitation is associated with poor prognosis at long-term follow-up

Background Although the presence of an RV lead is a potential cause of tricuspid regurgitation (TR), the clinical impact of significant lead-induced TR is unknown. Objective To evaluate the effect of significant lead-induced TR on cardiac performance and long-term outcome after cardioverter-defibrillator (ICD) or pacemaker implantation. Methods A retrospective cohort of 239 ICD (n=191) or pacemaker (n=48) recipients (age 60±14u2005years, 77% male) from a tertiary care university hospital, with an echocardiographic evaluation before and within 1–1.5u2005years after device implantation were included. Significant lead-induced TR was defined as TR worsening, reaching a grade ≥2 at follow-up echocardiography. During long-term follow-up (median 58, IQR 35–76u2005months), all-cause mortality and heart failure related events were recorded. Results Before device implantation, most patients had TR grade 1 or 2 (64.0%) or no TR (33.9%), but after lead placement, significant TR was seen in 91 patients (38%). Changes in cardiac volumes and function at follow-up were similar between patients with and without significant lead-induced TR, except for larger RV diastolic area (17±6mm2 vs 16±5mm2, p=0.009), larger right atrial diameter (39±10u2005mm vs 36±8u2005mm, p<0.001) and higher pulmonary arterial pressures (41±15u2005mmu2005Hg vs 33±10u2005mmu2005Hg, p<0.001) in patients with significant lead-induced TR. Patients with significant lead-induced TR had worse long-term survival (HR=1.687, p=0.040) and/or more heart failure related events (HR=1.641, p=0.019). At multivariate analysis, significant lead-induced TR was independently associated with all-cause mortality (HR=1.749, p=0.047) together with age, LVEF and percentage RV pacing. Conclusions Significant lead-induced TR is associated with poor long-term prognosis.

Seasonal influence on the admittance of pre-eclampsia patients in Tygerberg Hospital

Background. Previous studies suggest that the occurrence of pre‐eclampsia is seasonally distributed. This retrospective study aims to determine whether there is a seasonal variation in the number of admissions and the prevalence of women with pre‐eclampsia in Tygerberg Hospital, South Africa. Methods. The number of women admitted with a diagnosis of pre‐eclampsia, eclampsia or haemolysis elevated liver enzymes low platelets (HELLP) syndrome (together called pre‐eclampsia) was obtained from hospital records from 2002 to 2003 for each season and month. Associations were analysed with Odds Ratios (OR). Furthermore, these data was compared with the Cape Town temperatures recorded on each day over the period, as well as the total rainfall for each month. Bivariate logistic regression of the probability of pre‐eclampsia on temperature and rainfall was performed. Results. Pre‐eclampsia occurred in 11.5% of all admissions (1,329/11,585). The prevalence was highest in winter (13.6% pre‐eclampsia patients from all admissions). Women admitted in winter had a higher risk of developing pre‐eclampsia compared to those admitted in summer (OR =1.69, 95% CI: 1.07–1.53). The risk of developing pre‐eclampsia in June was higher than in February (summer in South Africa, reference month) (OR =2.81, 95% CI: 2.06–3.83). There was a significant correlation between the number of admissions with pre‐eclampsia and the minimum daily temperature (r = −0.620, p = 0.032). Conclusions. Pre‐eclampsia occurs more frequently in winter at Tygerberg Hospital, South Africa. The findings have implications for future research related to the aetiology of pre‐eclampsia as well as for clinical care.

Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis

Objectives Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with cyclophosphamide have an increased malignancy risk compared with the general population. We investigated whether treatment with rituximab instead of cyclophosphamide has decreased the malignancy risk in patients with AAV. Methods The study included patients with AAV treated at a tertiary vasculitis referral centre between 2000 and 2014. The malignancy incidence in these patients was compared with the incidence in the general population by calculating standardised incidence ratios (SIRs), adjusted for sex, age and calendar year. Malignancy incidence was compared between rituximab-treated and cyclophosphamide-treated patients. Results Of the 323 included patients, 33 developed a total of 45 malignancies during a mean follow-up of 5.6u2005years. This represented a 1.89-fold increased (95% CI 1.38 to 2.53) malignancy risk, and a non-significantly increased risk if non-melanoma skin cancer was excluded (SIR, 1.09; 95% CI 0.67 to 1.69). The risk of non-melanoma skin cancer was 4.58-fold increased (95% CI 2.96 to 6.76). Cyclophosphamide-treated patients had an increased malignancy risk compared with the general population (SIR, 3.10; 95% CI 2.06 to 4.48). In contrast, rituximab-treated patients had a malignancy risk similar to the general population (SIR, 0.67; 95% CI 0.08 to 2.43). The malignancy risk in cyclophosphamide-treated patients was 4.61-fold higher (95% CI 1.16 to 39.98) than in rituximab-treated patients. Conclusions The malignancy risk in patients with AAV was lower in rituximab-treated patients than in cyclophosphamide-treated patients. Notably, rituximab treatment was not associated with an increased malignancy risk compared with the general population. Rituximab could therefore be a safe alternative to cyclophosphamide in the treatment of AAV.

Interobserver Reliability in the Histopathological Diagnosis of Cartilaginous Tumors in Patients with Multiple Osteochondromas

The distinction between benign and malignant cartilaginous tumors located peripherally in the bone may be a challenging task in surgical pathology. The aim of this study was to investigate interobserver reliability in histological diagnosis of cartilaginous tumors in the setting of multiple osteochondromas and to evaluate possible histological parameters that could differentiate among osteochondroma, low- and high-grade secondary peripheral chondrosarcoma. Interobserver reliability was assessed by 12 specialized bone-tumor pathologists in a set of 38 cases. Substantial agreement on diagnosis among all the reviewers was observed (intraclass correlation coefficient=0.78). Our study confirmed that mitotic figures and nuclear pleomorphism are hallmarks of high-grade secondary peripheral chondrosarcoma. However, despite the substantial agreement, we demonstrated that histology alone cannot distinguish osteochondroma from low-grade secondary peripheral chondrosarcoma in the setting of multiple osteochondromas, as nodularity, the presence of binucleated cells, irregular calcification, cystic/mucoid changes and necrosis were not helpful to indicate malignant transformation of an osteochondroma. On the other hand, among the concordant cases, the cartilage cap in osteochondroma was significantly less thicker than in low- and high-grade secondary peripheral chondrosarcoma. Therefore, our study showed that a multidisciplinary approach integrating clinical and radiographical features and the size of the cartilaginous cap in combination with a histological assessment are crucial to the diagnosis of cartilaginous tumors.

Support for two increased vasopressinergic activities in depression at large and the differential effect of antidepressant treatment

Animal models of depression support a pathogenetic role for vasopressinergic activation involving increased arginine vasopressin (AVP) release and AVP receptor (V1b) synthesis. Evidence of this has been found particularly in patients with highly anxious-retarded (HAR) and above-normal AVP (ANA) depression. A general pathogenetic theory however predicts vasopressinergic activities to play a role in at least all major depressive disorders, and antidepressant (AD) treatment to be mediated by vasopressinergic reduction. We tested these hypotheses by re-analysing the data of 66 depressed patients; 27 with and 39 without AD treatment. The plasma AVP concentration and the AVP-cortisol correlation were used as presumed parameters of AVP release and pituitary V1b receptor function. A high AVP-cortisol correlation (ru2009=u20090.72; pu2009<u20090.001) was found in the non-AD group, and no correlation in the AD treatment group. AD treatment did not relate to plasma AVP concentration. The AVP-cortisol correlation in HAR and ANA depression was not explained by a low rate of AD treatment. These human data support the hypothesis of increased AVP release and receptor function as pathogenetic characteristics of major depression, and show selective normalization of the AVP-cortisol correlation, which is supposed to reflect the receptor function, by AD treatment.

Reduced cooperativeness and reward-dependence in depression with above-normal plasma vasopressin concentration

The neuropeptide vasopressin is centrally involved in the regulation of social behaviour and response to stress. We previously found support for a subcategory of depression defined by above-normal plasma vasopressin (AVP) concentration. This subcategory is validated by a positive family history of depression and correlating plasma AVP and cortisol concentrations. The data support the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression. The aim of the present study was to test whether above-normal plasma AVP concentration in depression is related to personality characteristics reflecting a specific social behaviour style. The data of 78 patients from a previously investigated sample were reanalysed. Fifty-eight patients were available after 2 years, 15 of whom with initially above-normal plasma AVP. The dimensions of the Temperament and Character Inventory (TCI) were scored, with particular focus on the dimensions of Cooperativeness (CO) and Reward-dependence (RD). Normative subjects and other depressed subjects were used as controls. After full remission, patients with initially above-normal AVP had low CO compared with normal and patient controls. During depression, these patients had both low CO and low RD compared with normal controls and low RD compared with patient controls. Low CO is a presumably premorbid trait and reduced RD a state-dependent characteristic in depression with above-normal plasma AVP. The low CO further supports the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression.

Tissue microchimerism is increased during pregnancy: a human autopsy study.

Microchimerism is the occurrence of small populations of cells with a different genetic background within an individual. Tissue microchimerism is considered to be primarily pregnancy-derived and is often studied relative to female-dominant autoimmune diseases, pregnancy complications, malignancies, response to injury, and transplantation outcomes. A particular distribution pattern of chimeric cells across various organs was recently described in a model of murine pregnancies. Our aim was to determine the frequency and distribution of tissue microchimerism across organs during and after pregnancy in humans. We performed in situ hybridization of the Y chromosome on paraffin-embedded autopsy samples of kidneys, livers, spleens, lungs, hearts and brains that were collected from 26 women who died while pregnant or within 1 month after delivery of a son. Frequencies of chimeric cells in various tissues were compared with those of a control group of non-pregnant women who had delivered sons. Tissue microchimerism occurred significantly more frequently in the lungs, spleens, livers, kidneys and hearts of pregnant women compared with non-pregnant women (all P < 0.01). We showed that some of the chimeric cells were CD3+ or CD34+. After correction for cell density, the lung was most chimeric (470 Y chromosome-positive nuclei per million nuclei scored), followed by the spleen (208 Y+/10(6) nuclei), liver (192 Y+/10(6) nuclei), kidney (135 Y+/10(6) nuclei), brain (85 Y+/10(6) nuclei) and heart (40 Y+/10(6) nuclei). Data from this unique study group of women who died while pregnant or shortly after delivery provide information about the number and physiologic distribution of chimeric cells in organs of pregnant women. We demonstrate that during pregnancy, a boost of chimeric cells is observed in women, with a distribution across organs, that parallels findings in mouse models.

Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement

Objectives. Neuropsychiatric (NP) involvement is a poorly understood manifestation of SLE. We studied post-mortem histopathology in relation to clinical NPSLE syndromes and complement deposition in brains of NPSLE and SLE patients and controls. Furthermore, we investigated the correlation between cerebral post-mortem histopathology and ex vivo 7 T MRI findings in SLE and NPSLE. Methods. A nationwide search for autopsy material yielded brain tissue from 16 NPSLE and 18 SLE patients. Brains obtained from 24 patients who died of acute cardiac events served as controls. Apart from a histopathological evaluation, paraffin-embedded cortical tissue was stained for components of the classical, lectin and terminal complement pathways. Results. Diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE than SLE patients and were absent in controls. Focal vasculopathy was found in both SLE patients and controls. Complement deposition was strongly associated with both SLE and NPSLE, but not with controls (P < 0.001). Microthrombi were found uniquely in NPSLE and were associated with C4d and C5b-9 deposits (P < 0.05). A 7 T MRI was unable to detect most small vessel injury that was visible histopathologically. Conclusion. Our study demonstrates that histopathological lesions in NPSLE represent a continuum, ranging from non-specific lesions such as focal vasculopathy, to more specific lesions including C4d- and C5b-9-associated microthrombi and diffuse vasculopathy related to clinical syndromes defining NPSLE. Complement deposition may be a key factor in the interaction between circulating autoantibodies and thromboischaemic lesions observed in NPSLE. Therefore, complement inhibition may have novel therapeutic potential in NPSLE.