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Background: Head and neck cancer is particular due to its infiltrative nature and lymphatic extension, with multidisciplinary treatment. Immunotherapy may be a brand-new therapeutic approach.Case P...

Despite widespread drug exposure, for example during gestation or in prematurely born children, organ-specific developmental toxicity of most drugs is poorly understood. Developmental and functional abnormalities are a major cause of kidney diseases during childhood; however, the potential causal relationship to exposure with nephrotoxic drugs during nephrogenesis is widely unknown. To identify developmental nephrotoxic drugs in a large scale, we established and performed an automated high-content screen to score for phenotypic renal alterations in theTg(wt1b:EGFP)zebrafish line. During early nephrogenesis, embryos were exposed to a compound library of approved drugs. After treatment, embryos were aligned within microtiter plates using 3D-printed orientation tools enabling the robust acquisition of consistent dorsal views of pronephric kidneys by automated microscopy. To qualitatively and quantitatively score and visualize phenotypes, we developed software tools for the semi-automated analysis, processing and visualization of this large image-based dataset. Using this scoring scheme, we were able to categorize compounds based on their potential developmental nephrotoxic effects. About 10% of tested drugs induced pronephric phenotypes including glomerular and tubular malformations, or overall changes in kidney morphology. Major chemical compound groups identified to cause glomerular and tubular alterations included dihydropyridine derivatives, HMG CoA reductase inhibitors, fibrates, imidazole, benzimidazole and triazole derivatives, corticosteroids, glucocorticoids, acetic acid derivatives and propionic acid derivatives. In conclusion, the presented study demonstrates the large-scale screening of kidney-specific toxicity of approved drugs in a live vertebrate embryo. The associated technology and tool-sets can be easily adapted for other organ systems providing a unique platform forin vivolarge-scale assessment of organ-specific developmental toxicity or other biomedical applications. Ultimately, the presented data and associated visualization and browsing tools provide a resource for potentially nephrotoxic drugs and for further investigations.

Background: Belimumab is a monoclonal antibody against BAFF/BLyS and has been approved for patients with active systemic lupus erythematosus (SLE) despite standard of care immunosuppressive treatment (ST). Nevertheless, the interference of belimumab with pathogenetic pathways of SLE is not fully[for full text, please go to the a.m. URL], 46. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 32. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), Wissenschaftliche Herbsttagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. In the present case report, two patients with advanced and metastatic uterine leiomyosarcomas (ULMS) with significant progression-free survival (PFS) and overall survival (OS) administered Trabectedin as second and third line treatment are reported. The first case received third line Trabectedin with a PFS of 24 months and an OS of 35 months. The second case received second line Trabectedin with a PFS of 24 months and an OS of 30 months. In addition, a good safety record was obtained in the long-term administration of Trabectedin (more so in case 1 than case 2), with a good quality of life.

CD33 is an immunomodulatory receptor linked to Alzheimer’s disease (AD) susceptibility via regulation of phagocytosis in microglia. Divergent features between human CD33 (hCD33) and murine CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new αmCD33 monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. Notably, cell surface expression of mCD33 is entirely dependent on Dap12 due to an interaction with the transmembrane lysine in mCD33. In RAW264.7 cultured macrophages, BV-2 cultured microglia, primary neonatal and adult microglia, uptake of cargo — including aggregated Aβ1–42 — is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis, highlighting the importance of studying hCD33 in AD susceptibility., Abhishek Bhattacherjee et al. investigate the functional differences between human and mouse CD33, an immunomodulatory receptor linked to Alzheimer’s disease. They find that loss of mouse CD33 does not affect cargo uptake in macrophages in contrast to human CD33, which represses phagocytosis when expressed in cells or mice.

Metastasis of non-gynaecological tumours to the cervix is a rare event, and metastasis from breast cancer is even rarer, with only a limited number of such cases reported in the literature to date. We herein report the case of an 86-year-old female patient who had undergone mastectomy and axillary lymphadenectomy for invasive ductal cell breast carcinoma 2 years prior, followed by adjuvant hormonal therapy with letrozole. During hospitalization for anemia associated with an inflammatory syndrome and abdominal pain with menorrhagia, an abdominal ultrasound examination revealed a suspicious uterine mass with irregular contours and abnormal vascularization with associated increase of the blood level of cancer antigen 15-3 to 34 kU/l. The histological and immunohistochemical analysis of a cervical biopsy sample discover a secondary lesion metastatic from the primary ductal cell breast carcinoma. The metastatic tissue was hormone-negative, which was compatible with disease progression during hormonal therapy. Considering the multiple metastasis, comorbidities, unfavourable performance status and the quick deterioration of the patient's clinical condition, only best supportive care was administered.

Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in >= 3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components - even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus - in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV). (C) 2014 Elsevier Ireland Ltd. All rights reserved., NIH -National Institutes of Health

Whether angiotensin receptor blockers can dose-dependently remodel the arterial wall during long-term treatment has been largely debated. In this phase III, multicenter, randomized, double-blind, parallel-group study, 133 subjects with hypertension and metabolic syndrome were assigned to olmesartan, either 20 mg (n=44), 40 mg (n=42), or 80 mg (n=47) once a day, according to a force titration design during a 1-year period. Office blood pressure, 24-hour blood pressure, aortic stiffness (carotid-femoral pulse wave velocity), and carotid parameters were measured at baseline, 24 weeks, and 52 weeks. Pulse wave velocity significantly decreased ( P P =0.0685) for a smaller effect of 20 mg, compared with 40 and 80 mg at week 52. When the 40 and 80 mg doses were combined (40/80 mg versus 20 mg), a significant blood pressure–independent reduction in pulse wave velocity (−0.61 m/s) was observed at week 52 ( P =0.0066), whereas the nonadjusted reduction was −1.31 m/s ( P

Background Since patients with diabetes mellitus have increased rates of cardiovascular morbidity and mortality, it is critical to evaluate cardiovascular risk perioperatively. Although several preoperative risk indices have been developed, including the Goldman and Detsky indices, none have been designed specifically for diabetic patients. In this study, we attempted to identify predictors of postoperative cardiac and noncardiac complications in diabetic patients undergoing elective general surgery. Study Design A cohort of 107 diabetic patients undergoing elective surgery was assembled. Basic demographic and clinical data were recorded perioperatively, and all patients were followed up prospectively daily for 7 days postoperatively. Patients were interviewed at 5 years postoperatively. Univariate and multivariate analyses were performed to identify predictors of postoperative complications and long-term cardiac and vascular morbidity and mortality. Results Total cardiac complications and myocardial infarction were predicted by the Goldman index. Wound complications were not predicted by any of the variables studied. At 5 years postoperatively, cardiac and vascular deaths and events were predicted by age, history of myocardial infarction or stroke, presence of vascular disease, Goldman index, duration of diabetes or hypertension, Charlson comorbidity score, and postoperative myocardial infarction or cardiac arrest. Blood sugar control during surgery was not predictive of any short- or long-term cardiovascular complications. Conclusions Total cardiac complications had a significant preoperative predictor: the Goldman index. Both preoperative and postoperative variables and indices predicted long-term cardiac and vascular complications. Further study is necessary to investigate these relationships to better assess and manage the diabetic patient in the perioperative setting.

PubMed ID: 25112663, Aims: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated. Methods and results: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculatedas percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45 436 subjects out of 82 930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratifiedbysex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose. Conclusion: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women. © 2014 Published on behalf of the European Society of Cardiology.

UNLABELLED: (99m)Tc-cAbVCAM1-5, a single-domain antibody fragment directed against mouse or human vascular cell adhesion molecule 1 (VCAM-1), recently has been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, (99m)Tc-cAbVCAM1-5 specifically bound to VCAM-1-positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate (99m)Tc-cAbVCAM1-5 imaging sensitivity using a reference statin therapy. METHODS: Thirty apolipoprotein E-deficient mice were fed a western-type diet. First, the relationship between the level of VCAM-1 expression and (99m)Tc-cAbVCAM1-5 uptake was evaluated in 18 mice using immunohistochemistry and autoradiography. Second, longitudinal SPECT/CT imaging was performed on control (n = 9) or atorvastatin-treated mice (0.01% w/w, n = 9). RESULTS: (99m)Tc-cAbVCAM1-5 uptake in atherosclerotic lesions correlated with the level of VCAM-1 expression (P < 0.05).Atorvastatin exerted significant antiatherogenic effects, and (99m)Tc-cAbVCAM1-5 lesion uptake was significantly reduced in 35-wk-old atorvastatin-treated mice, as indicated by ex vivo γ-well counting and autoradiography (P < 0.05). SPECT imaging quantification based on contrast-enhanced CT was reproducible (interexperimenter intraclass correlation coefficient, 0.97; intraexperimenter intraclass correlation coefficient, 0.90), and yielded results that were highly correlated with tracer biodistribution (r = 0.83; P < 0.0001). Therefore, reduced (99m)Tc-cAbVCAM1-5 uptake in atorvastatin-treated mice was successfully monitored noninvasively by SPECT/CT imaging (0.87 ± 0.06 vs. 1.11 ± 0.09 percentage injected dose per cubic centimeter in control group, P < 0.05). CONCLUSION: (99m)Tc-cAbVCAM1-5 imaging allowed the specific, sensitive, and reproducible quantification of VCAM-1 expression in mouse atherosclerotic lesions. (99m)Tc-cAbVCAM1-5 therefore exhibits suitable characteristics for the evaluation of novel antiatherogenic agents.

For several years the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) decided not to produce their own guidelines on the diagnosis and treatment of hypertension but to endorse the guidelines on hypertension issued by the World Health Organization (WHO) and International Society of Hypertension (ISH)1,2 with some adaptation to reflect the situation in Europe. However, in 2003 the decision was taken to publish ESH/ESC specific guidelines3 based on the fact that, because the WHO/ISH Guidelines address countries widely varying in the extent of their health care and availability of economic resource, they contain diagnostic and therapeutic recommendations that may be not totally appropriate for European countries. In Europe care provisions may often allow a more in-depth diagnostic assessment of cardiovascular risk and organ damage of hypertensive individuals as well as a wider choice of antihypertensive treatment. The 2003 ESH/ESC Guidelines3 were well received by the clinical world and have been the most widely quoted paper in the medical literature in the last two years.4 However, since 2003 considerable additional evidence on important issues related to diagnostic and treatment approaches to hypertension has become available and therefore updating of the previous guidelines has been found advisable. In preparing the new guidelines the Committee established by the ESH and ESC has agreed to adhere to the principles informing the 2003 Guidelines, namely 1) to try to offer the best available and most balanced recommendation to all health care providers involved in the management of hypertension, 2) to address this aim again by an extensive and critical review of the data accompanied by a series of boxes where specific recommendations are given, as well as by a concise set of practice recommendations to be published soon thereafter as already done in 2003; …

To more clearly define the scope and impact of violence in health care facilities, national data on assaults in VA medical centers and freestanding clinics were examined.A survey was distributed to all VA medical centers and freestanding clinics asking for cumulative data for one fiscal year (October 1990 through September 1991). Data were obtained on number, types, and locations of physical assaults and other assaultive behavior; the types of staff assaulted and number of workdays lost due to injuries; diagnoses of perpetrators; recommendations made after the incidents were reviewed; training in prevention and management of assaultive behavior; and the impact of training on rates of assaultive behavior.During the survey year, 24,219 incidents of assaultive behavior were reported by 166 VA facilities; 8,552 incidents involved battery or physical assault. Weapon possession by perpetrators was common (8.5 percent of incidents), and weapons were used in 130 assaults (1.5 percent of assaults). Assaults occurred most frequently in psychiatric units (43.1 percent), followed by long-term-care units (18.5 percent) and admitting or triage areas (13.4 percent). Assault-related injuries were most common among nursing personnel. Perpetrators of assaults were most typically diagnosed as having psychoses, substance use disorders, or dementia. On inpatient psychiatry units, an inverse correlation was found between expenditures on staffing and the frequency of assaultive incidents. Staff training on management of assaultive behavior varied widely.Assaultive behavior is a significant problem for health care workers. Staff in all clinical areas need to be prepared to deal with assaultive patients. More research is needed on staff training and interventions for preventing and limiting assaults.

The study aim was to determine the prevalence of repeated assaults on staff and other patients and characteristics of patients who commit repeated assaults in the Veterans Health Administration of the Department of Veterans Affairs.Patients in VA medical centers and freestanding outpatient clinics who committed two or more assaults in fiscal years 1995 and 1996 were identified through a survey of facility quality or risk managers. For each repeatedly assaultive patient, structured information, including incident reports, was obtained for all assault occasions.A total of 153 VA facilities responded, for a response rate of 99 percent. The survey identified 8,968 incidents of repeated assault by 2,233 patients, for a mean of 4.02 assaults per patient in the two-year study period. In 92 percent of the incidents, the assaultive patient had a primary or secondary psychiatric diagnosis. The mean age of the repeat assaulters was 62 years. Ninety-eight percent of the repeat assaulters were male, and 76.6 percent were Caucasian. At least 16 percent of the assaulters, 22 percent of the patients assaulted, and 20 percent of the staff assaulted required medical attention for injuries, which, along with the number of lost work days, indicates that repeated assaults are costly.Repeatedly assaultive patients represent major challenges to their own safety as well as to that of other patients and staff. Identifying patients at risk for repeated assaults and developing intervention strategies is critically important for ensuring the provision of health care to the vulnerable population of assaultive patients.

SummaryStaphylokinase (Sak), a 15.5-kDa bacterial protein, forms a complex with human plasmin, which in turn activates other plasminogen molecules to plasmin. Three recombinant DNA-based approaches, (i) site directed substitution with alanine, (ii) search for proximity relationships at the complex interface, and (iii) active-site accessibility to protease inhibitors have been used to deduce a coherent docking model of the crystal structure of Sak on the homology-based model of micro-plasmin (μPli), the serine protease domain of plasmin. Sak binding on μPli is primarily mediated by two surface-exposed loops, loops 174 and 215, at the rim of the active-site cleft, while the binding epitope of Sak on μPli involves several residues located in the flexible NH2-terminal arm and in the five-stranded mixed β-sheet. Several Sak residues located within the unique μ-helix and the β2 strand do not contribute to the binding epitope but are essential to induce plasminogen activating potential in the Sak:μPli complex. These residues form a topologically distinct activation epitope, which, upon binding of Sak to the catalytic domain of μPli, protrudes into a broad groove near the catalytic triad of μPli, thereby generating a competent binding pocket for micro-plasminogen (μPlg), which buries approximately 2500 Å of the Sak:μPli complex upon binding. This structural and functional model may serve as a template for the design of improved Sak-derived thrombolytic agents. Following the completion and presentation of the present study, the deduced Sak:μPli:μPlg complex was fully confirmed by X-ray crystallography, which further illustrates the power and potential of the present approach.

Staphylokinase (Sak), a 16-kDa bacterial protein, forms a 1:1 stoichiometric complex with the serine proteinase domain of human plasmin, which in turn converts other plasminogen molecules into plasmin. To identify amino acid residues critical for generating the Sak:plasmin activator complex, alanine-scanning mutagenesis was performed on phage-displayed micro-plasminogen (microPlg). Substitution of Arg719 with Ala [microPlg(R719A)] disrupted complex formation, although the sensitivity of phage-displayed microPlg(R719A) to activation by urokinase and the amidolytic activity of the micro-plasmin derivative [microPli(R719A)] remained unaffected. Likewise, the soluble microPlg(R719A) molecule did not generate a functional activator complex with Sak, whereas quantitative activation into plasmin was obtained upon incubation with either urokinase or the Sak:plasmin complex. Real-time biospecific affinity measurements revealed that the Arg --> Ala substitution at position 719 increased the equilibrium dissociation constant between microPlg(R719A) and Sak from 46 nM to 1 microM, primarily by reducing the association rate constant. Arg719 has recently also been implied in the functional complex formation between human plasmin and streptokinase [Dawson, K. M., Marshall, J. M., Raper, R. H., Gilbert, R. J., and Ponting, C. P. (1994) Biochemistry 33, 12042-12047.], suggesting that both bacterial cofactors may share common structural and/or mechanistic aspects for plasminogen activation.

The effectiveness of clozapine treatment in a treatment-refractory sample of older adult veterans with primary psychosis was examined.Data were collected over a five-year period for patients age 55 and older who were given clozapine because of a history of treatment-refractory or treatment-intolerant psychosis. At initiation of clozapine therapy, baseline demographic, clinical, and psychopathology data were collected. At baseline and quarterly, patients' psychopathology was rated with the Brief Psychiatric Rating Scale (BPRS), and involuntary movements were rated with the Abnormal Involuntary Movement Scale (AIMS).The 329 patients age 55 or older who received clozapine during the study period represented 10 percent of all patients on clozapine therapy in the VA system. Of the 312 patients for whom demographic information was available, 294 were men and 18 were women. Overall, patients improved on clozapine therapy, although wide variation in drug response was observed. Complete BPRS and AIMS data were available for 97 patients. The 55- to 64-year-old group had a mean improvement in total BPRS score of 19.8 percent, with 42.6 percent showing more than a 20 percent improvement; those age 65 and older had a mean improvement of 5.7 percent, with 17.2 percent showing an improvement greater than 20 percent. The 97 patients with complete AIMS data showed a mean improvement of 16.6 percent in total score.Clozapine is an important therapeutic agent for older adults with treatment-refractory psychosis. Patients between the ages of 55 and 64 may have a better response than those age 65 and older.

Since most antibodies directed against protein antigens recognize epitopes composed of several discontinuous segments of the polypeptide chain, attempts to delineate the amino acids constituting these epitopes with the use of linear peptides have generally been unsuccessful. Here, a method is described based on error-prone PCR, phage display and negative selection, whereby amino acid residues constituting the functional epitope are identified in the context of the native protein. First a library of randomized antigen variants containing most single, double and triple amino acid mutants generated by single nucleotide substitutions is produced by error-prone PCR amplification of the DNA sequence encoding the protein antigen. The phage-displayed library is then negatively selected for epitope loss mutants by passing through an affinity matrix derivatized with a specific antibody and positively selected for retention of function. This method was applied to the mapping of the epitopes of two murine monoclonal antibodies (MA-7H11 and MA-3G10) on staphylokinase, a 136 amino acid plasminogen activator secreted by some strains of Staphylococcus aureus. After two negative/positive selection cycles, DNA sequencing of several clones revealed preferential amino acid mutations at positions 35 and 130 (with MA-7H11), and at positions 62, 66 and 136 (with MA-3G10). Affinity measurements of staphylokinase variants carrying single amino acid mutations at these positions confirmed their contribution to the free energy of binding to MA-7H11 and MA-3G10. This approach may be useful for isolating mutants with altered antigenic or functional properties and in general to map critical regions for protein-protein interactions.

Background The “charged cluster–to-alanine” substitution variants SakSTAR(K35A,E38A,K74A,E75A,R77A) and SakSTAR(K74A,E75A,R77A,E80A,D82A), previously identified as SakSTAR.M38 and SakSTAR.M89, respectively, induce less antibody formation in patients than wild-type recombinant staphylokinase (SakSTAR), but their specific activities are reduced by 50%. Therefore, the effect of the reversal of one or more of these substituted amino acids on the ratio of activity to antigenicity was studied. Methods and Results Fourteen mutants with one to four “alanine-to–wild-type” reversals were expressed in Escherichia coli and highly purified (>95%). In rabbits immunized with wild-type SakSTAR, the combined K35,E38,K74,E75,R77 or K74,E75,R77,E80,E82 epitope accounted for only 30% of antibody absorption from plasma, and no clear immunodominant residue could be identified. In baboons immunized with SakSTAR, the K35,E38 and K74,E75,R77 epitopes or the K74,E75,R77 and E80,D82 epitopes contributed equally to account for 50% of total antibody binding, but no immunodominant residues were apparent. In pooled plasma from patients with peripheral arterial occlusion treated with wild-type SakSTAR, about 40% of the antibodies depended on K74 of epitope K74,E75,R77 for binding, whereas epitopes K35,E38 and E80,D82 had a negligible contribution toward antibody recognition. Conclusions The recognition pattern by SakSTAR variants of antibodies induced with wild-type SakSTAR differs markedly among species. This implies that a systematic evaluation of reduced antigen recognition and antibody induction in humans will require the development of human or humanized systems. Surprisingly, SakSTAR(K 74 ), with a single substitution of Lys74 with Ala, had an intact specific activity but did not absorb 40% of the antibodies induced in patients by treatment with wild-type SakSTAR.

Clozapine therapy for 2,996 patients with treatment-refractory schizophrenia was examined over a five-year period in the Veterans Affairs health care system. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). BPRS scores, which were available for 522 patients, indicated a significant improvement, as did AIMS scores, which were available for 252 patients. Compared with individuals who showed a modest improvement, those with a more robust response to clozapine had higher initial BPRS scores and were three times more likely to have been suicidal in the month before starting clozapine therapy.

International audience; Wiskott–Aldrich syndrome (WAS) is an immune deficiency with thrombopenia resulting from mutations in the WASP gene. This gene normally encodes the Wiskott–Aldrich syndrome protein (WASP), a major cytoskeletal regulator expressed in hematopoietic cells. Gene therapy is a promising option for the treatment of WAS, requiring that clinically applicable WASP gene transfer vectors demonstrate efficacy in preclinical studies. Here, we describe a self-inactivating HIV-1-derived lentiviral vector encoding human WASP and show that it effectively transduced bone marrow progenitor cells of WASP knockout (WKO) mice. Transplantation of these transduced cells into lethally irradiated WKO recipients led to stable expression of WASP and correction of immune, inflammatory and cytoskeletal defects. Splenic T-cell proliferation was restored, podosomes were reinstated on bone-marrow-derived dendritic cells and colon inflammation was reduced. This shows for the first time (a) that cytoskeletal defects can be corrected in WKO mice, (b) that human WASP is biologically active in mice and (c) that a lentiviral vector is effective to express human WASP in vivo over several months. These data support further development of such lentiviral vectors for the gene therapy of WAS.

A procedure is described to screen panels of hybridomas or purified monoclonal antibodies using antigen displayed on the surface of filamentous bacteriophage. In this system, samples containing murine monoclonal antibodies are incubated with phage-displayed antigen in microtiter plates coated with rabbit anti-mouse IgG, and bound antibody–phage complex is detected with horseradish peroxidase–sheep anti-phage M13 conjugate. The assay has been validated with a panel of 16 monoclonal antibodies directed against human plasminogen, using phage-displayed miniplasmin(ogen) (amino acids Ala 444 through Asn 791 comprising kringle 5 and the proteinase domain of plasminogen) or microplasminogen (amino acids Ala 543 through Asn 791 comprising the proteinase domain). Six monoclonal antibodies were identified directed against miniplasminogen and miniplasmin; this was confirmed using a microtiter plate coated with antigens. One of these monoclonal antibodies (MA-42B12) did not react with microplasminogen, suggesting that its epitope is comprised within the kringle 5 domain. This test is rapid and sensitive (detecting 10–20 ng/ml of monoclonal antibody), and screening can be performed using phage-displayed zymogens or active enzymes or selected domains thereof. The procedure eliminates the need for large amounts of purified antigen for screening. Furthermore, immunization can be performed with partially purified antigen because only antibodies raised against the antigen of interest will be identified with the use of phage-displayed antigen. Therefore, this test may offer distinct advantages over the classical one-site enzyme-linked immunosorbent assay using antigen-coated microtiter plates.

The relationship between steady-state plasma concentration and clinical response was studied in 22 hospitalized unipolar depressed patients. In a double-blind format the patients were randomly assigned to receive amitriptyline or nortriptyline. Dosage was adjusted based on plasma level with the aim of achieving a concentration of 60-180 ng/ml. By week 4 of treatment, 83% of amitriptyline patients and all nortriptyline patients were within the targeted plasma range. Based on final ratings of clinical state, the drug level adjustment improved the outcome for nortriptyline-treated patients, but not amitriptyline-treated patients. Nortriptyline patients with plasma levels of 60-230 ng/ml had lower Hamilton Rating Scale depression scores than patients outside that range. By contrast, amitriptyline plasma levels were not associated with depression ratings. After 1 week, patients treated with nortriptyline had a significantly greater mean reduction in Hamilton depression score, i.e., 55% compared to 25% for amitriptyline patients.

The authors describe a training program on prevention and management of violent behavior for the staff of a Veterans Administration hospital. The one-day workshop focuses on preventive identification of potentially violent situations and on methods of verbal and physical management of violent behavior. A study of workshop participants showed that trainees had improved knowledge about and performance in handling violent behavior after completing the program. Future developments in training in prevention and management of violent behavior should include greater availability of educational resource materials and incorporation of the subject in undergraduate and graduate health care training.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

It remains unclear which blood pressure (BP) characteristics best predict cardiovascular risk in different age groups and between sexes. We leveraged data from the MORGAM (MONICA [Monitoring of Trends and Determinants in Cardiovascular Disease], Risk, Genetics, Archiving and Monograph) Project to investigate determinants of BP characteristics and their prognostic importance, in younger and older (P interaction P P P P =0.03), enhanced continuous net reclassification improvement (0.150 [95% CI, 0.087–0.215]) and improved the prognostic value of the European Society of Cardiology/European Society of Hypertension hypertension definition (categorical net reclassification improvement=0.0255, P =0.005). In conclusion, diastolic BP may provide additional prognostic utility beyond systolic BP, in predicting composite cardiovascular events among younger individuals.

International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Introduction Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM. Methods and analysis MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP

See Related Editorial, pp 238–239 > Quis custodiet ipsos custodes?—Who will guard the guards themselves? > > —Decimus Iunius Iuvenalis (Juvenal), 1st–2nd century AD, Satire VI, lines 347–348 Guidelines are traditionally scripted by a panel of experts who are intimately familiar with the topic in question. Practicing physicians inherently trust guideline authors and rarely ever question their expertise, especially when guidelines are endorsed by such venerable societies as the American College of Physicians (ACP) and the American Academy of Family Practitioners (AAFP) and are published in high-impact journals, such as the Annals of Internal Medicine . The >250 000 members of the ACP and AAFP have come to expect that any set of clinically meaningful guidelines has been put together by authors who were selected because of their outstanding skills and expertise pertaining to the topic in question. Thus, there is little if any reason to voice doubt as to the validity of published guidelines The Free Dictionary defines expertise as special skills or knowledge acquired by a person through education, training, or experience. For a physician unfamiliar with the experts, there are several simple ways to get a grasp on the quality and quantity of expertise: 1. One can scrutinize the publication list of the experts to assess how often they have been involved with the guideline topic. Any expert is expected to be well published in the specific area of the expertise. 2. One may take into account an expert’s membership in professional organizations pertaining to the subject matter. Obviously, membership and participation in annual meetings demonstrates an ongoing interest in the guideline topic. 3. One may examine whether the physician/scientist has been invited to serve on editorial boards of journals dealing with the topic in question. Being a member of an editorial board and peer reviewing submissions attest to some expertise pertaining to the …

Several sets of guidelines have been published recently and more are in the works. The very recent American College of Physicians/American Academy of Family Practitioners guidelines were put together by a set of authors and consultants without any expertise in the topic under discussion, that is, hypertension. Although we are not maintaining that all guidelines should be written exclusively by experts, complete lack of expertise among guideline authors is not acceptable. ispartof: Journal Of Hypertension vol:35 issue:8 pages:1564-1566 ispartof: location:Netherlands status: published

International audience; : Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

In the BEAUTY study we investigated whether utilizing non-invasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management-IHM) compared to conventional drug selection may improve home BP in patients with uncontrolled hypertension.Uncontrolled (office systolic blood pressure (SBP) 140 mmHg and ambulatory daytime SBP135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to 5 European Hypertension Excellence Centers and, if eligible, were randomized into IHM-guided vs conventional treatment adjustment. Home blood pressure (BP) was taken with 2 repeated readings at 1-2 min intervals in the morning and in the evening (before drug intake and eating) during the week preceding the visit at the outpatient clinic after 5 min rest using a validated semi-automatic oscillometric arm cuff device and with a correct cuff bladder placement. Home blood pressure was measured in a sub-group of patients (n = 84) not significantly different from the other patients.Home SBP changed from 152.1+/-15.8 and 149.8+/-11.8 mmHg to 131.0 +/-11.1 and 139.6+/-12.8 mmHg in IHM group (n = 46) and Control group (n = 38), respectively, showing significantly greater reduction in IHM than in Control group (d= -10.9 mmHg, 95% CI -17.77, -4.02), p = 0.002. The reduction remained significant after multiple adjustments, particularly for baseline home SBP, recruiting center, age, sex and BMI (SBPDrug selection algorithm based on non-invasive hemodynamic monitoring induced larger reduction in home BP compared to conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence Centers. Although the main BEAUTY study was negative, these home BP measurements taken by patients themselves may suggest that the integrated hemodynamic monitoring is useful in patients with uncontrolled hypertension. This finding might depend on specific features of home BP measurements which could make it recommended BP measurement method for drug trials.

OBJECTIVE:: To evaluate perindopril 3.5mg/amlodipine 2.5mg once daily, a novel fixed-dose combination adapted for first-step treatment in patients with hypertension. This fixed dose had to be equivalent to amlodipine 5mg in terms of blood pressure efficacy, but with an expected better tolerability profile. We selected two drugs with complementary modes of action, with doses chosen so that each drug would contribute similarly to the overall blood pressure-lowering effect METHODS:: An international, randomized, double-blind, placebo-controlled study with six equal parallel treatment arms and an 8-week randomized treatment period, whose design, clinical significance and non-inferiority criteria were in accordance with European guidelines. RESULTS:: In all, 1581 patients with mild-to-moderate uncomplicated hypertension (mean age 51.7 years) were randomized and 94.7% completed the study. The combination was statistically and clinically superior to placebo (between-group differences: SBP: -7.22mmHg, DBP: -4.12mmHg, P

Background The recent finding that aortic pulse wave velocity ( aPWV ) is increased in patients with inflammatory bowel disease may explain why the cardiovascular risk is increased despite the low prevalence of traditional cardiovascular risk factors. We aimed to test whether inflammation is associated with aortic stiffening in this setting after adjustment for major confounders and to perform subgroup analyses. Methods and Results A systematic literature search for aPWV in inflammatory bowel disease was performed using PubMed, Scopus, Web of Science, and Google Scholar databases (last accessed May 7, 2017). Inclusion criterion was peer‐reviewed publications on clinical studies reporting original data. This study followed the Preferred Reporting Items for Systematic Review and Meta‐Analyses of individual participant data 2015 guidelines. Data were provided for 4 cohorts in 3 countries (151 participants with ulcerative colitis, 159 with Crohn's disease, and 227 control patients). Using aPWV , cohort‐specific z scores were calculated after log e ‐transform and combined in meta‐analysis to form pooled effects using a random‐effects model. Compared with controls, aPWV was increased in patients with Crohn's disease (mean difference 0.78 z score; 95% confidence interval, 0.56–1.00 z score [ P z score; 95% confidence interval, 0.52–0.97 z score [ P aPWV was associated with disease duration (years, β=0.05 z score; 95% confidence interval, 0.02–0.08 z score [ P z score; 95% confidence interval, 0.02–0.11 z score [ P =0.002]) but not with markers of acute inflammation (C‐reactive protein and erythrocyte sedimentation rate), cardiovascular risk factors, and therapy. Conclusions The increased aPWV reported in patients with inflammatory bowel disease is associated with inflammation. Clinical Trial Registration URL : http://www.crd.york.ac.uk . Unique identifier: PROSPERO 2016: CRD 42016053070.

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Brachial cuff blood pressure (BP) is clinically important, but may be an inaccurate substitute for central BP. Many non-invasive devices have been developed that purport to estimate central BP from peripheral artery sites, yet with no standardized guidelines; the accuracy testing of these new devices has not been undertaken in a uniform fashion with comparable protocols. This is an abridged paper describing the recommendations reached by an international task force convened to identify issues that need to be addressed and reach consensus relating to methods for assessing and reporting the accuracy (validation) of central BP devices. The recommendations are endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society, as well as the European Society of Hypertension (ESH) Working Group on Arterial Structure and Function, and the ESH Working Group on Blood Pressure Monitoring and Cardiovascular Variability. Researchers interested in validating central BP monitors should read the full version of the statement.

Background and aims We assess the respective relationship of high depressive symptoms and antidepressant use (ATD) with baroreflex sensitivity (BRS) in subjects from the community who enrolled the Paris Prospective Study III. Methods Recruitment took place in a large health preventive centre in Paris (France), between May 2008 and June 2012. BRS was investigated by spectral analysis of the spontaneous carotid distension rate and RR intervals using non-invasive high-resolution ultrasound carotid-echotracking. A total score ≥7 on a 13-item standardized questionnaire defined the presence of high depressive symptoms. Information on ATD use was obtained on a face-to-face interview with a medical doctor who checked the most recent medical prescriptions and/or medical package. Results There were 9213 participants aged 50–75 years (38.6% of women), including 5.6% with high-depressive symptoms and 5.2% on ATD. High depressive symptoms were not associated with low BRS (below the median) even in unadjusted logistic regression analysis (OR = 1.09; 95%CI: 0.91–1.30). Instead, ATD use was related to low BRS in multivariate logistic regression analysis (OR = 1.27; 95% CI: 1.04–1.54). This association remains after adjusting for and matching on propensity score of receiving ATD. A specific association with serotonin and norepinephrine reuptake inhibitors was observed (OR = 1.94; 95% CI: 1.16–3.22). Conclusions ATD use and serotonin and norepinephrine reuptake inhibitors in particular, but not high depressive symptoms, is associated with low BRS. If confirmed, these results may bring novel insights into the mechanisms linking depressive symptoms and/or ATD use with cardiovascular disease onset.

Arterial hypertension is often part of a constellation of anthropometric and metabolic abnormalities that occur simultaneously to a higher degree than would be expected by chance alone, supporting the existence of a discrete disorder, the so-called metabolic syndrome. It is the result of interactions among a large number of interconnected mechanisms, which eventually lead to both an increase in cardiovascular and renal risk, and the development of diabetes. Mechanisms involved in the metabolic syndrome are obesity, insulin resistance, and a constellation of independent factors, which include molecules of hepatic, vascular, and immunologic origin with pro-inflammatory properties. At each of these key points are interactions of demographics, lifestyle, genetic factors, and environmental fetal programming. Superimposing upon these are infections or chronic exposure or both to certain drugs that can also make their contribution. Skeletal muscle and the liver, not adipose tissue, are the two key insulin-response tissues involved in maintaining glucose balance, although abnormal insulin action in the adipocytes also plays a role in development of the syndrome. Factors commonly associated with and partly dependent on obesity, insulin resistance, such as overactivity of the sympathetic, stimulation of the renin-angiotensin-aldosterone systems, abnormal renal sodium handling, endothelial dysfunction, and large vessels' alterations, may play a key role in the blood pressure elevation of the syndrome. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

In the BEtter control of BP in hypertensive pAtients monitored Using the HOTMAN sYstem study, we investigated whether utilizing noninvasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management - IHM) compared with conventional drug selection may improve uncontrolled hypertension in European Hypertension Excellence centers.Uncontrolled (office SBP140 mmHg and ambulatory daytime SBP135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to five European Hypertension Excellence centers and, if eligible, were randomized to IHM-guided (n = 83) vs. conventional (control, n = 84) treatment adjustment in an investigator-initiated multicenter prospective randomized parallel groups controlled study.The average number of antihypertensive drugs increased from 3.1 to 4.1 in both groups and differed only in a rise of the use of diuretics in the IHM groups (from 13 to 31%). Daytime SBP, defined as the primary endpoint, decreased markedly and to the same extent from baseline to 6 months in IHM (-15.8 ± 14.8 mmHg) and control (-15.4 ± 14.5 mmHg) groups (P = 0.87), with a similar behavior of office SBP (no between group differences, P = 0.18). Average number of adverse events was significantly lower in IHM than in controls (P = 0.008) but of the more general type and not necessarily related to drug treatment.Thus, noninvasive hemodynamic monitoring associated with a drug selection algorithm induced similar reductions in ambulatory daytime and office SBP compared with conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence centers.Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01482364.

INTRODUCTION AND OBJECTIVE Blood pressure variability (BPV) within 24 h or between visits has been found to represent an independent risk factor for cardiovascular disease. The present study was aimed at determining whether a clinical significance can be given also to the BP variations occurring within a single clinical visit. METHODS BPV was quantified as coefficient of variation and as standard deviation (SD) of the mean of three systolic SBP values within a visit in the context of a large-cross subclinical survey (BP-CARE) of treated hypertensive patients living in Eastern European countries. The study population was divided into coefficient of variation and SD quartiles and for each quartile a relationship was sought with a large number of cardiovascular risk factors based on patients' history, physical and laboratory examinations. RESULTS The 6425 hypertensive patients had an age of 59.2 ± 11 years (mean ± SD); they were equally distributed by sex and displayed an average SD and coefficient of variation amounting to 5.1 ± 6.2 mmHg and 3.5 ± 4.0%, respectively. Compared with the lowest coefficient of variation quartile (Q1), patients in the highest quartile (Q4) showed a significantly greater prevalence of several cardiovascular risk factors, such as age (Q1: 58.5 ± 11 vs. Q4: 60.3 ± 11 years, P

Objective: Abnormal large artery function plays an important role in the pathogenesis of cardiovascular (CV) diseases. Prior studies have suggested that the principal determinants of arterial stiffening are age, Blood Pressure (BP) and others CV risk factors such as dyslipidemia and diabetes. However, scanty data are available on the role of psychological factors on arterial stiffness. Previous work have shown that arterial stiffness was associated with depression in the elderly and in healthy adolescents, but no study has focused on the role of depression and other psychological variables in hypertensive patients. The aim of the current cross-sectional study was to evaluate the association between depression, anxiety, perceived stress, Type A personality, and Type D personality and Pulse Wave Velocity (PWV) in a cohort of hypertensive patients, using baseline examination data of the TIPICO project. Design and method: A total of 259 outpatients (ages 18–80 years) followed by the Hypertension Unit of S. Gerardo Hospital (Monza, Italy) affected by essential hypertension were recruited. Aortic stiffness was evaluated by PWV between the carotid and the femoral artery of the same side with the patient in the supine position. Moreover, anamnestic data, clinical BP, and laboratory data were evaluated. Patients were asked to complete a battery of psychological questionnaires under the guidance of a psychologist. The associations between psychological variables and PWV was explored using multivariate stepwise linear regression analysis and regression coeffi cients (b) were given per 1-point increment. Results: The mean age was 55.9 ± 10.1years, SBP and DBP were 135.6 ± 17.7 and 82.5 ± 9.1mmHg and PWV was 8.6 ± 2.1m/s. The results from the multivariate stepwise linear regression analysis showed that age (beta = 0.284, p < 0.001), pulse pressure (beta = 0.369, p < 0.001), dyslipidemia (beta = 0.130, p = 0.012), family history of CV disease (beta = -0.123, p = 0.017), and depression (beta = 0.126, P = 0.014) were signifi cantly and independently associated with PWV. Conclusions: The current study shows that, among psychological factors, higher levels of depression is related to higher PWV, while anxiety, perceived stress, Type A personality, and Type D personality are not associated with arterial stiffness. Depression assessment and target intervention to reduce it are recommended in hypertensive patients.

BACKGROUND AND OBJECTIVES:: It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke. RESULTS:: A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak. CONCLUSION:: A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.