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The shape of the cell is connected to its function; however, we do not fully understand underlying mechanisms by which global shape regulates a cell's functional capabilities. Using theory, experiments and simulation, we investigated how physiologically relevant cell shape changes affect subcellular organization, and consequently intracellular signaling, to control information flow needed for phenotypic function. Vascular smooth muscle cells going from a proliferative and motile circular shape to a contractile fusiform shape show changes in the location of the sarcoplasmic reticulum, inter-organelle distances, and differential distribution of receptors in the plasma membrane. These factors together lead to the modulation of signals transduced by the M3 muscarinic receptor/Gq/PLCβ pathway at the plasma membrane, amplifying Ca2+ dynamics in the cytoplasm, and the nucleus resulting in phenotypic changes, as determined by increased activity of myosin light chain kinase in the cytoplasm and enhanced nuclear localization of the transcription factor NFAT. Taken together, our observations show a systems level phenomenon whereby global cell shape affects subcellular organization to modulate signaling that enables phenotypic changes. [ABSTRACT FROM AUTHOR]

Harmonic lattice dynamics calculations have been performed for the antiferroelectric P213 ordered phase of α-carbon monoxide and for two related structures with a different head–tail ordering of the CO molecules. The potential used is an ab initio CO–CO potential with its anisotropy expanded in spherical harmonics, as well as a site–site model fitted to this ab initio potential. Good agreement with experiment is obtained for the structure, the cohesion energy, and the phonon frequencies without any adjustment of the potential. Head–tail reordering of the molecules is energetically almost neutral if it is accompanied by a translational displacement along the bond axes, which is symmetric with respect to the inversion centers of the average Pa3 structure. This displacement is induced in particular by the strong head–tail anisotropy in the short-range repulsion. Translation–rotation coupling is found to be important; it affects especially the frequency of the lowest optical mode. [ABSTRACT FROM AUTHOR]

Abstract. Hillege HL, Janssen WMT, Bak AAA, Diercks GFH, Grobbee DE, Crijns HJGM, van Gilst WH, de Zeeuw D, de Jong PE for the PREVEND Study group (University of Groningen and University Hospital Groningen, Groningen; University Medical centre, Utrecht, the Netherlands). Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 2001; 249: 519–526. Objectives. To assess the prevalence of microalbuminuria in the general population, especially in nondiabetic and nonhypertensive subjects, and its association with known cardiovascular risk factors and cardiovascular morbidity. Design. Cross-sectional cohort study. Setting. Inhabitants of the city of Groningen, the Netherlands. Subjects. All inhabitants, aged between 28 and 75 years, were send a postal questionnaire and a vial to collect an early morning urine sample (n=85 421). Of these 40 856 subjects (47.8%) responded. Cardiovascular risk factors and morbidity were validated in a well defined nondiabetic and nonhypertensive group of 5241 subjects. Main outcome measures. Microalbuminuria, self-reported cardiovascular risk and cardiovascular morbidity in the total study cohort, and additionally more detailed measurements in a subset of the total population. Results. Microalbuminuria (20–200 mg L–1) was present in 7.2% of the subjects and independently associated with age, gender, hypertension, diabetes, smoking, previous myocardial infarction and stroke. Some of these associations were already observed at albuminuria levels of 10–20 mg L–1. After exclusion of the diabetic and hypertensive subjects, microalbuminuria was still prevalent in 6.6% of the subjects. Conclusions. Microalbuminuria appears to be common not only in the general population but also in a nondiabetic, nonhypertensive population and is independently associated with increased cardiovascular risk factors and cardio-vascular morbidity. Importantly, some of these associations are present at urinary albumin levels currently considered to be normal. These findings suggest that urinary albumin measurements may be useful in early risk profiling and prevention of cardiovascular disease in the population at large. [ABSTRACT FROM AUTHOR]

Purpose: Gastrointestinal disease occurs frequently in antibody deficiencies. This study aims to explore the relation between gastrointestinal infections and mucosal homeostasis in patients with antibody deficiencies. Methods: We performed an observational study including 54 pediatric antibody deficient patients (48 % CVID, 41 % CVID-like, 11 % XLA) and 66 healthy controls. Clinical symptom scores and stool samples were collected prospectively. Stool samples were evaluated for bacteria, parasites, viruses, secretory IgA- and for calprotectin levels. Results were compared between patients and controls. Results: 24 % of antibody deficient patients versus 9 % of healthy controls tested positive for gastrointestinal viruses ( p = 0.028). Fecal calprotectin levels were significantly higher in virus positive patients compared to virus negative patients ( p = 0.002). However, in controls, fecal calprotectin levels were similar between virus positive and virus negative controls. Moreover, gastrointestinal virus positive patients had low serum IgA levels in 13/14 cases (94 %) versus 40/62 (62 %) patients in the virus negative patient group ( p = 0.04). The virus positive patient group also displayed significantly lower secretory IgA levels in stool (median 13 ug/ml) than patients without gastrointestinal viruses detected or healthy controls (median 155 ug/ml) ( p = 0.046). Conclusion: We here report an increased prevalence of gastrointestinal viruses and gastrointestinal complaints in antibody deficient patients. Patients that tested positive for gastrointestinal viruses showed diminished serum- and secretory IgA levels, and only in patients, virus positivity was associated with signs of mucosal inflammation. These findings suggest that particularly patients with low IgA are at risk for longstanding replication of gastrointestinal viruses, which may eventually result in CVID-related enteropathy. [ABSTRACT FROM AUTHOR]

Chronic congestive heart failure (HF) has a rising prevalence and increasing impact on health care systems. Current treatment consists of diuretics, renin-angiotensin-aldosterone system blockers, and restriction of salt and fluids. This strategy is often hampered by a drop in effective circulating volume and hence renal perfusion and function, triggering harmful counter regulatory mechanisms. Slow ultrafiltration by peritoneal dialysis (PD) might be an effective treatment strategy to relieve fluid overload without compromising cardiac output and thereby renal function. In this review, we discuss the (patho)physiological mechanisms of the cardiorenal interaction and the current literature on PD strategies in congestive HF. [ABSTRACT FROM AUTHOR]

Comparison of seclusion figures between wards in Dutch psychiatric hospitals showed substantial differences in number and duration of seclusions. In the opinion of nurses and ward managers, these differences may predominantly be explained by differences in patient characteristics, as these are expected to have a large impact on these seclusion rates. Nurses assume more admissions of severely ill patients are related to higher seclusion rates. In order to test this hypothesis, we investigated differences in patient and background characteristics of 718 secluded patients over 5,097 admissions on 29 different admission wards over seven Dutch psychiatric hospitals. We performed an extreme group analysis to explore the relationship between patient and ward characteristics and the wards' number of seclusion hours per 1,000 admission hours. In a multivariate and a multilevel analysis, various characteristics turned out to be related to the number of seclusion hours per 1,000 admission hours as well as to the likelihood of a patient being secluded, confirming the nurses assumptions. The extreme group analysis showed that seclusion rates depended on both patient and ward characteristics. A multivariate and multilevel analyses revealed that differences in seclusion hours between wards could partially be explained by ward size next to patient characteristics. However, the largest deal of the difference between wards in seclusion rates could not be explained by characteristics measured in this study. We concluded ward policy and adequate staffing may, in particular on smaller wards, be key issues in reduction of seclusion. [ABSTRACT FROM AUTHOR]

Background: The physical environment is presumed to have an effect on aggression and also on the use of seclusion on psychiatric wards. Multicentre studies that include a broad variety of design features found on psychiatric wards and that control for patient, staff and general ward characteristics are scarce.Aims: To explore the effect of design features on the risk of being secluded, the number of seclusion incidents and the time in seclusion, for patients admitted to locked wards for intensive psychiatric care.Method: Data on the building quality and safety of psychiatric as well as forensic wards (n = 199) were combined with data on the frequency and type of coercive measures per admission (n = 23 868 admissions of n = 14 834 patients) on these wards, over a 12-month period. We used non-linear principal components analysis (CATPCA) to reduce the observed design features into a smaller number of uncorrelated principal components. Two-level multilevel (logistic) regression analyses were used to explore the relationship with seclusion. Admission was the first level in the analyses and ward was the second level.Results: Overall, 14 design features had a significant effect on the risk of being secluded during admission. The 'presence of an outdoor space', 'special safety measures' and a large 'number of patients in the building' increased the risk of being secluded. Design features such as more 'total private space per patient', a higher 'level of comfort' and greater 'visibility on the ward', decreased the risk of being secluded.Conclusions: A number of design features had an effect on the use of seclusion and restraint. The study highlighted the need for a greater focus on the impact of the physical environment on patients, as, along with other interventions, this can reduce the need for seclusion and restraint. [ABSTRACT FROM AUTHOR]

Over the immediate past 4 years, our program has collected hematopoietic progenitor cells by apheresis from 48 individuals aged 61 and over (range 61-71 years of age). We have retrospectively analyzed the collection and transplant results associated with employing these donors, and have compared them with 175 donors aged 60 or less who were collected during the same time period. We have found no significant difference in venous access (P=0.208), rate of post-transplant engraftment of neutrophils (P=0.117) and platelets (P=0.692), or in rate and grade of acute GVHD (P=0.806). However, we have found that these older donors have a significantly lower mobilization of CD34+ cells as reflected in lower absolute counts of circulating CD34+ cells pre-apheresis (P=0.016). This, in turn, results in lower CD34+ cell yields in apheresis products (P<0.001), trending towards requiring more apheresis procedures (22.9 vs 13.7%, P=0.095) to collect sufficient CD34+ cells for transplantation. We conclude that it is practical when necessary to employ donors aged 60 and above, as well as safe for both donor and intended recipient. However, concern over reduced CD34+ cell mobilization may be sufficient grounds to seek younger donors when possible. [ABSTRACT FROM AUTHOR]

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene (ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C > T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy. [ABSTRACT FROM AUTHOR]

Acute GVHD (aGVHD) is a major cause of morbidity and mortality in hematopoietic allograft recipients. The best therapy for patients failing to respond, or not tolerating, systemic glucocorticoids remains undefined. We evaluated the efficacy of sirolimus in 34 patients, median age of 49 (23–67) years, with steroid-refractory (n=31) or steroid-intolerant (n=3) aGVHD. aGVHD was diagnosed at a median of 34 (7–1042) days post allografting, and confirmed by biopsy in all cases. Initial aGVHD treatment consisted of prednisone up to 2 mg/kg. Sirolimus was initiated at a median of 9 (1–255) days after glucocorticoid initiation. A sirolimus loading dose was administered to 19 (56%) of 34 patients, median 6 (3–8) mg, followed by maintenance of 1–2 mg/day to target therapeutic trough levels between 4 and 12 ng/ml. Overall response rate was 76%. Fifteen (44%) of 34 patients achieved CR, defined as complete resolution of aGVHD sustained for at least 1 month, after sirolimus initiation without additional immunosuppressive agents. CR was achieved in 11 (42%) of 31 steroid-refractory and 2 (67%) of 3 steroid-intolerant patients. Median OS after initiation of sirolimus was 5.6 months, and 1-year OS was 44% (95% CI: 27–60%). Sirolimus is effective in controlling steroid-refractory aGVHD. [ABSTRACT FROM AUTHOR]

Relapse remains a leading cause for treatment failure after hematopoietic cell transplantation (HCT) in patients with intermediate- or high-risk myelodysplastic syndrome (MDS). To discern the impact of 5-azacitine treatment pretransplant on the risk for relapse after HCT, we analyzed the post transplant outcomes of all 54 consecutive patients with MDS or chronic myelomonocytic leukemia who received HCT from HLA-compatible donors according to pretransplant 5-azacitidine exposure. Thirty patients received a median of four (1–7) cycles of 5-azacitidine, and 24 patients did not receive 5-azacitidine before HCT. The 1-year estimates of overall survival, relapse-free survival and cumulative incidence of relapse were 47, 41 and 20%, for 5-azacitidine patients and 60, 51 and 32%, respectively, for non-5-azacytidine patients. These observations suggest that outcomes are similar in both groups with a trend toward decreased early relapse in patients receiving 5-azacitidine. 5-Azacitidine may be of value in stabilizing the disease, thereby allowing time for patients to reach transplant and does not appear to affect transplant outcomes. [ABSTRACT FROM AUTHOR]

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The use of seclusion in psychiatric practice is a controversial issue in the Netherlands, as a number of recent studies have shown seclusion to be a predominant restrictive measure. In contrast to many surrounding countries, Dutch legislation is arranged in such a way that the protection of the physical integrity of the patient is more important than professional considerations with respect to the treatment of severe mental illness. The opening of a new admission ward provided the opportunity to study the effect of a number of preventive measures both before and after admission on the use of seclusion. Two admission wards with the approximately the same staff compilation, the same admission criteria, and a comparable catchment area were followed for 29 months. In the experimental ward, a project was started with the aim to abandon seclusion in three years while, at the same time, reducing all other forms of restrain; the comparable ward had care as usual. The data show a decrease of number and duration of seclusion in the experimental ward in comparison to the ward providing care as usual. This difference could be related to a number of patient and ward characteristics. [ABSTRACT FROM AUTHOR]

The activities of cell therapy establishments are associated with substantial amounts of information. For reasons of best practice, regulation and adherence to prevailing standards, the data generated in the course of cell therapy product processing must be recorded and retained in an organized manner. Because cell therapy products are functionally pharmaceuticals, the paradigm of the pharmaceutical manufacturing batch process record (BPR) is proposed as a unit for collecting the data resulting from processing. Considerations for cell-processing facilities for the design of BPR and possible selection of electronic data-recording tools are reviewed, including data to collect in response to regulatory or accreditation mandates and different types of electronic data management tools that may be employed. Additionally, considerations for selection, qualification and validation of computer software for maintenance of the BPR are addressed. [ABSTRACT FROM AUTHOR]

Piezoresistive accelerometer signals are frequently used in movement analysis. However, their use and interpretation are complicated by the fact that the signal is composed of different acceleration components. The aim of the study was to obtain insight into the components of accelerometer signals from the trunk and thigh segments during four different sit-to-stand (STS) movements (self-selected, slow, fast and fullflexion). Nine subjects performed at least six trials of each type of STS movement. Accelerometer signals from the trunk and thigh in the sagittal direction were decomposed using kinematic data obtained from an opto-electronic device. Each acceleration signal was decomposed into gravitational and inertial components, and the inertial component of the trunk was subsequently decomposed into rotational and translational components. The accelerometer signals could be reliably reconstructed: mean normalised root mean square (RMS) trunk: 6.5% (range 3-12%), mean RMS thigh: 3% (range 2-5%). The accelerometric signals were highly characteristic and repeatable. The influence of the inertial component was significant, especially on the timing of the specific event of maximum trunk flexion in the accelerometer signal. The effect of inertia was larger in the trunk signal than in the thigh signal and increased with higher speeds. The study provides insight into the acceleration signal, its components and the influence of the type of STS movement and supports its use in STS movement analysis. [ABSTRACT FROM AUTHOR]

Verhave JC, Hillege HL, Burgerhof JGM, Janssen WMT, Gansevoort RT, Navis GJ, de Zeeuw D, de Jong PE for the PREVEND study group (Groningen University Institute of Drug Exploration (GUIDE), Groningen, The Netherlands). Sodium intake affects urinary albumin excretion especially in overweight subjects.J Intern Med2004;256: 324–330.To examine the relationship between sodium intake and urinary albumin excretion, being an established risk marker for later cardiovascular morbidity and mortality.Cross-sectional cohort study using linear regression analysis.University hospital outpatient clinic.A cohort drawn from the general population, consisting of 7850 subjects 28–75 years of age, all inhabitants of the city of Groningen, the Netherlands. The cohort is enriched for the presence of subjects with elevated urinary albumin concentration.The results show a positive relationship between dietary sodium intake and urinary albumin excretion. The association was independent of other cardiovascular risk factors (such as sex, age, blood pressure, body mass index (BMI), waist-to-hip ratio, serum cholesterol, plasma glucose and smoking) and other food constituents (calcium, potassium and protein). The relationship between sodium intake and urinary albumin excretion was steeper in subjects with a higher BMI compared with a lower BMI.Sodium intake is positively related to urinary albumin excretion. This relation is more pronounced in subjects with a higher BMI. These results suggest that high sodium intake may unfavourably influences cardiovascular prognosis especially in overweight and obese subjects. [ABSTRACT FROM AUTHOR]

Background: Smoking induces albuminuria and accelerates progression to renal failure in persons with diabetes, but little is known about the relation between smoking and renal function in nondiabetic persons.Objective: To investigate whether smoking is related to albuminuria and abnormal renal function in nondiabetic persons.Design: Cross-sectional study.Setting: Groningen, The Netherlands.Participants: 7476 participants in the PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study.Measurements: Microalbuminuria and high normal albuminuria were defined as urinary albumin excretion of 30 to 300 mg/24 h and 15 to 30 mg/24 h, respectively. Elevated or decreased glomerular filtration rate (GFR) was defined as a creatinine clearance that exceeded or was less than two times the standard deviation of the mean value in nondiabetic, nonsmoking participants who had an albumin excretion of 0 to 15 mg/24 h, adjusted for age and sex.Results: Current smokers had a higher median albumin excretion than nonsmokers and were more likely to have microalbuminuria and high normal albuminuria with elevated or decreased GFR. After adjustment for several potential confounding factors, persons who smoked 20 or fewer cigarettes/d and persons who smoked more than 20 cigarettes/d, respectively, showed a dose-dependent association between smoking and high normal albuminuria (relative risk, 1.33 [95% CI, 1.10 to 1.61] and 1.98 [CI, 1.49 to 2.64]), microalbuminuria (relative risk, 1.92 [CI, 1.54 to 2.39] and 2.15 [CI, 1.52 to 3.03]), elevated GFR (relative risk, 1. 82 [CI, 1.31 to 2.53] and 1.84 [CI, 1.12 to 3.02]), and decreased GFR (relative risk, 1.53 [CI, 1.04 to 2.24] and 1.83 [CI, 1.05 to 3. 20]), respectively. Quitting smoking was associated only with microalbuminuria.Conclusions: Smoking is associated with albuminuria and abnormal renal function. However, these associations are less pronounced or absent in former smokers. [ABSTRACT FROM AUTHOR]

Background A proportion of candidates for high-dose chemotherapy with autologous PBPC support (HDC-PBPCS) will not provide an adequate PBPC yield from their first mobilization. The value of re-mobilization and the best regimen for re-mobilization in these patients is unclear. Methods: In 23 patients who failed to provide ≥ 3 × 10[sup 6] CD34[sup +] cells/kg after their first mobilization, PBPC were re-mobilized using a regimen of simultaneous administration of G-CSF and GM-CSF (10 μg/kg/day each) with leukaphereses (LP) starting Day 4 or 5 of CSF administration. Yields of WBC/kg, MNC/kg and CD34[sup +] cells/kg/L of processed blood total CD34[sup +] were compared between the first and second mobilization in each patient. The ability of the combined yield from the two mobilizations to achieve the desired threshold PBPC yield and the tolerability of the re-mobilization were determined. Results: The re-mobilization regimen was well-tolerated and no patient discontinued the regimen because of toxicity. Median collected WBC/kg/L (1.37 × 10[sup 7] versus 2.62 × 10[sup 7], p = 0.0065), MNC/kg/L (0.77 × 10[sup 7] versus 1.97 × 10[sup 7], p = 0.0003), CD34[sup +]cells/kg/L (1.64 × 10[sup 7] versus 4.18 × 10[sup 7], p = 0.001) were significantly higher after the second mobilization (G-CSF/GM-CSF combination). Percentage of CD34[sup +] cells in the leukapheresis was also significantly higher after the second mobilization (median 0.104% versus 0.195%, p = 0.036). Twelve of 22 patients achieved the target PBPC dose (> 3 × 10[sup 6]/CD34[sup +] cells/kg) after two mobilizations (six patients achieved the target from the second mobilization alone). A further eight underwent HDC-PBPCS without achieving the target PBPC dose. These patients experienced a significant delay in neutrophil and platelet engraftment when compared with those patients achieving the target dose. Discussion: This study demonstrates that the combination of G-CSF and GM-CSF is an effective and tolerable method for re-mobilization of PBPC in patients who fail to provide an adequate yield from their first mobilization. [ABSTRACT FROM AUTHOR]

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