[Lithium therapy in patients with mild mental retardation]. / Lithium bij patiënten met een lichte verstandelijke beperking.

In the psychiatric treatment of patients with mild learning disabilities or borderline intellectual functioning, signs and symptoms of psychiatric disorders are sometimes misinterpreted as behaviour that reflects problems that are known to patients with mental retardation. We report on two case studies in which lithium therapy made a substantial contribution to (partial) recovery. One patient had bipolar disorder and the other had a major depressive disorder combined with suicidal behaviour. Each patient also had a mild learning disability or borderline intellectual functioning.

[Diagnosing psychiatric disorders in people with (very) mild intellectual disabilities]. / Diagnostiek van psychiatrische stoornissen bij mensen met een (zeer) lichte verstandelijke beperking.

BACKGROUND: There is a good chance that you, as a psychiatrist, will come in to contact with patients who have a borderline or mild intellectual disability (50 > iq < 85). Referral to specialised care is not always an option and may not always be necessary. However, diagnosing psychiatric disorders in these patients can present challenges. AIM: To increase our knowledge about the diagnosing of psychiatric disorders in people with borderline or mild intellectual disabilities. METHOD: In this article we describe some key considerations in making a diagnosis or a differential diagnosis of psychiatric disorders in people with an intellectual disability. RESULTS/ In the differential diagnosis of psychiatric symptoms and behavioral problems in persons with a RESULTS/CONCLUSION: borderline or mild intellectual disability, one needs to take into account the patient's cognitive and social emotional level and any possible underlying somatic conditions; in addition, one must search for the cause of the intellectual disability paying attention to the context and the facilities offered by the care system.

The impact of the COVID-19 pandemic on rates of adolescents receiving psychopharmacological medication in Austria.

BACKGROUND: The COVID-19 pandemic has impacted many aspects of everyday life, including the (mental) healthcare system. An increase in depression and anxiety symptoms has been reported worldwide, and is particularly pronounced in females and young people. We aimed to evaluate changes in prescription rates for psychopharmacological medication, which is often used to treat depression and anxiety. METHOD: Based on data from the Austrian public health insurance institutions, we conducted an interrupted time series analysis of antidepressants and antipsychotics, comparing prescription rate developments before and throughout the COVID-19 pandemic (2013 to 2021), with a special focus on adolescents (10-19 years) in comparison to the general population. Data were based on all public prescriptions in the outpatient sector nationwide. Age- and sex-stratified time-series models were fitted to the pre-COVID period (first quarter (Q1) of 2013 to second quarter (Q2) of 2020). These were used to generate forecasts for the period from the third quarter (Q3) of 2020 to the fourth quarter (Q4) of 2021, which were subsequently compared to observed developments in order to assess significant deviations from the forecasted development paths. RESULTS: For the majority of the evaluated period, we found a significant excess of antidepressant prescriptions among both male and female adolescents (10-14 and 15-19 years) compared to the forecasted development path, while the general population was mostly within 97.5% confidence intervals of the forecasts. Regarding antipsychotics, the interrupted time series analysis revealed a significant excess in the group of female adolescents in almost all quarters, which was especially pronounced in the 15-19 age group. Prescription rates of antipsychotics in the general population only showed a significant excess in two quarters. CONCLUSION: Increased rates of adolescents receiving psychopharmacological treatment echo the epidemiological trends of an increase in depression and anxiety symptoms reported in the literature. This increase is especially pronounced in female adolescents.

A systematic review of delays in seeking medical attention after transient ischaemic attack.

BACKGROUND: Prompt assessment and investigation of transient ischaemic attack (TIA) followed by early initiation of secondary prevention is effective in reducing recurrent stroke. Nevertheless, many patients are slow to seek medical advice after TIA. A systematic review was undertaken to examine potential factors associated with delay in seeking medical review after TIA. METHODS: The electronic databases MEDLINE, EMBASE, and Science Citation Index were searched for observational studies assessing patient delay in presentation after TIA. The search was restricted to studies published between December 1995 and September 2008. RESULTS: The electronic search yielded nine studies with data on presentation delay in patients with TIA; variations existed in study size, population and methodology. One study included patients with TIA only (n = 241), whereas the remaining eight studies recruited both stroke and TIA patients. Overall, TIA patients (n = 821) made up only a small proportion of the total number of patients in this analysis (n = 3,202). Length of delay varied greatly across all studies. In most studies, patients with TIA who attended an emergency department arrived there within hours. Where patients first presented to their general practitioner, 50% attended within 24 hours whereas 25% waited 2 days or more. Recognition of symptoms as stroke/TIA did not reduce the delay. CONCLUSIONS: The majority of delay in seeking assessment after TIA is due to a lack of response by the patient-many patients do not recognise the symptoms of stroke/TIA, and even when they do, many fail to seek emergency medical attention. The public needs educating on the importance of contacting the emergency medical services or attending an emergency department immediately after TIA.

Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene.

The human Dubin-Johnson syndrome and its animal model, the TR(-) rat, are characterized by a chronic conjugated hyperbilirubinemia. TR(-) rats are defective in the canalicular multispecific organic anion transporter (cMOAT), which mediates hepatobiliary excretion of numerous organic anions. The complementary DNA for rat cmoat, a homolog of the human multidrug resistance gene (hMRP1), was isolated and shown to be expressed in the canalicular membrane of hepatocytes. In the TR(-) rat, a single-nucleotide deletion in this gene resulted in a reduced messenger RNA level and absence of the protein. It is likely that this mutation accounts for the TR(-) phenotype.

Effects of reciprocal treatment with estrogen and estrogen plus parathyroid hormone on bone structure and strength in ovariectomized rats.

Intermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogen-deficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 micrograms/kg per day of rPTH(1-34) plus 15 micrograms/kg per day of 17 beta-estradiol or 17 beta-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis.

Coupling of mitotic chromosome tethering and replication competence in epstein-barr virus-based plasmids.

The Epstein-Barr virus (EBV) replicates once per cell cycle and segregates with high efficiency yet does not encode the enzymes needed for DNA replication or the proteins required to contact mitotic spindles. The virus-encoded EBNA-1 (EBV nuclear antigen 1) and latent replication origin (oriP) are required for both replication and segregation. We developed a sensitive and specific fluorescent labeling strategy to analyze the interactions of both EBNA-1 with viral episomes and viral episomes with host chromosomes. This enabled investigation of the hypothesis that replication and chromosome tethering are linked through the EBNA-1 protein. We show that deleting EBNA-1 or oriP disrupts mitotic chromosome tethering but removing the dyad symmetry element of oriP does not. Microscopic and biochemical approaches demonstrated that an EBNA-1 mutant lacking residues 16 to 372 bound to oriP plasmids but did not support their mitotic chromosome association and that the mutant lost the ability of wild-type EBNA-1 to associate with interphase chromatin. Importantly, the transient-replication abilities of various mutant forms of EBV plasmids, including the mutant form with the EBNA-1 internal deletion, correlated directly with their chromosome-tethering abilities. These data lead us to propose that EBNA-1 recruits oriP-containing plasmids into chromatin subdomains in interphase nuclei to both engage the host replication machinery and enable the plasmids to adhere to host chromosomes to increase their segregation efficiency.

Binding and degradation of tissue-type plasminogen activator by the human hepatoma cell line Hep G2.

In this study, binding and degradation of tissue-type plasminogen activator (t-PA) by the human hepatoma cell line Hep G2 was investigated. Binding at 4 degrees C was time-dependent and reached a maximum after ca. 2 hours. Scatchard analysis of saturation experiments showed about 170,000 high affinity binding sites for t-PA per cell with an apparent Kd of 90 nM. These binding sites were calcium-dependent. Part of the binding to the hepatoma cells was non-saturable, owing to a large amount of low affinity binding sites which are at least partially located on the extracellular matrix of the cells. Competition with mannose- and galactose-terminated glycoproteins had no effect on total binding of 125I-t-PA. Degradation products of 125I-t-PA were found in the supernatant after a short lag phase and then increased linearly for at least 5 hours at 37 degrees C. Degradation could be inhibited by chloroquine, NH4Cl and NaN3. We conclude that the human hepatoma cell line Hep G2 has a specific binding mechanism for t-PA which is not mediated by known carbohydrate receptor systems. Binding is followed by cellular uptake and degradation in the lysosomes.

Characterization of the interaction of a complex of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 with rat liver cells.

The present study was undertaken in order to determine the recognition site for tissue-type plasminogen activator-plasminogen activator inhibitor type 1 [t-PA-PAI-1] complexes in rat liver in vivo and in vitro. After intravenous injection into rats t-PA-PAI-1 complexes were rapidly removed from the plasma and the liver took up 80% of the injected dose. Within the liver parenchymal and endothelial liver cells contributed mainly to the uptake of t-PA-PAI-1, and were responsible for 62% and 24% of the liver uptake, respectively. The interaction of t-PA-PAI-1 with isolated rat parenchymal liver cells was of high affinity (Kd 17 nM). A well-known antagonist of the alpha 2-macroglobulin receptor (alpha 2MR/low-density lipoprotein receptor-related protein (LRP), GST-39kDa protein (GST-39kDaP) efficiently inhibited the binding (IC50 0.7 nM) of t-PA-PAI-1 to rat parenchymal liver cells. The interaction of t-PA-PAI-1 with LRP on rat parenchymal liver cells was not Ca2(+)-dependent and is most probably mediated by a specific determinant on PAI-1, since an anti-PAI-1 monoclonal antibody inhibited the binding of t-PA-PAI-1, where as free t-PA did not. The binding of t-PA-PAI-1 to rat hepatocytes could not be inhibited by a complex of plasmin and alpha 2-antiplasmin nor by various other ligands of LRP like beta-VLDL and lactoferrin. Binding of t-PA-PAI-1 to rat parenchymal liver cells was followed by internalization and subsequent degradation in the lysosomal compartment. It is concluded that parenchymal and endothelial liver cells mediate the removal of t-PA-PAI-1 complexes from the circulation. LRP on rat parenchymal liver cells is responsible for the uptake and degradation of t-PA-PAI-1 and may therefore be important for the regulation of the t-PA levels in the circulation.

Evidence for different sources of stress-generated potentials in wet and dry bone.

Physiologically moist bone and dry bone behave differently when tested for electrical response to cantilever bending. To characterize this difference more precisely, voltages were generated in the same specimen in each of the two states via the same testing procedure--changing the electrode-to-force distance by moving the electrodes and holding the force position constant. In the dry state, a non-systematic pattern of voltages versus electrode position was generated. In the wet state, a linear relationship was found. Furthermore, the sign of the concave positive regions reversed to concave negative on wetting the specimen. The implication is that different electromechanical transduction mechanisms are involved in the wet and dry cases. The dominant mechanism in the wet case is taken to be the streaming potential rather than piezoelectricity.

Streaming potentials in chemically modified bone.

Direct streaming experiments with no significant mechanical deformation have been performed to determine the constituent or constituents of bovine tibia mainly responsible for the production of streaming potentials. Following the approach of Frank and Grodzinsky (5), selective removal of either main constituent--collagen or hydroxyapatite--of the tissue was performed by chemical means, and the streaming potential was remeasured. Demineralized samples were prepared by soaking in formic acid/sodium citrate, and anorganic samples were prepared by boiling and also by sodium hypochlorite treatment. Demineralized samples demonstrated zeta potentials close to those of whole bone samples, whereas anorganic samples had much smaller zeta potentials. Collagen rather than hydroxyapatite mineral is therefore implicated as the constituent of whole bone dominating the streaming potential, in agreement with the observation that collagenous tissues containing no mineral phase, i.e., tendon and cartilage, also exhibit streaming potentials. No sign change was observed in whole bone at high NaCl concentration in solutions containing calcium or at low pH. Although the sign of the signal for anorganic bone could be reversed by the addition of Ca2+ or PO4(3+) to the test solutions, the sign of the signal in neither whole bone nor demineralized bone could be so affected. Sign changes in whole bone were observed only with solutions containing basic organic molecules, e.g., protamine sulphates.

Transcortical streaming potentials are generated by circulatory pressure gradients in living canine tibia.

Electrical potentials associated with the pulse pressure have been observed in a canine tibia model in vivo. As the medullary pressure rises during pulsing, the periosteal bone surface becomes positive with respect to the endosteal surface. This pattern is consistent with streaming potentials generated by outward flow of fluid through bone with a negatively charged matrix (negative zeta potential). Both the medullary pressure and electric potential oscillations are halted by occlusion of the femoral artery. Furthermore, systemic administration of epinephrine decreases the amplitude of the medullary pressure and the electric potential by the same fraction. Streaming potentials generated by blood flow are distinct from those generated by mechanical deformation and may have additional significance in relation to fracture healing and/or etiology of osteoporosis.

A comparative analysis of streaming potentials in vivo and in vitro.

Streaming potentials (SPs) measured in vivo at a specific site on intact cortical bone (canine tibia) have been compared with measurements from the same site in vitro, tested as an excised bone strip soaked in Hank's balanced salt solution. The amplitude of SPs per periosteal strain in vitro was larger in 13 tibias than in vivo (by an average x6.5 at 1 Hz), but values per transcortical strain difference were similar. In vitro, SP magnitudes rose more sharply to an asymptotic value as a function of bending frequency than did in vivo signals, possibly because of a difference in the internal state of canaliculi and/or Haversian systems. Similarly, SP response to step-loading decreased to zero more slowly with time in vitro than in vivo. Difficulties encountered in preliminary measurements due to electrical shunting through electrolyte and soft tissues suggest the need for caution in using both in vivo and in vitro SP measurements to extrapolate to electric field strengths on the cellular level.

Streaming potential measurements at low ionic concentrations reflect bone microstructure.

Streaming potentials (SPs) have been proposed as one transduction pathway for mechanically driven bone remodeling. The fluid spaces in which SPs are generated will determine, in part, the structural information that they can provide to bone cells. Streaming potential measurements across cortical bone strips soaked in a range of saline concentrations were used to estimate the mean radii of fluid spaces that contribute to generation of electrokinetic fields. Using a cylindrical pore model, a pore radius of less than 200 A fit SP magnitude as a function of concentration. This pore size was shown to be consistent with estimates obtained from data reported earlier for SP as a function of concentration using a non-specific model, but was smaller than previously reported estimates for pore radius. A pore size in this range indicates that flow either in bone microporosity, or canaliculi that are substantially occluded by cellular material, must generate streaming potentials. Further, the fact that such small pores generate SPs in bone indicates that SPs could provide information regarding local matrix structure to bone cells.

An improved design of electrodes for measurement of streaming potentials on wet bone in vitro and in vivo.

Streaming potentials are generated by mechanical stress in wet bone and may constitute a control mechanism for bone remodeling. Measurement of streaming potentials in bone has attracted considerable effort in past years but quantitative studies have been hampered by relatively poor repeatability when using Ag.AgCl electrodes which contact bone via a wick moistened with electrolyte. Improvement now has been achieved with an electrode design that limits the specific area of contact of an agar/salt bridge by means of a silastic seal, thus permitting the same equipotential surface to be contacted for each set of measurements. This reduces variations caused by bone structure and impedance, and facilitates quantitative comparisons of the response of bone samples to selected variables. The new design also permits considerable qualitative improvement in recordings made from bone during locomotor function in experimental animals in vivo.

Skeletal cell stresses and bone adaptation.

There is no tissue in which mechanical stresses have been studied in more detail than the skeletal system, this focus arising primarily because bone plays a clear structural role in the body. However, the hypothesis that the skeleton represents an optimally designed structure has contributed remarkably little to our understanding of the development and adaptive capabilities of bone tissue. Recent investigations on the consequences of mechanical, hydrostatic, and electrical stresses on the cells of bone tissue have served to redirect the discussion of bone modeling and remodeling processes. These studies have refocused attention on the importance of chronic low-level dynamic stresses in mediating the physiologic response of bone tissue. Important recent observations suggest that an approach premised on the self-organizational properties of bone tissue may lead to significant improvements in our understanding and control of bone morphologic development, adaptation, and healing.

Does bone perfusion/reperfusion initiate bone remodeling and the stress fracture syndrome?

Stress fractures have been proposed to arise from repetitive activity of training inducing an accumulation of microfractures in locations of peak strain. However, stress fractures most often occur long before accumulation of material damage could occur; they occur in cortical locations of low, not high, strain; and intracortical osteopenia precedes any evidence of micro-cracks. We propose that this lesion arises from a focal remodeling response to site-specific changes in bone perfusion during redundant axial loading of appendicular bones. Intramedullary pressures significantly exceeding peak arterial pressure are generated by strenuous exercise and, if the exercise is maintained, the bone tissue can suffer from ischemia caused by reduced blood flow into the medullary canal and hence to the inner two-thirds of the cortex. Site specificity is caused by the lack, in certain regions of the cortex, of compensating matrix-consolidation-driven fluid flow which brings nutrients from the periosteal surface to portions of the cortex. Upon cessation of the exercise, re-flow of fresh blood into the vasculature leads to reperfusion injury, causing an extended no-flow or reduced flow to that portion of the bone most strongly denied perfusion during the exercise. This leads to a cell-stress-initiated remodeling which ultimately weakens the bone, predisposing it to fracture.

Characterization of rat exploratory behavior using the exploration box test.

A method to measure various aspects of exploratory behavior was further characterized using standard pharmacological treatments known to induce anxiety, or anxiolysis, or locomotor activation. FG 7142, an anxiogenic beta-carboline, induced a dose-dependent reduction in the rat exploratory behavior. A single FG 7142 (20 mg/kg) treatment before behavioral testing had a carry-over effect on rats' behavioral performance on the two subsequent days. When FG 7142 (20 mg/kg) was administered during five consecutive days before behavioral testing, its anxiogenic-like effect first deepened, but waned off by the fifth session. Diazepam at the dose of 0.5 mg/kg had no effect of its own, but blocked the anxiogenic-like effect of FG 7142 (10 mg/kg) treatment. At a higher dose (1 mg/kg), diazepam treatment reduced exploratory behavior, but this effect was not carried over to the drug-free sessions on the subsequent day. Buspirone and gepirone (both 1 mg/kg), the 5-HT1A receptor agonists, had no effect. D-Amphetamine, a locomotion-enhancing drug which has anxiogenic-like properties in several tests of exploratory behavior, increased the activity of rats at the dose of 0.5 mg/kg, but at the dose of 1 mg/kg the only effect was a reduction in the number of rearings: this effect was not carried over to the subsequent retest. On the basis of the results described in this article and elsewhere, we suggest that this technique can be useful for separating a true anxiogenic drug from other compounds which influence exploratory activity.