Empirical evidence for definitions of episode, remission, recovery, relapse and recurrence in depression: a systematic review.

AIMS.: For the past quarter of a century, Frank et al.'s (1991) consensus-based definitions of major depressive disorder (MDD) episode, remission, recovery, relapse and recurrence have been the paramount driving forces for consistency in MDD research as well as in clinical practice. This study aims to review the evidence for the empirical validation of Frank et al.'s proposed concept definitions and to discuss evidence-based modifications. METHODS.: A literature search of Web of Science and PubMed from 1/1/1991 to 08/30/2017 identified all publications which referenced Frank et al.'s request for definition validation. Publications with data relevant for validation were included and checked for referencing other studies providing such data. RESULTS.: A total of 56 studies involving 39 315 subjects were included, mainly presenting data to validate the severity and duration thresholds for defining remission and recovery. Most studies indicated that the severity threshold for defining remission should decrease. Additionally, specific duration thresholds to separate remission from recovery did not add any predictive value to the notion that increased remission duration alleviates the risk of reoccurrence of depressive symptoms. Only limited data were available to validate the severity and duration criteria for defining a depressive episode. CONCLUSIONS.: Remission can best be defined as a less symptomatic state than previously assumed (Hamilton Rating Scale for Depression, 17-item version (HAMD-17) ⩽4 instead of ⩽7), without applying a duration criterion. Duration thresholds to separate remission from recovery are not meaningful. The minimal duration of depressive symptoms to define a depressive episode should be longer than 2 weeks, although further studies are required to recommend an exact duration threshold. These results are relevant for researchers and clinicians aiming to use evidence-based depression outcomes.

Will you still need me, will you still feed me when I'm 64? The health impact of caregiving to one's spouse.

Informal care may substitute for formal long-term care that is often publicly funded or subsidized. The costs of informal caregiving are borne by the caregiver and may consist of worse health outcomes and, if the caregiver has not retired, worse labor market outcomes. We estimate the impact of providing informal care to one's partner on the caregiver's health using data from the Survey of Health, Ageing, and Retirement in Europe. We use statistical matching to deal with selection bias and endogeneity. We find that in the short run caregiving has a substantial effect on the health of caregivers and, for female caregivers, on their health care use. These effects should be taken into account when comparing the costs and benefits of formal and informal care provision. The health effects may, however, be short-lived, as we do not find any evidence that they persist after 4 or 7 years.

Real-life use of Rivaroxaban in the Netherlands: data from the Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation (XANTUS) registry.

BACKGROUND: The Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation (XANTUS) registry investigated the safety and efficacy of the factor Xa inhibitor rivaroxaban. We studied the Dutch XANTUS cohort to a ssess drug safety and prescription patterns in the Netherlands. METHODS: The XANTUS registry was designed as a European prospective, observational study among patients with non-valvular atrial fibrillation. Major bleeding and all-cause mortality were assessed every three months during a 1-year follow-up period. In this Dutch sub-cohort we were also specifically interested in dosing regimens and the incidence and reasons for temporary or permanent discontinuation. RESULTS: Patients (n = 899) had a mean age of 69 (SD ± 9) years and 64.8% were male. The median CHA2DS2-VASc score was 2 (IQR 2-4) and the median HAS-BLED score was 2 (IQR 1-2). Major bleeding occurred in 19 patients (2.4 per 100 patient-years) and 8 patients (1.0 per 100 patient-years) died during the 1­year follow-up period. According to renal function, label-discordant dosing was observed in 48 (8.3%) patients. Finally, 124 patients (13.8%) reported a temporary interruption of rivaroxaban treatment and 11.8% switched to another oral anticoagulant therapy after permanent discontinuation of rivaroxaban. CONCLUSION: In the Dutch subset of the XANTUS registry, we observed low rates of major bleeding and label-discordant dosing and high persistence rates during one year of follow-up in patients receiving rivaroxaban in routine clinical practice. However, documenting the motivation of novel oral anticoagulant (NOAC) type and dose is essential to study label-discordant prescription, a potential safety paradox and identify patient characteristics to optimise NOAC use and adherence.

The supercoiling state of DNA determines the handedness of both H3 and CENP-A nucleosomes.

Nucleosomes form the unit structure of the genome in eukaryotes, thereby constituting a fundamental tenet of chromatin biology. In canonical nucleosomes, DNA wraps around the histone octamer in a left-handed toroidal ramp. Here, in single-molecule magnetic tweezers studies of chaperone-assisted nucleosome assembly, we show that the handedness of the DNA wrapping around the nucleosome core is intrinsically ambidextrous, and depends on the pre-assembly supercoiling state of the DNA, i.e., it is not uniquely determined by the octameric histone core. Nucleosomes assembled onto negatively supercoiled DNA are found to exhibit a left-handed conformation, whereas assembly onto positively supercoiled DNA results in right-handed nucleosomes. This intrinsic flexibility to adopt both chiralities is observed both for canonical H3 nucleosomes, and for centromere-specific variant CENP-A nucleosomes. These data support recent advances suggesting an intrinsic adaptability of the nucleosome, and provide insights into how nucleosomes might rapidly re-assemble after cellular processes that generate positive supercoiling in vivo.

[Periprosthetic Acetabulum Fractures]. / Periprothetische Azetabulumfrakturen.

In contrast to periprosthetic fractures of the femur, periprosthetic fractures of the acetabulum are rare complications - both primary fractures and fractures in revision surgery. This topic is largely under-reported in the literature; there are a few case reports and no long term results. Due to an increase in life expectancy, the level of patients' activity and the number of primary joint replacements, one has to expect a rise in periprosthetic complications in general and periprosthetic acetabular fractures in particular. This kind of fracture can be intra-, peri- or postoperative. Intraoperative fractures are especially associated with insertion of cementless press-fit acetabular components or revision surgery. Postoperative periprosthetic fractures of the acetabulum are usually related to osteolysis, for example, due to polyethylene wear. There are also traumatic fractures and fractures missed intraoperatively that lead to some kind of insufficiency fracture. Periprosthetic fractures of the acetabulum are treated conservatively if the implant is stable and the fracture is not dislocated. If surgery is needed, there are many possible different surgical techniques and challenging approaches. That is why periprosthetic fractures of the acetabulum should be treated by experts in pelvic surgery as well as revision arthroplasty and the features specific to the patient, fracture and prosthetic must always be considered.

Loss of spatial organization and destruction of the pericellular matrix in early osteoarthritis in vivo and in a novel in vitro methodology.

OBJECTIVES: Current repair procedures for articular cartilage (AC) cannot restore the tissue's original form and function because neither changes in its architectural blueprint throughout life nor the respective biological understanding is fully available. We asked whether two unique elements of human cartilage architecture, the chondrocyte-surrounding pericellular matrix (PCM) and the superficial chondrocyte spatial organization (SCSO) beneath the articular surface (AS) are congenital, stable or dynamic throughout life. We hypothesized that inducing chondrocyte proliferation in vitro impairs organization and PCM and induces an advanced osteoarthritis (OA)-like structural phenotype of human cartilage. METHODS: We recorded propidium-iodine-stained fetal and adult cartilage explants, arranged stages of organization into a sequence, and created a lifetime-summarizing SCSO model. To replicate the OA-associated dynamics revealed by our model, and to test our hypothesis, we transduced specifically early OA-explants with hFGF-2 for inducing proliferation. The PCM was examined using immuno- and auto-fluorescence, multiphoton second-harmonic-generation (SHG), and scanning electron microscopy (SEM). RESULTS: Spatial organization evolved from fetal homogeneity, peaked with adult string-like arrangements, but was completely lost in OA. Loss of organization included PCM perforation (local micro-fibrillar collagen intensity decrease) and destruction [regional collagen type VI (CollVI) signal weakness or absence]. Importantly, both loss of organization and PCM destruction were successfully recapitulated in FGF-2-transduced explants. CONCLUSION: Induced proliferation of spatially characterized early OA-chondrocytes within standardized explants recapitulated the full range of loss of SCSO and PCM destruction, introducing a novel in vitro methodology. This methodology induces a structural phenotype of human cartilage that is similar to advanced OA and potentially of significance and utility.

A non-comparative phase II study of dose intensive chemotherapy with doxorubicin and ifosfamide followed by high dose ICE consolidation with PBSCT in non-resectable, high grade, adult type soft tissue sarcomas.

The objective was to determine the role of dose intensive induction chemotherapy in patients with soft tissue sarcomas (STS) that were considered unresectable. Treatment consisted of 2-3 cycles of doxorubicin (Dox) and ifosfamide (Ifo) followed by high dose chemotherapy with ifosfamide, carboplatin, etoposide (HD-ICE) plus peripheral blood stem cell transplantation (PBSCT). 30 out of 631 consecutive patients, median age 46 years (21-62), with high grade STS were included. 29 patients completed at least 2 cycles of Dox/Ifo. HD-ICE was withheld because of progressive disease (PD) in 5 patients, neurotoxicity in 6 cases, insufficient peripheral blood stem cell (PBSC) mobilization, complete remission (CR) and refusal in 1 patient each. HD-ICE was associated with non-haematological grade III toxicity including emesis, mucositis, fever, neurotoxicity, and transaminase level elevation. Two additional patients attained a partial response after HD-ICE. Overall, 24 of 30 (80%) patients underwent surgery, with complete tumor resections in 19 patients (63% of all patients, 79% of the operated subgroup); however, 2 of these required amputation. After a median follow up period of 50 months in surviving patients (range, 26-120), 5-year PFS and OS rates were 39% and 48%, respectively. Induction chemotherapy plus consolidation HD-ICE is generally feasible, but is associated with significant neurotoxicity. The advantage of HD-ICE over conventional dose chemotherapy plus external beam radiation therapy (EBRT) in non-resectable disease remains unproven.

Benzo[a]pyrene-induced transcriptomic responses in primary hepatocytes and in vivo liver: toxicokinetics is essential for in vivo-in vitro comparisons.

The traditional 2-year cancer bioassay needs replacement by more cost-effective and predictive tests. The use of toxicogenomics in an in vitro system may provide a more high-throughput method to investigate early alterations induced by carcinogens. Recently, the differential gene expression response in wild-type and cancer-prone Xpa (-/-) p53 (+/-) primary mouse hepatocytes after exposure to benzo[a]pyrene (B[a]P) revealed downregulation of cancer-related pathways in Xpa (-/-) p53 (+/-) hepatocytes only. Here, we investigated pathway regulation upon in vivo B[a]P exposure of wild-type and Xpa (-/-) p53 (+/-) mice. In vivo transcriptomics analysis revealed a limited gene expression response in mouse livers, but with a significant induction of DNA replication and apoptotic/anti-apoptotic cellular responses in Xpa (-/-) p53 (+/-) livers only. In order to be able to make a meaningful in vivo-in vitro comparison we estimated internal in vivo B[a]P concentrations using DNA adduct levels and physiologically based kinetic modeling. Based on these results, the in vitro concentration that corresponded best with the internal in vivo dose was chosen. Comparison of in vivo and in vitro data demonstrated similarities in transcriptomics response: xenobiotic metabolism, lipid metabolism and oxidative stress. However, we were unable to detect cancer-related pathways in either wild-type or Xpa (-/-) p53 (+/-) exposed livers, which were previously found to be induced by B[a]P in Xpa (-/-) p53 (+/-) primary hepatocytes. In conclusion, we showed parallels in gene expression responses between livers and primary hepatocytes upon exposure to equivalent concentrations of B[a]P. Furthermore, we recommend considering toxicokinetics when modeling a complex in vivo endpoint with in vitro models.

Deregulation of cancer-related pathways in primary hepatocytes derived from DNA repair-deficient Xpa-/-p53+/- mice upon exposure to benzo[a]pyrene.

The current method to predict carcinogenicity of chemicals or drugs is the chronic 2-year rodent bioassay, which has disadvantages in duration, animal use, and specificity. An attractive alternative is the DNA repair-deficient Xpa(-/-)p53(+/-) mouse model that is sensitive to both genotoxic and nongenotoxic carcinogens. A next step in alternative carcinogenicity testing is the development of reliable in vitro systems. We investigated the use of primary hepatocytes, isolated from wild-type (WT) and Xpa(-/-)p53(+/-) mice, in combination with transcriptome analyses for their usefulness to predict carcinogenic features of compounds. As a proof of principle, we studied the response of hepatocytes to the genotoxic carcinogen benzo[a]pyrene (B[a]P). Upon treatment, both WT and Xpa(-/-)p53(+/-) hepatocytes appeared to be metabolically active. However, Xpa(-/-)p53(+/-) hepatocytes were more sensitive than WT hepatocytes to B[a]P treatment in terms of cell survival. In B[a]P-treated WT hepatocytes, DNA repair and cell cycle control genes were transcriptionally activated. Xpa(-/-)p53(+/-) hepatocytes were more responsive to B[a]P exposure, resulting in the downregulation of cancer-related pathways. Deregulation of mitogen-activated protein kinase signaling seems to play an essential role in this and might be the underlying reason for the increased susceptibility of Xpa(-/-)p53(+/-) mice toward carcinogens. Our conclusion is that primary hepatocytes combined with transcriptomics are promising to identify the carcinogenic features of chemicals. Furthermore, these cells seem suitable to gain further insight into the molecular mechanisms of the increased sensitivity of Xpa(-/-)p53(+/-) mice toward both genotoxic and nongenotoxic carcinogens.

[Dutch Zoological Gardens (until 1940) in historical context]. / Nederlands Dierentuinen (tot 1940) in historische context.

The history of the zoological gardens is an example of transformation through the ages; it is one of the ways men are dealing with their enviroment. Through the ages there were six reasons to keep wild animals: (1) Religion; 2. Power and Richness; (3) To get acquainted with animals (from tropical regions); (4) Study and Education; (5) Amusement and (6) Preservation of the species. The first Dutch "zoos", of the Dukes of Guelders in the 14th and of the stadholders in the 19th century, can serve as examples of the will to demonstrate power and richness. The Amsterdam Zoological Garden, "Artis", the zoological gardens of Rotterdam and of The Hague were founded for reasons of study and/ or education. Burgers' Dierenpark (Arnhem), Ouwehand's Dierenpark (Rhenen), Dierenpark Emmen en Dierenpark Wassenaar originated as leisure activities of their owners.

Effects of allopurinol on plasma uric acid levels in normouricaemic and hyperuricaemic green iguanas (Iguana iguana).

A two-phase cross-over therapeutic study was performed with 19 green iguanas (Iguana iguana) maintained within a preferred optimum temperature range of 26 to 37 degrees C. During phase 1, they were fed a normal vegetarian diet and medicated orally with either allopurinol or a placebo control once a day for seven days. Uric acid concentrations, total protein, packed-cell volumes (pcv) and bodyweights were recorded from each lizard before and after treatment to determine the effects of allopurinol. In phase 2, after a 10-day washout period, the iguanas were fed a high protein diet to induce hyperuricaemia. Normo- and hyperuricaemic iguanas that received 24.2 (3.2) mg/kg allopurinol had significantly lower mean (sd) uric acid concentrations (100.3 [53.1] micromol/l) than the controls (159.3 [100.3] micromol/l). There were no detectable interactions between the doses of allopurinol or placebo, and the iguanas' diet, weight, pcv or total protein. The allopurinol was well tolerated, and there was no significant clinical, gross or histological evidence of hepatic or renal toxicity in the iguanas that received the drug. However, in the kidneys of the hyperuricaemic iguanas that did not receive allopurinol there were proliferative changes in the glomeruli and degeneration of tubular epithelia. Allopurinol given orally at 25 mg/kg daily is able to reduce plasma uric acid levels by 41 to 45 per cent, and is therefore recommended for the treatment of hyperuricaemia in the green iguana.

Inclusion body disease in snakes: a review and description of three cases in boa constrictors in Belgium.

Inclusion body disease, a fatal disorder in Boidae, is reviewed, and three cases in boa constrictors, the first reported cases in Belgium, are described. The snakes showed nervous signs, and numerous eosinophilic intracytoplasmic inclusions, which are considered to be characteristic of the disease, were found in the liver and pancreas. The disease is suspected to be caused by a retrovirus, but transmission electron microscopic examinations of several tissues from one of the snakes did not reveal particles with a typical retroviral morphology.

[Developmental delay in breastfed children due to inadequate diet of the mother]. / Ontwikkelingsachterstand bij borstgevoede kinderen door ontoereikend dieet van de moeder.

Two infant boys of 7 and 12 months respectively who presented with symptoms of failure to thrive and developmental delay were diagnosed with vitamin B12 deficiency. This deficiency is a rare condition in infants living in developed countries. It does occur, however, in infants who are breastfed by mothers with an inadequate diet. Both of the children studied were breastfed by vegetarian mothers. Following vitamin suppletion, both children showed signs of recovery. The importance of considering vitamin deficiencies in similar infants presenting with failure to thrive is emphasized. Moreover, maternal dietary habits in breastfed children should be checked. To prevent irreversible neurological damage, early recognition of any nutritional deficiencies is important.

Anomalous signal indicators in protein crystallography.

A Monte Carlo procedure is described that generates random structure factors with simulated errors corresponding to an X-ray data set of a protein of a specific size and given heavy-atom content. The simulated data set can be used to estimate Bijvoet ratios and figures of merit as obtained from SAD phasing routines and can be used to gauge the feasibility of solving a structure via the SAD method. In addition to being able to estimate results from phasing, the simulation allows the estimation of the correlation coefficient between |DeltaF|, the absolute Bijvoet amplitude difference, and FA, the structure-factor amplitude of the heavy-atom model. As this quantity is used in various substructure-solution routines, the estimate provides a rough estimate of the ease of substructure solution. Furthermore, the Monte Carlo procedure provides an easy way of estimating the number of significant Bijvoet intensity differences, denoted as the measurability, and is proposed as an intuitive measure of the quality of anomalous data.

[Causes, treatment and clinical outcome in infants admitted because of excessive crying to the paediatric department of the Isala clinics, Zwolle, the Netherlands, 1997/'03]. / Oorzaken, behandeling en beloop bij zuigelingen die vanwege excessiefhuilen waren opgenomen op de kinderafdeling van de Isala klinieken te Zwolle, 1997/'03.

OBJECTIVE: Evaluation of the strategy of admitting excessively crying infants after no improvement is seen following measures taken by the family physician. DESIGN: Retrospective. METHOD: By studying medical records, data were collected for all infants who were admitted to the paediatric department of the Isala clinics in Zwolle because of excessive crying in the period 1997/'03. Excessive crying here was defined as 'crying that was regarded by the parents as excessive', whereby strict time criteria did not have to be met. RESULTS: In the study period of 6.5 years, 88 children were admitted because of excessive crying: 51 boys and 37 girls, with an average age of 10 weeks (range: 0.5-40). Measures taken without success prior to referral included: hypoallergenic feeding in 51 cases (58%), alternative medical treatment in 18 (20%) and antacids in 9 (10%). In 3 patients (3%) a possible cause of the excessive crying was identified and improvement occurred after treatment: cow's milk allergy (n = 2) and recurrent respiratory tract infections caused by a humoral immunodeficiency (n = 1). Clinical indications for an underlying cause were present in another 8 patients but this could be neither confirmed nor excluded. In 77 patients (88%) the crying rapidly improved within a few days without a specific intervention. In most children, hypoallergenic feeding could be replaced by regular cow's milk formulas without any problems. After discharge, there were so re-admissions for excessive crying (11%). CONCLUSION: In the majority of infants admitted to hospital for excessive crying, no underlying cause was found and the crying rapidly improved within a few days without a specific intervention. We therefore recommend that excessively crying infants merely be observed clinically for several days. There is no indication for immediate diagnostic or therapeutic interventions. It is important, however, to counsel parents about their own anxiety and distress and the influence these may have on the infant's crying behaviour.

Modelling bound ligands in protein crystal structures.

Methods for automated identification and building of protein-bound ligands in electron-density maps are described. An error model of the geometrical features of the molecular structure of a ligand based on a lattice distribution of positional parameters is obtained via simulation and is used for the construction of an approximate likelihood scoring function. This scoring function combined with a graph-based search technique provides a flexible model-building scheme and its application shows promising initial results. Several ligands with sizes ranging from 9 to 44 non-H atoms have been identified in various X-ray structures and built in an automatic way using a minimal amount of prior stereochemical knowledge.

[Excessive crying in infants: a problem for both parents and children (only rarely caused by milk allergy)]. / Excessief huilen van zuigelingen: een probleem van kind én ouders (en slechts zelden veroorzaakt door koemelkallergie).

According to a systematic review published in 1998, hypoallergenic formula can be useful in treating infants who cry excessively. For this reason it is normal practice in the Netherlands to prescribe hypoallergenic formula for these infants. However, two of the three studies on which this systematic review was based were carried out in specialist paediatric allergy centres where there is a higher chance of encountering food allergy than in normal well-baby clinics. The third study was carried out in a well-baby clinic but only included babies who cried for more than 3 hours a day on more than 3 days per week. Experience with crying diaries has shown that by no means all babies who cry excessively according to their parents satisfy these criteria. It is not known if prescribing hypoallergenic formula is a useful intervention in infants whose parents report that they cry excessively. The tension and distress felt by the parents of infants who cry excessively are also important factors. In our opinion, support and guidance for the parents is a more effective treatment for excessive crying in infants than intervention with hypoallergenic formula.

The influence of positional errors on the Debye effects.

The relation between a Gaussian perturbation of the atomic positional parameters and the average squared structure-factor amplitude is presented. Using an error-dependent radial distance distribution of an atomic protein model, it can be shown that the Debye effects diminish exponentially as a function of increasing positional errors. These relations can be used to estimate the quality of an atomic model and the corresponding phases. The limiting case of equal atoms with an infinitely large coordinate error results in the classical Wilson model.

Distance distributions and electron-density characteristics of protein models.

The analytical expression for the distribution of an interatomic distance resulting from a known error-free distance and a Gaussian perturbation of the atomic coordinates is presented. This is used to estimate the coordinate error on the basis of known geometric features of protein models via the nearest-neighbour or the radial distance distribution. A simple relation is presented that describes the dependence of the map correlation on the positional error of the protein model, the resolution of the X-ray data and the overall atomic displacement parameter. The distribution of geometrical features and the relation between the map correlation and the positional error can be used in assisting the decision-making process during automated model-building procedures.