Studies on diagnosis and treatment of renal artery stenosis

This thesis describes studies on ~onosis and treatment of renal artery stenosis in patients with drug-resistant hypertension. In Chapter 1, the clinical problem of renal artery stenosis is discussed. Renal artery stenosis, a narrowing of the renal artery, is a potential cause of secondary hypertension. For this reason, it is important to di~onose a stenosis, so that treatment can be initiated. Treatment of patients with hypertension and renal artery stenosis may potentially prevent cardiovascular complications and renal insufficiency. The research questions on diagnosis concerned (1) the interobserver agreement of captopril renography for the detection of renal artery stenosis, and (2) the value of clinical characteristics for predicting the probability of stenosis in patients with drug-resistant hypertension. The research questions on treatment concerned (1) the comparison of clinical outcomes after balloon angioplasty versus drug therapy for patients with drug-resistant hypertension and atherosclerotic renal artery stenosis, and (2) the cost-effectiveness of several treatment strategies in this patient group

Risk factors for septic arthritis in patients with joint disease: A prospective study

Objective. To quantify potential risk factors for septic arthritis, in order to identify a basis for prevention. Methods. The occurrence of potential risk factors for septic arthritis in patients with joint diseases attending a rheumatic disease clinic was prospectively monitored at 3-m onth intervals over a period of 3 years. Potential risk factors investigated were type of joint disease, comorbidity, medication, joint prosthesis, infections, and invasive procedures. The frequencies of risk factors in patients with and those without septic arthritis were compared using multiple logistic regression analysis. Results. There were 37 patients with and 4,870 without septic arthritis. Risk factors for developing septic arthritis were age ≥80 years (odds ratio [OR] = 3.5, 95% confidence interval [95% CI] 1.4–8.6), diabetes mellitus (OR = 3.3, 95% CI 1.1–10.1), rheumatoid arthritis (OR = 4.0, 95% CI 1.9–8.3), hip and/or knee prosthesis (OR = 15, 95% CI 4.1–54.3), joint surgery (OR = 5.1, 95% CI 2.2–11.9), and skin infection (OR = 27.2, 95% CI 7.6–97.1) Conclusion. These findings indicate that preventive measures against septic arthritis in patients with joint diseases should mainly be directed at those with joint prostheses and/or skin infection

Adoptive cell therapy of triple negative breast cancer with redirected cytokine-induced killer cells

Cytokine-Induced Killer (CIK) cells share several functional and phenotypical properties of both T and natural killer (NK) cells. They represent an attractive approach for cell-based immunotherapy, as they do not require antigen-specific priming for tumor cell recognition, and can be rapidly expanded in vitro. Their relevant expression of Fc\u3b3RIIIa (CD16a) can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their lytic activity in an antigen-specific manner. Here, we report the efficacy of this combined approach against triple negative breast cancer (TNBC), an aggressive tumor that still requires therapeutic options. Different primitive and metastatic TNBC cancer mouse models were established in NSG mice, either by implanting patient-derived TNBC samples or injecting MDA-MB-231 cells orthotopically or intravenously. The combined treatment consisted in the repeated intratumoral or intravenous injection of CIK cells and cetuximab. Tumor growth and metastasis were monitored by bioluminescence or immunohistochemistry, and survival was recorded. CIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either in patient-derived tumor xenografts or MDA-MB-231 cell line models. Moreover, this approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and led to an enrichment of the CD16a+ subset. Data highlight the potentiality of this novel immunotherapy strategy where a nonspecific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells. List of abbreviations: ACT, Adoptive Cell Transfer; ADCC, Antibody-Dependent Cell-mediated Cytotoxicity; ADP, Adenosine diphosphate; BLI, Bioluminescence Imaging; CAR, Chimeric Antigen Receptor; CIK, Cytokine Induced Killer cells; CTX, Cetuximab; DMEM, Dulbecco\u2019s Modified Eagle Medium; EGFR, Human Epidermal Growth Factor 1; ER, Estrogen; FBS, Fetal Bovine Serum; FFPE, Formalin-Fixed Paraffin-Embedded; GMP, Good Manufacturing Practices; GVHD, Graft Versus Host Disease; HER2, Human Epidermal Growth Factor 2; HRP, Horseradish Peroxidase; IFN-\u3b3, Interferon-\u3b3; IHC, Immunohistochemistry; IL-2, Interleukin-2; ISO, Irrelevant antibody; i.t., intratumoral; i.v., intravenous, mAbs, Monoclonal Antibodies; mIHC, Multiplex Fluorescence Immunohistochemistry; MHC, Major Histocompatibility Complex; NK, Natural Killer; NKG2D, Natural-Killer group 2 member D; NSG, NOD/SCID common \u3b3 chain knockout; PARP, Poly ADP-ribose polymerase; PBMCs, Peripheral Blood Mononuclear Cells; PBS, Phosphate-buffered saline; PDX, Patient-derived xenograft; PR, Progesterone; rhIFN-\u3b3, Recombinant Human Interferon-\u3b3; RPMI, Roswell Park Memorial Institute; STR, Short tandem Repeat; TCR, T Cell Receptor; TNBC, Triple Negative Breast Cancer; TSA, Tyramide Signal Amplification

Esiopetuksen pedagogiset oppimisympäristöt päiväkodeissa ja kouluissa

Tiivistelmä. Tutkimme ja vertailimme esiopetuksen pedagogisia oppimisympäristöjä päiväkoti- ja koulukonteksteissa. Tutkimuskysymyksenä on millaisia ovat esiopetuksen pedagogiset oppimisympäristöt päiväkodeissa ja kouluissa. Aikaisempien havaintojemme perusteella olimme epävarmoja tasa-arvoisen esiopetuksen toteutumisesta eri konteksteissa, jonka vuoksi koimme aiheen tärkeäksi. Tutkimus on kvalitatiivinen ja aineiston keräsimme teemahaastatteluilla. Haastatteluihin osallistui kuusi esiopetuksen opettajaa. Teoriaosuudessa avaamme oppimisympäristön käsitettä ja tarkastelemme esiopetusta pedagogisen oppimisympäristön näkökulmasta. Pedagogisessa oppimisympäristössä keskityimme tarkastelemaan erityisesti ulkoisia vaikuttavia tekijöitä, toimintaa ja vuorovaikutusta. Ulkoisia tekijöitä ovat päiväjärjestys, ryhmäkoko sekä fyysiset tilat ja käytettävissä olevat välineet. Toimintaan liittyen käsittelemme suunnittelua, toteutusta ja arviointia. Tutkimme vuorovaikutusta esiopetuksessa ja yhteistyötä vanhempien kanssa sekä koulun ja päiväkodin välillä. Opettaja luo pedagogista oppimisympäristöä. Suunnittelun pohjana toimivat kaikki edellä mainitut pedagogiseen oppimisympäristöön vaikuttavat tekijät. Suunnittelu ohjaa millaista opetusta lapset saavat ja miten opettaja toimii. Ryhmäkoko vaikuttaa siihen, kuinka opettaja pystyy huomioimaan jokaisen lapsen kehityksen yksilöllisesti. Esiopetuksessa yhteisten tavoitteiden lisäksi jokaisella lapsella on yksilölliset tavoitteet, jotka laaditaan yhdessä vanhempien kanssa. Arviointi tulee toteuttaa peilaten asetettuihin tavoitteisiin. Esiopetuskontekstien välillä oli eroja, mutta laadullisesti esiopetus on tasa-arvoista kummassakin kontekstissa. Esiopetuksen toteutumiseen vaikuttavia tekijöitä on monia, sillä niin konteksti, esiopetuksen opettaja kuin ryhmä vaikuttavat siihen millaista esiopetus on. Esiopetuksen yhdenvertaisuutta lisää esiopetussuunnitelma, jonka mukaan esiopetuksen opettaja suunnittelee toimintaa. Tasavertainen esiopetus on jokaisen lapsen oikeus

The value of computed tomography in detecting distal radioulnar joint instability after a distal radius fracture

This study evaluated the value of computed tomography scans for the diagnosis of distal radioulnar joint instability. A total of 46 patients, conservatively treated for a unilateral distal radius fracture, were evaluated. Clinical instability was tested using the stress test and clunk test. A computed tomography scan of both wrists was performed in pronation and supination. Two independent observers reviewed the computed tomography scans using: the radioulnar line, subluxation ratio, epicentre and radioulnar ratio methods. Radiological distal radioulnar joint instability was assessed by comparing the measurements of the injured wrist with those of the contralateral uninjured wrists. A

Agreement on fixation of pediatric supracondylar humerus fractures

Background Pediatric supracondylar humerus fractures (pSCHFs) may be challenging injuries to treat because of the potential residual deformity. There is debate regarding the technical aspects of adequate closed reduction and crossed Kirschner wire (K-wire) fixation. Purpose Do surgeons have an agreement on the aspects of the fixation of pSCHFs? Methods Radiographs of 20 patients from a cohort of 154 patients with pSCHFs treated with closed reduction and crossed K-wire fixation were selected. Forty-four surgeons viewed the postoperative radiographs and diagnosed the presence or absence of technical flaws and made a recommendation for or against reoperation. An expert panel of three orthopedic and trauma surgeons provided a reference standard for technical factors. Furthermore, final outcome 2 years after trauma was assessed. Results There was limited agreement on potential technical flaws (ICC 0.15-0.28), radiographic measures of alignment (ICC for anterior humeral line and Baumann angle of 0.37 and 0.23 respectively), the quality of postoperative reduction, position of the elbow in cast, and recommendation for repeat surgery (ICCs between 0.23 and 0.40). Sensitivity and specificity for these questions ranged from 0.59 to 0.90. There was no correlation between the voted quality of postoperative reduction and loss of reduction or final function. Conclusions Surgeons have limited agreement on the quality of postoperative results in pSCHFs and the indication for reoperation. Reviewing postoperative radiographs may present a good learning opportunity and could help improve skills, but it is not a validated method for quality control and has to be seen in light of clinical outcome

Long-term quality of life and cost-effectiveness of treatment of partial thickness burns: A randomized controlled trial comparing enzyme alginogel vs silver sulfadiazine (FLAM study)

The clinical effectiveness and scar quality of the randomized controlled trial comparing enzyme alginogel with silver sulfadiazine (SSD) for treatment of partial thickness burns were previously reported. Enzyme alginogel did not lead to faster wound healing (primary outcome) or less scar formation. In the current study, the health-related quality of life (HRQoL), costs, and cost-effectiveness of enzyme alginogel compared with SSD in the treatment of partial thickness burns were studied. HRQoL was evaluated using the Burn Specific Health Scale-Brief (BSHS-B) and the EQ-5D-5L questionnaire 1 week before discharge and at 3, 6, and 12 months postburn. Costs were studied from a societal perspective (health care and nonhealth-care costs) for a follow-up period of 1 year. A cost-effectiveness analysis was performed using cost-effectiveness acceptability curves and comparing differences in societal costs and Quality Adjusted Life Years (QALYs) at 1 year postburn. Forty-one patients were analyzed in the enzyme alginogel group and 48 patients in the SSD group. None o

Hyaluronan is a natural and effective immunological adjuvant for protein-based vaccines

One of the main goals of vaccine research is the development of adjuvants that can enhance immune responses and are both safe and biocompatible. We explored the application of the natural polymer hyaluronan (HA) as a promising immunological adjuvant for protein-based vaccines. Chemical conjugation of HA to antigens strongly increased their immunogenicity, reduced booster requirements, and allowed antigen dose sparing. HA-based bioconjugates stimulated robust and long-lasting humoral responses without the addition of other immunostimulatory compounds and proved highly efficient when compared to other adjuvants. Due to its intrinsic biocompatibility, HA allowed the exploitation of different injection routes and did not induce inflammation at the inoculation site. This polymer promoted rapid translocation of the antigen to draining lymph nodes, thus facilitating encounters with antigen-presenting cells. Overall, HA can be regarded as an effective and biocompatible adjuvant to be exploited for the design of a wide variety of vaccines

The impact of regionalized trauma care on the distribution of severely injured patients in the Netherlands

BACKGROUND: Twenty years ago, an inclusive trauma system was implemented in the Netherlands. The goal of this study was to evaluate the impact of structured trauma care on the concentration of severely injured patients over time. METHODS: All severely injured patients (Injury Severity Score [ISS] ≥ 16) documented in the Dutch Trauma Registry (DTR) in the calendar period 2008–2018 were included for analysis. We compared severely injured patients, with and without severe neurotrauma, directly brought to trauma centers (TC) and non-trauma centers (NTC). The proportion of patients being directly transported to a trauma center was determined, as was the total Abbreviated Injury Score (AIS), and ISS. RESULTS: The documented number of severely injured patients increased from 2350 in 2008 to 4694 in 2018. During this period, on average, 70% of these patients were directly admitted to a TC (range 63–74%). Patients without severe neurotrauma had a lower chance of being brought to a TC compared to those with severe neurotrauma. Patients directly presented to a TC were more severely injured, reflected by a higher total AIS and ISS, than those directly transported to a NTC. CONCLUSION: Since the introduction of a well-organized trauma system in the Netherlands, trauma care has become progressively centralized, with more severely injured patients being directly presented to a TC. However, still 30% of these patients is initially brought to a NTC. Future research should focus on improving pre-hospital triage to facilitate swift transfer of the right patient to the right hospital

Search for New Physics with Jets and Missing Transverse Momentum in pp collisions at sqrt(s) = 7 TeV

A search for new physics is presented based on an event signature of at least three jets accompanied by large missing transverse momentum, using a data sample corresponding to an integrated luminosity of 36 inverse picobarns collected in proton--proton collisions at sqrt(s)=7 TeV with the CMS detector at the LHC. No excess of events is observed above the expected standard model backgrounds, which are all estimated from the data. Exclusion limits are presented for the constrained minimal supersymmetric extension of the standard model. Cross section limits are also presented using simplified models with new particles decaying to an undetected particle and one or two jets