The MINDMAP project: mental well-being in urban environments : Design and first results of a survey on healthcare planning policies, strategies and programmes that address mental health promotion and mental disorder prevention for older people in Europe.

BACKGROUND: The MINDMAP consortium (2016-2019) aims to identify opportunities provided by the urban environment for the promotion of mental well-being and functioning of older people in Europe by bringing together European cities with urban longitudinal ageing studies: GLOBE, HAPIEE, HUNT, LASA, LUCAS, RECORD, Rotterdam Study, Turin Study. A survey on mental healthcare planning policies and programmes dedicated to older persons covering the range from health promotion to need of nursing care was performed for profound data interpretation in Amsterdam, Eindhoven, Hamburg, Helsinki, Kaunas, Krakow, London, Nord-Trøndelag, Paris, Prague, Rotterdam and Turin. OBJECTIVES: To collect detailed information on healthcare planning policies and programmes across these European cities to evaluate variations and to delineate recommendations for sciences, policies and planners using experience from evidence-based practice feedback from the MINDMAP cities. MATERIALS AND METHODS: The MINDMAP partners identified experts in the 12 cities with the best background knowledge of the mental health sector. After pretesting, semi-structured telephone interviews (1-2 h) were performed always by the same person. A structured evaluation matrix based on the geriatric functioning continuum and the World Health Organization (WHO) Public Health Framework for Healthy Ageing was applied. RESULTS: A complete survey (12 out of 12) was performed reporting on 41 policies and 280 programmes on the city level. It appeared from extensive analyses that the focus on older citizens, specific target groups, and multidimensional programmes could be intensified. CONCLUSION: There is a broad variety to cope with the challenges of ageing in health, and to address both physical and mental capacities in older individuals and their dynamic interactions in urban environments.

Correction to: The MINDMAP project: mental well-being in urban environments : Design and first results of a survey on healthcare planning policies, strategies and programmes that address mental health promotion and mental disorder prevention for older people in Europe.

Correction to: Z Gerontol Geriat 2017 https://doi.org/10.1007/s00391-017-1290-7 The article "The MINDMAP project: mental well-being in urban environments. Design and first results of a survey on healthcare planning policies, strategies and programmes that address mental health promotion and mental disorder prevention for older people in …The original article was corrected.

Different glycosylation pattern of human IgG1 and IgG3 antibodies isolated from transiently as well as permanently transfected cell lines.

The effector functions of IgG depend on the presence of carbohydrates attached to asparagine 297 in the Fc-portion. In this report, glycosylation profiles of recombinant wild-type and mutant IgG1 and IgG3 antibodies produced from three cell lines were analysed using LC-ESI-Orbitrap. Clear differences were detected between IgG1 and IgG3 glycoforms, where IgG1 generally contained fucosylated glycoforms, whilst IgG3 mainly were non-fucosylated. When using NS-0 and J558L cells for permanent transfection, IgG1 wt glycoforms differed between the two cell lines, whilst IgG3 wt glycoforms did not. Transiently transfected HEK 293E cells were used to produce IgG1 and IgG3 wt and mutants, affecting complement activation. Cell supernatants were harvested at early and late time points and analysed separately. IgGs harvested late showed simpler and less developed glycosylation structure compared to those harvested early. The IgG harvested early was slightly more effective in complement activation than those harvested late, whilst the antibody-dependent cell-mediated cytotoxicity was unaltered. Generally, the glycosylation pattern of the mutants tested, including a hinge truncate mutant of IgG3, did not differ significantly from the wild-type IgGs. The striking difference in glycosylation pattern of IgG1 compared to IgG3 therefore appears not to be due to the long hinge region of IgG3 (62 amino acids) relative to the IgG1 hinge region (15 amino acids). Furthermore, mutation variants at or near the C1q binding site showed similar glycosylation structure and difference in their complement activation activity observed earlier is thus most likely due to differences in protein structure only.

Lysosomes as a possible target of enniatin B-induced toxicity in Caco-2 cells.

Enniatins are cyclic hexadepsipeptidic mycotoxins with ionophoric, antibiotic, and insecticidal activity. Enniatin B (EnnB), the most important analogue, is produced by many Fusarium species and is a common contaminant in grain-based foods. The compound's cytotoxic potential has been shown in different experiments; however, the mode of action has not been detailed so far. In the present study, several mutually confirmative experiments have been performed indicating that EnnB-initiated cytotoxicity could be connected with lysosomal membrane permeabilization (LMP). Lysosomal functionality, as assessed by the Neutral Red assay, was already affected after 3 h of toxin exposure. After 24 h, cell proliferation was decreased, and there was indication for a cell cycle arrest in the G(2)/M phase leading to the initiation of apoptosis or necrosis. Intracellular ROS-production was observed. However, antioxidants did not alter the observed EnnB-induced loss of lysosomal functionality leading to the conclusion that ROS was not an initial factor but one produced later in the event cascade. The collected data suggested that lysosomal destabilization is an upstream event in EnnB-initiated cytotoxicity followed by a certain extent of translocation of cathepsins into the cytosol, which was observed using immunological and proteomic methods. It appeared that cell death induced by EnnB was delayed and occurred not as a massive lysosomal breakdown but was probably progressing and leading to partial and selective LMP, starting a nonapoptotic cell death pathway with morphological features that had been previously considered as necrotic. The molecular mechanism of EnnB-triggered lysosomal destabilization, and the cellular processes leading to mitochondrial permeabilization and cell death are still unknown. They may, however, be connected to the compound's ionophoric properties.

ORF 2 from the Bacillus cereus linear plasmid pBClin15 encodes a DNA binding protein.

AIMS: To isolate and identify DNA-binding protein(s) with affinity for the mobile chromosomal repeat element bcr1 in Bacillus cereus group bacteria. METHODS AND RESULTS: A biotinylated bcr1 element was immobilized to streptavidin-coated magnetic beads and used to pull out a 20 kDa DNA-binding protein from a whole cell protein extract of B. cereus ATCC 14579. The protein was identified as the product of ORF 2 encoded by the bacteriophage-related autonomously replicating linear genetic element pBClin15 carried by the strain. DNA binding was not bcr1-specific. By Northern blotting ORF 2 was co-transcribed with ORF 1, and also in certain instances with ORF 3 by transcriptional readthrough of the terminator located between ORF 2 and ORF 3. CONCLUSIONS: ORF 2 from pBClin15 encodes a DNA-binding protein. ORF 2 is co-transcribed with its upstream gene ORF 1, and in a subset of the transcripts also with the downstream gene ORF 3 through alternative transcription termination. SIGNIFICANCE AND IMPACT OF THE STUDY: The B. cereus group contains bacterial species of medical and economic importance. Bacteriophages or phage-encoded proteins from these bacteria have been suggested as potential therapeutic agents. Understanding the biology of bacteriophage-related genetic elements through functional characterization of their genes is of high relevance.

Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar?

3-Hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88) inhibitors are the most effective drugs to lower cholesterol in transplant patients. However, immunosuppressants and several other drugs used after organ transplantation are cytochrome P4503A (CYP3A, EC 1.14.14.1) substrates. Pharmacokinetic interaction with some of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, specifically lovastatin and simvastatin, leads to an increased incidence of muscle skeletal toxicity in transplant patients. It is our objective to review the role of drug metabolism and drug interactions of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin. In the treatment of transplant patients, from a drug interaction perspective, pravastatin, which is not significantly metabolized by CYP enzymes, and fluvastatin, presumably a CYP2C9 substrate, compare favorably with the other statins for which the major metabolic pathways are catalyzed by CYP3A.

Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations.

A combination of quantum chemical calculations and molecular simulations (DOCKing and molecular dynamics) is used to investigate the metabolism of sirolimus (rapamycin) and its derivative everolimus (SDZ-RAD) by cytochrome P450 3A4. Both molecules are drugs with high immunosuppressive activity. Our calculations yield qualitative predictions of the regiospecificities of the hydroxylations and O-dealkylations occurring in these two substrates which are in good agreement with recent experimental results. An analysis of the modeled enzyme-substrate interactions allows us to rationalize the reduced metabolic activity of the larger substrate everolimus compared to sirolimus. Moreover, our simulations suggest that hydrogen donor functionalities close to the metabolic site are important for anchoring the substrate at the active center of the enzyme. In particular, we predict that replacing one hydroxyl group by a fluorine atom should considerably suppress the major metabolic reaction in sirolimus, 39-O-demethylation.

Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain.

Clinical studies have shown enhancement of cyclosporine toxicity when co-administered with the immunosuppressant sirolimus. We evaluated the biochemical mechanisms underlying the sirolimus/cyclosporine interaction on rat brain metabolism using magnetic resonance spectroscopy (MRS) and compared the effects of sirolimus with those of the structurally related RAD. Two-week-old rats (25 g) were allocated to the following treatment groups (all n=6): I. control, II. cyclosporine (10 mg kg(-1) d(-1)), III. sirolimus (3 mg kg(-1) d(-1)), IV. RAD (3 mg kg(-1) d(-1)), V. cyclosporine+sirolimus and VI. cyclosporine+RAD. Drugs were administered by oral gavage for 6 days. Twelve hours after the last dose, metabolic changes were assessed in brain tissue extracts using multinuclear MRS. Cyclosporine significantly inhibited mitochondrial glucose metabolism (glutamate: 78+/-6% of control; GABA: 67+/-12%; NAD(+): 76+/-3%; P<0.05), but increased lactate production. Sirolimus and RAD inhibited cytosolic glucose metabolism via lactate production (sirolimus: 81+/-3% of control, RAD: 69+/-2%; P<0.02). Sirolimus enhanced cyclosporine-induced inhibition of mitochondrial glucose metabolism (glutamate: 60+/-4%; GABA: 59+/-8%; NAD(+): 45+/-5%; P<0.02 versus cyclosporine alone). Lactate production was significantly reduced. In contrast, RAD antagonized the effects of cyclosporine (glutamate, GABA, and NAD(+), not significantly different from controls). The results can partially be explained by pharmacokinetic interactions: co-administration increased the distribution of cyclosporine and sirolimus into brain tissue, while co-administration with RAD decreased cyclosporine brain tissue concentrations. In addition RAD, but not sirolimus, distributed into brain mitochondria. The combination of cyclosporine/RAD compares favourably to cyclosporine/sirolimus in regards to their effects on brain high-energy metabolism and tissue distribution in the rat.

Autologous breast reconstruction with use of transverse rectus abdominis musculocutaneous flap: Mayo clinic experience with 147 cases.

OBJECTIVE: To assess the results of transverse rectus abdominis musculocutaneous (TRAM) flap reconstructions of the breast. DESIGN: We retrospectively reviewed 147 consecutive cases of TRAM reconstructions of the breast performed at the Mayo Clinic between 1981 and 1992. MATERIAL AND METHODS: The median patient age was 47 years, and the median duration of follow-up was 29 months. In 25 patients, both rectus pedicles were used, 15 of those for bilateral reconstruction. The other 122 patients had unipedicled unilateral reconstruction. Only 9% of the breast reconstructions were immediate. Analysis of risk factors in the patient population revealed smoking in 16%, preoperative irradiation of the chest wall in 20%, preoperative chemotherapy in 27%, and both radiotherapy and chemotherapy in 12%. RESULTS: The mean overall operative time was 4 hours and 43 minutes (4 hours and 20 minutes for unipedicled flaps and 5 hours and 46 minutes for bipedicled reconstructions). No blood transfusion was needed in 47% of patients; of those who received transfusions, 78% required 2 units or less. In 58 of the 147 patients (39%), an operation was performed on the contralateral breast. Follow-up operations were necessary in 71% of patients. The overall frequency of complications was as follows: hernia that necessitated surgical repair, 7.5%; full TRAM ischemic loss, 3.7%; partial TRAM loss, 9.9%; and fat necrosis, 11.7%. No pattern of increased complications was noted in subgroups of patients who smoked or who had received preoperative irradiation, chemotherapy, or both. In comparison with our early cases, the last 50 TRAM procedures were generally associated with fewer complications. The rates of occurrence of complications in our series of patients were similar to those reported in the literature. CONCLUSION: The TRAM flap provides satisfactory results for reconstruction of the breast.

Heparin activity monitoring during vascular surgery.

Twelve patients undergoing vascular surgery were administered heparin according to preexisting protocols. The response to heparin and the rate of decay were measured by use of the activated coagulation time (ACT). The results showed a significant patient variability to response to and decay of heparin. In addition, a dose-response curve for heparin administration was established in sixteen patients undergoing vascular surgery. The ACT proved to be a simple and accurate monitor of heparin activity. It also made possible a steady state of anticoagulation throughout the duration of the vascular procedure. The reversal of the heparin effect could also be precisely determined by this test.

Massive abdominal-wall hernia reconstruction with expanded external/internal oblique and transversalis musculofascia.

We describe a technique for expansion and primary closure of massive and large recalcitrant abdominal-wall hernias in the middle and lower abdomen utilizing expanders placed in the lateral abdominal wall between the external oblique and the deeper complex of the internal oblique and transversalis fasciae. Since this technique describes expansion of the lateral abdominal wall, insertion incisions are made in the lateral abdominal wall away from the primary zone of injury surrounding the abdominal hernia and without interrupting the blood supply or innervation to the abdominal-wall muscle, fascia, or skin. This technique, described in four patients with massive abdominal-wall hernias, has been used successfully for primary closure with vascularized autogenous abdominal-wall fascia, obviating the need for interposition of prosthetic material or extraabdominal flaps.

Temperature instability as an early predictive factor of brain death in paediatric near-drowning victims.

Predicting outcome after near-drowning has been extensively studied. During four years, 42 near drowned children were aggressively treated with positive pressure ventilation, barbiturates and hypothermia. This mode of treatment makes it difficult to clinically assess the child's prognosis. Temperature instability after rewarming is an early negative predictive factor following treatment of near-drowning, and in conjunction with cerebral flow studies avoids the potential commitment to prolonged and unwarranted cardiovascular and respiratory support.

Brain tissue oxygen monitoring to assess reperfusion after intra-arterial treatment of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a retrospective study.

BACKGROUND AND PURPOSE: Cerebral vasospasm resistant to medical management frequently requires intra-arterial spasmolysis. Angiographic resolution of vasospasm does not provide physiologic data on the adequacy of reperfusion. We recorded pre- and postspasmolysis PbO(2) data in the endovascular suite to determine whether this physiologic parameter could be used to determine when successful reperfusion was established. MATERIALS AND METHODS: Eight patients with 10 Licox monitors and cerebral vasospasm underwent intra-arterial spasmolysis. Pre- and postspasmolytic PbO(2) was recorded for comparison. Other physiologic parameters, such as CPP, ICP, SaO(2), and Fio(2), were also recorded. RESULTS: Mean prespasmolysis PbO(2) recordings were 35.2 and 27.3 for the mild-to-moderate and moderate-to-severe vasospasm group, respectively. Mean postspasmolysis PbO(2) increased to 40.3 and 38.4, respectively, which was statistically significant (P < .05) for both groups. In 100% of instances in the moderate-to-severe group and 83% of instances in mild-to-moderate group, the mean PbO(2) increased after spasmolysis and correlated with improvement in angiographic vasospasm. Other physiologic parameters, such as CPP, ICP, SaO(2), and Fio(2), did not show any statistically significant difference before and after spasmolysis. CONCLUSIONS: PbO(2) monitoring provides the interventionalist with an objective physiologic parameter to determine adequate spasmolysis. Further investigation is needed to establish target PbO(2) rates indicative of adequate reperfusion, which can be used in the endovascular suite.

Closed blunt chest trauma causing mediastinal abscess.

Posttraumatic bacterial mediastinal abscess resulting from closed blunt trauma without penetrating injury or tracheal or esophageal rupture is, to our knowledge, previously unreported. We report a case of a patient injured in a motor vehicle collision that resulted in closed blunt chest trauma and mediastinal abscess 14 days after injury. Initial chest roentgenogram revealed a widened mediastinum. Computed tomographic scan of the chest revealed comminuted fractures of the upper sternum, manubrium, and the 3rd and 4th left anteriolateral ribs and a retrosternal hematoma. Transesophageal echocardiography was negative. The patient was dismissed 2 days after injury and returned to the hospital 14 days after injury with a fluctuant, pulsatile, upper midline chest wall and anteriolateral chest wall staphylococcal abscesses. The abscesses were drained and the sternomanubrial wound debrided in stages. The mediastinal defect was reconstructed with a pectoralis major muscle flap. This most likely represents bacterial seeding of the mediastinal hematoma from a distant source.

In vitro evaluation of the disposition of A novel cysteine protease inhibitor.

K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl) is a potent, irreversible cysteine protease inhibitor. Its therapeutic targets are cruzain, a cysteine protease of the protozoan parasite Trypanosoma cruzi, and cathepsins B and L, which are associated with cancer progression. We evaluated the metabolism of K11777 by human liver microsomes, isolated cytochrome P450 (CYP) enzymes, and flavin-containing monooxygenase 3 (FMO3) in vitro. K11777 was metabolized by human liver microsomes to three major metabolites: N-oxide K11777 (apparent K(m) = 14.0 +/- 4.5 microM and apparent V(max) = 3460 +/- 3190 pmol. mg(-1). min(-1), n = 4), beta-hydroxy-homoPhe K11777 (K(m) = 16.8 +/- 3.5 microM and V(max) = 1260 +/- 1090 pmol. mg(-1). min(-1), n = 4), and N-desmethyl K11777 (K(m) = 18.3 +/- 7.0 microM and V(max) = 2070 +/- 1830 pmol. mg(-1). min(-1), n = 4). All three K11777 metabolites were formed by isolated CYP3A and their formation by human liver microsomes was inhibited by the CYP3A inhibitor cyclosporine (50 microM, 54-62% inhibition) and antibodies against human CYP3A4/5 (100 microg of antibodies/100 microg microsomal protein, 55-68% inhibition). CYP2D6 metabolized K11777 to its N-desmethyl metabolite with an apparent K(m) (9.2 +/- 1.4 microM) lower than for CYP3A4 (25.0 +/- 4.0 microM) and human liver microsomes. The apparent K(m) for N-oxide K11777 formation by cDNA-expressed FMO3 was 109 +/- 11 microM. Based on the intrinsic formation clearances and the results of inhibition experiments (CYP2D6, 50 microM bufuralol; FMO3 mediated, 100 mM methionine) using human liver microsomes, it was estimated that CYP3A contributes to >80% of K11777 metabolite formation. K11777 was a potent (IC(50) = 0.06 microM) and efficacious (maximum inhibition 85%) NADPH-dependent inhibitor of human CYP3A4 mediated 6'beta-hydroxy lovastatin formation, suggesting that K11777 is not only a substrate but also a mechanism-based inhibitor of CYP3A4.

Safety and efficacy of combined upper blepharoplasties and open coronal browlift: a consecutive series of 600 patients.

Surgical rejuvenation of the upper face involves the correction of excess and lax forehead, eyelid, and periorbital skin. Improving the appearance by correcting the effects of aging involves a combination of blepharoplasty and open coronal foreheadplasty. Many surgeons and several reports question the safety of both procedures being performed concomitantly. The difficulty arises in precisely balancing the skin excision from the frontal forehead and upper eyelid areas. Over-resection of skin may result in incomplete closure of the eyelid and dry-eye syndrome, while an inadequate resection may produce a poor aesthetic result. There is no large series that documents the safety and effectiveness of these two procedures being performed concomitantly. Furthermore, with the recent and rapid development of complex multiplanar endoscopic facial rejuvenation techniques, the basic open foreheadplasty has become increasingly overlooked as a legitimate, efficacious technique for rejuvenation of the upper face. The technique utilized in this series is presented in detail. The consistently excellent results obtained satisfy the aesthetic goals of patients as well as the goals of surgeons, and suggest a renewed interest in the technique based upon its simplicity and easily reproducible results.

Paradoxical air embolism associated with a central total parenteral nutrition catheter.

Central vein cannulation is used frequently as a route for total parenteral nutrition (TPN); however, it is not without complications. This report describes a paradoxical air embolism resulting in circulatory collapse and in residual neurological deficit.