The general health status of newly arrived asylum seekers in Denmark.

AIMS: The number of asylum seekers in Europe is increasing and is likely to do so continuously due to conflicts, poverty and climate. Asylum seekers are exposed to many health risk factors related to their migration process and this study aimed to explore their general health status on arrival at an immigration country. METHODS: A retrospective study including 1907 general health assessments (GHAs) of adult asylum seekers arriving in Denmark between 1 September 2017 and 31 December 2019 was undertaken. The GHA is offered to all adult asylum seekers as part of the health-care reception programme. Only asylum seekers who attended the GHA within 1 month of their arrival in Denmark were included. Data comprised sociodemographic factors, health outcomes, and indication of exposure to trauma and torture. Data were described by absolute and relative frequencies, means and through regression analyses. RESULTS: The majority of asylum seekers were male (58.6%) of Middle Eastern origin with a mean age of 33.6 years (SD = 12.1). More than half (60.1%) of the participants had one or more physical health complaints, whereas mental health complaints were less frequent (25.0%). Asylum seekers, who had been exposed to trauma were more likely to have physical health complaints (OR 1.52, 95% CI 1.22;1.89) and to have symptoms of mental health problems (OR 12.71, 95% CI 8.76;18.45). These complaints were substantially elevated for survivors of torture. CONCLUSIONS: This relatively high prevalence of health complaints, both physical and mental, emphasises the necessity of providing appropriate and timely health care from the very beginning of the asylum process.

Lesions of the diagonal band of broca enhance drinking in the rat.

This study examined the role of the diagonal band of Broca (DBB) in drinking behaviour and vasopressin release. Adult male rats were anaesthetized (pentobarbital 50 mg/kg) and received DBB injections of either ibotenic acid (0.5 microl of 5 micro g/ microl) or vehicle (0.5 microl of phosphate-buffered saline). Although baseline drinking and urine output were not affected, drinking to 30% polyethylene glycol (MW 8000; 1 ml/100 g s.c.) and angiotensin II (0, 1.5 and 3.0 mg/kg s.c.) were significantly increased in ibotenic acid in phosphate-buffered saline (DBBX) rats. Drinking to hypertonic saline (0.9, 4 and 6%; 1 ml/100 g), and water deprivation were not significantly affected. DBBX rats had significantly lower basal heart rates than controls but the cardiovascular responses to infusions of angiotensin II (100 ng/kg/min i.v. for 45 min) were not affected. DBBX rats had significantly higher basal vasopressin, but angiotensin-stimulated vasopressin release was not significantly different. Although the DBB is not involved in basal water intake, it is involved in dipsogenic responses to hypovolemic stimuli and possibly basal autonomic function and basal vasopressin release.

NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II.

To stimulate transcriptional elongation of HIV-1 genes, the transactivator Tat recruits the positive transcription elongation factor b (P-TEFb) to the initiating RNA polymerase II (RNAPII). We found that the activation of transcription by RelA also depends on P-TEFb. Similar to Tat, RelA activated transcription when tethered to RNA. Moreover, TNF-alpha triggered the recruitment of P-TEFb to the NF-kappaB-regulated IL-8 gene. While the formation of the transcription preinitiation complex (PIC) remained unaffected, DRB, an inhibitor of P-TEFb, prevented RNAPII from elongating on the IL-8 gene. Remarkably, DRB inhibition sensitized cells to TNF-alpha-induced apoptosis. Thus, NF-kappaB requires P-TEFb to stimulate the elongation of transcription and P-TEFb plays an unexpected role in regulating apoptosis.

The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain.

Glucocorticoids repress NFkappaB-mediated activation of proinflammatory genes such as interleukin-8 (IL-8) and ICAM-1. Our experiments suggest that the glucocorticoid receptor (GR) confers this effect by associating through protein-protein interactions with NFkappaB bound at each of these genes. That is, we show that the GR zinc binding region (ZBR), which includes the DNA binding and dimerization functions of the receptor, binds directly to the dimerization domain of the RelA subunit of NFkappaB in vitro and that the ZBR is sufficient to associate with RelA bound at NFkappaB response elements in vivo. Moreover, we demonstrate in vivo and in vitro that GR does not disrupt DNA binding by NFkappaB. In transient transfections, we found that the GR ligand binding domain is essential for repression of NFkappaB but not for association with it and that GR can repress an NFkappaB derivative bearing a heterologous activation domain. We used chromatin immunoprecipitation assays in untransfected A549 cells to infer the mechanism by which the tethered GR represses NFkappaB-activated transcription. As expected, we found that the inflammatory signal TNFalpha stimulated preinitiation complex (PIC) assembly at the IL-8 and ICAM-1 promoters and that the largest subunit of RNA polymerase II (pol II) in those complexes became phosphorylated at serines 2 and 5 in its carboxy-terminal domain (CTD) heptapeptide repeats (YSPTSPS); these modifications are required for transcription initiation. Remarkably, GR did not inhibit PIC assembly under repressing conditions, but rather interfered with phosphorylation of serine 2 of the pol II CTD.

Hypothalamic A14 and A15 catecholamine cells provide the dopaminergic innervation to the supraoptic nucleus in rat: a combined retrograde tracer and immunohistochemical study.

This study investigated the origin of a dopaminergic innervation of the hypothalamic supraoptic nucleus. In pentobarbital-anaesthetized male Long-Evans rats, a transpharyngeal approach was used to inject a retrograde tracer, rhodamine latex microspheres, into the supraoptic nucleus. After 13-26 h survival under anaesthesia, animals were perfused transcardially, the brain sectioned and processed for tyrosine hydroxylase immunofluorescence, a marker for hypothalamic dopaminergic neurons. In six cases with injections restricted to the supraoptic nucleus, rhodamine-labelled microspheres were observed in a population of tyrosine hydroxylase-positive neurons located in the A15 cells below the anterior commissure (A15 dorsal) and above the optic chiasm (A15 ventral), and the dorsal and lateral periventricular A14 cell group. Occasional double-labelled cells were seen in the medial and lateral hypothalamus and bed nucleus of the stria terminalis, but rarely in other known dopaminergic cell groups, notably the ventral tegmental area (A10), zona incerta (A13) and substantia nigra. In support of a role for dopamine in neurohypophysial regulation, these observations indicate that the major dopaminergic input to magnocellular neurons in the hypothalamic supraoptic nucleus is derived from a relatively sparse population of neurons located in the A14 and A15 cell groups.

Inactivity of N229A thymidylate synthase due to water-mediated effects: isolating a late stage in methyl transfer.

Mutation of thymidylate synthase N229(177) to alanine results in an essentially inactive enzyme, yet it leads to formation of a stable ternary complex. The kinetics of N229(177)A show that kcat for Escherichia coli is reduced by 200-fold while the Km for dUMP is increased 200-fold and the Km for folate increased by tenfold versus the wild-type enzyme. The crystal structures of N229(177)A in complex with dUMP and CB3717, and in complex with dUMP alone are determined at 2.4 A, and 2.5 A resolution. These structures identify the covalently bound ternary complex and show how N229(177)A traps an intermediate, and so becomes inactive in a later step of the reaction. Since the smaller alanine side-chain at N229(177)A does not directly sterically impair binding of ligands, the structures implicate, and place quantitative limits on the involvement of the structured water network in the active site of thymidylate synthase in both catalysis and in determining the binding affinity for dUMP (in contrast, the N229(177)V mutation in Lactobacillus casei has minimal effect on activity).

Argon laser in difficult stapedotomy cases.

OBJECTIVE: The success and safety of argon lasers in stapedotomy surgery is now well documented. This study reviews results in problematic situations in which the argon laser may be of particular advantage to successful completion of the stapedotomy procedure. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective review of the author's most recent 200 stapedotomy cases was performed, identifying 32 patients who at surgery were either found to have a prolapsed dehiscent facial nerve (three cases), developed a floating footplate (eight cases), or were undergoing a revision stapedotomy (21 cases). Four-frequency, pure-tone average air and bone conduction thresholds were computed before and after surgery. Success was defined as closure of the air-bone gap to within 10 dB, while an air-bone gap within 20 dB was considered improvement. RESULTS: Successful closure of the air-bone gap was achieved in all eight patients with a mobilized footplate, in all three patients with a prolapsed dehiscent facial nerve, and in 43% of the patients undergoing a revision stapedotomy. The rate of improved air-bone gap in the revision cases was 62%. In one revision stapedotomy patient a decrease in speech discrimination occurred. Otherwise, there were no cases of sensorineural hearing loss. Neither intraoperative nor postoperative dizziness was reported by any patient, and all were discharged on an outpatient basis. CONCLUSION: The argon laser was found to be safe, effective, and a valuable adjunct for the difficult stapedotomy cases when unexpected obstacles such as a prolapsed dehiscent facial nerve or a mobilized footplate are encountered, as well as for the planned, more difficult revision cases.

D221 in thymidylate synthase controls conformation change, and thereby opening of the imidazolidine.

In thymidylate synthase (TS), the invariant residue Asp-221 provides the only side chain that hydrogen bonds to the pterin ring of the cofactor, 5,10-methylene-5,6,7,8-tetrahydrofolate. All mutants of D221 except cysteine abolish activity. We have determined the crystal structures of two ternary complexes of the Escherichia coli mutant D221N. In a complex with dUMP and the antifolate 10-propargyl-5,8-dideazafolate (CB3717), dUMP is covalently bound to the active site cysteine, as usual. CB3717, which has no imidazolidine ring, is also bound in the usual productive orientation, but is less ordered than in wild-type complexes. The side chain of Asn-221 still hydrogen bonds to N3 of the quinazoline ring of CB3717, which must be in the enol form. In contrast, the structure of D221N with 5-fluoro-dUMP and 5,10-methylene-5,6,7, 8-tetrahydrofolate shows the cofactor bound in two partially occupied, nonproductive binding sites. In both binding modes, the cofactor has a closed imidazolidine ring and adopts the solution conformation of the unbound cofactor. In one of the binding sites, the pterin ring is turned around such that Asn-221 hydrogen bonds to the unprotonated N1 instead of the protonated N3 of the cofactor. This orientation blocks the conformational change required for forming covalent ternary complexes. Taken together, the two crystal structures suggest that the hydrogen bond between the side chain of Asp-221 and N3 of the cofactor is most critical during the early steps of cofactor binding, where it enforces the correct orientation of the pterin ring. Proper orientation of the cofactor appears to be a prerequisite for opening the imidazolidine ring prior to formation of the covalent steady-state intermediate in catalysis.

Regulation of spontaneous phasic firing of rat supraoptic vasopressin neurones in vivo by glutamate receptors.

1. Vasopressin-secreting neurones in the rat hypothalamic supraoptic nucleus display patterned spontaneous phasic activity, which is apparently maintained in vivo through yet unidentified neurotransmitter system(s). The present investigation used extracellular recording techniques in anaesthetized Long-Evans rats to evaluate whether the neurotransmitter mechanism underlying phasic firing is provided via a family of ionotropic glutamate receptors. 2. N-Methyl-D-aspartate (NMDA) reliably evoked bursts of activity in twenty-seven of twenty-eight phasic neurones. Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate also elicited pronounced excitations in twenty-one of twenty-one and and fourteen of fifteen phasic cells, respectively. 3. A rapid blockade of on-going phasic activity was consistently induced following brief applications of both NMDA and non-NMDA receptor antagonists; extended application of antagonists resulted in prolonged silent periods, during which phasic activity failed to recur for minutes. Neither saline nor a cholecystokinin receptor antagonist influenced cell firing. 4. In contrast to putative vasopressin cells, application of NMDA receptor ligands did not affect the spontaneous activity in most putative oxytocin-secreting neurones, whereas kainate and AMPA potently excited seven of nine and four of five putative oxytocin cells, respectively. 5. These results imply that the maintenance of spontaneous phasic discharges in vivo in supraoptic vasopressin-secreting neurones requires tonic synaptic activation involving both NMDA and non-NMDA glutamate receptors. In putative oxytocin-secreting neurones, spontaneous firing appears to be predominantly regulated by non-NMDA receptors. Glutamatergic innervations may be in a unique position to influence the genesis of patterned electrical activity in supraoptic vasopressin neurones.

Perinuclear zone and diagonal band lesions enhance angiotensin responses of rat supraoptic neurons.

Sinoaortic denervation in the rat is associated with an increased sensitivity of vasopressin neurons in the supraoptic nucleus (SON) to peripheral angiotensin II (ANG II). Lesion studies have indicated that the diagonal band of Broca (DBB) and the perinuclear zone of the SON in the lateral hypothalamus (PNZ) are essential components in the central pathway for the baroreceptor inhibition of vasopressin SON neurons. The present study examined the effect of ibotenate lesions in either the DBB or the lateral hypothalamus, which includes the PNZ, on the responses of SON neurons to peripherally administered ANG II (500 pmol/kg ia). Extracellular recordings obtained from vasopressin SON neurons in pentobarbital-anesthetized rats indicate that DBB and PNZ lesions not only interrupted the baroreceptor-mediated inhibition of SON neurons but also significantly increased the excitatory effects of ANG II on putative vasopressin SON neurons. These results suggest that ibotenate lesions of the DBB and the lateral hypothalamus that include the PNZ affect the ANG II-induced activation of putative vasopressin SON neurons in a manner consistent with results obtained from baroreceptor-denervated rats.

GABA receptor mediation of median preoptic nucleus-evoked inhibition of supraoptic neurosecretory neurones in rat.

1. This study evaluated the influence of focal electrical and chemical microstimulation in the median preoptic nucleus (MnPO) on the excitability of putative vasopressin and oxytocin neurones recorded in the supraoptic nucleus of urethane- or pentobarbitone-anaesthetized rats. 2. In vasopressin neurones, single 1 Hz stimulation reduced the excitability of 120/139 cells. Trains of repetitive 5-30 Hz stimulation, or microinfusion of glutamate into the MnPO, similarly induced a cessation in spontaneous phasic or continuous firing in 17/18 and 17/20 vasopressin neurones, respectively. In 20/21 cells, locally applied bicuculline (100 microM) attenuated MnPO-evoked depressant responses whereas strychnine (100 microM) and timolol (20 microM) were without effect on 5/5 vasopressin neurones. In three cells, bicuculline applications were associated with marked increases in MnPO-evoked excitations. 3. In oxytocin neurones, single-pulse (1 Hz) electrical stimulation in MnPO evoked an increase in the excitability in 51/59 cells. However, in 6/7 oxytocin cells tested, glutamate microinfusions into MnPO induced prolonged suppression in firing. During trains of stimuli (5-30 Hz), 26/44 cells displayed an initial increase in firing associated with the first few impulses but this was then replaced by suppression of activity; another ten cells displayed excitation alone, and eight cells demonstrated only suppression. The depressant responses evoked during trains of MnPO stimulation were blocked by 100 microM bicuculline (6/6 cells tested) whereas strychnine was ineffective (2/2 cells tested). 4. These results suggest that the MnPO provides a mainly depressant influence on supraoptic vasopressin and oxytocin neurones, perhaps through the activation of postsynaptic GABAA receptors.

[Functional treatment of surgically treated empyema of the knee joint]. / Die funktionelle Behandlung des operierten Kniegelenkempyems.

Knee-joint empyema requires prompt surgical management. After debridement the joint needs to be irrigated for several days. Functional follow-up treatment with electromotive splints according to the CPM concept should begin soon after surgery. Follow-up examination of patients treated in this way for knee-joint empyema showed a protracted course with worse results for empyemas subsequent to arthrotomy, while joint infections after less severe injuries (skin lesions, puncture) healed successfully.

N-methyl-D-aspartate receptor antagonist ketamine selectively attenuates spontaneous phasic activity of supraoptic vasopressin neurons in vivo.

Supraoptic neurosecretory neurons express a prominent N-methyl-D-aspartate receptor system. Recent in vitro evidence reveals that N-methyl-D-aspartate receptor activation dramatically alters the spontaneous discharge patterns of supraoptic neurons. In this study we evaluate whether N-methyl-D-aspartate receptors in vivo contribute to the development of characteristic phasic discharge patterns displayed by vasopressin-secreting neurons. Intravenous administration of ketamine hydrochloride, a non-competitive N-methyl-D-aspartate receptor antagonist, was used to examine whether N-methyl-D-aspartate receptor blockade influences patterned spontaneous discharge observed in supraoptic neurosecretory neurons. Extracellular recordings were obtained from identified hypothalamic supraoptic neurons in pentobarbital-anaesthetized Long-Evans rats. Systemic administration of ketamine (< or = 1.5 mg/kg) potently suppressed spontaneous phasic discharge in 16/19 putative vasopressin-secreting cells. The ketamine-induced blockade was dose dependent, fully reversible and was associated with the complete blockade of activity evoked by local pressure application of N-methyl-D-aspartate, but not the activity evoked by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptor agonists (6/6 cells). Ketamine had no detectable effect on threshold or shape of antidromic action potentials. By comparison, the activity in 9/10 continuously active neurons (putative oxytocin-secreting) was unaffected by administration of identical doses of ketamine. These data suggest that N-methyl-D-aspartate receptors play an important role in regulating the onset and maintenance of spontaneous phasic activity patterns displayed by rat supraoptic vasopressin neurons in vivo.

Lateral hypothalamic lesions alter baroreceptor-evoked inhibition of rat supraoptic vasopressin neurones.

1. Previous electrophysiological studies on rat hypothalamic supraoptic nucleus neurones have demonstrated that both the activation of peripheral baroreceptors (induced by a brief rise in arterial pressure consequent to an intravenous injection of an alpha-adrenergic agonist, metaraminol) and electrical stimulation in the diagonal band of Broca evokes a GABA-mediated postsynaptic inhibition which selectively involves the phasic-firing (putative vasopressin-secreting) neuronal population. Although baroreceptor-triggered inhibitions are abolished after diagonal band lesions, anatomical data support the hypothesis that the GABAergic neurones mediating both the baroreflex and electrically induced inhibitions are not located in the diagonal band, but rather in the lateral hypothalamus adjacent to the supraoptic nucleus. To determine the validity of this hypothesis, excitotoxic lesions were placed in the lateral hypothalamus and their effects on both baroreceptor- and diagonal band-evoked inhibitions were evaluated. 2. Male Long-Evans rats were initially anaesthetized with intraperitoneal pentobarbitone, stereotaxically injected with an excitotoxin (ibotenic acid) or vehicle into the lateral hypothalamus on the left side and allowed to recover. Three or more days later, animals were again anaesthetized with pentobarbitone and the ventral surface of their hypothalamus was exposed for electrophysiological recording of neurones in the left supraoptic nucleus. In all injected animals, extracellular recordings from antidromically identified, phasically firing supraoptic neurones were evaluated for their response to activation of peripheral baroreceptors and to electrical stimulation in the diagonal band. 3. Increases in arterial pressure sufficient to activate peripheral baroreceptors were achieved by intravenous bolus infusions of metaraminol (10 micrograms/10 microliters). In vehicle control animals (n = 6), the activity of 34/39 neurones was inhibited by baroreceptor activation. In lesion control animals (n = 13) similar inhibitions were observed from 60/65 neurones. In the lateral hypothalamic lesioned group (n = 7), the activity of only 12/34 neurones were inhibited by similar elevations in blood pressure. 4. Ibotenic acid lesions in the lateral hypothalamus also disrupted the responsiveness of supraoptic neurones to electrical stimulation in the diagonal band. Whereas diagonal band stimulation in vehicle control and lesion control rats reduced the excitability in 7/9 cells and 15/19 cells respectively, only 1/7 cells responded in the lesioned animals. 5. Lesions having a significant effect on the responsiveness of vasopressin-secreting neurones to baroreceptor activation extended laterally towards the nucleus of the lateral olfactory tract, dorsally into the striatum and medially to the fornix.(ABSTRACT TRUNCATED AT 400 WORDS)

Norepinephrine injections in diagonal band of Broca selectively reduced the activity of vasopressin supraoptic neurons in the rat.

In the rat, transient drug-induced elevations of arterial blood pressure, which are sufficient to activate peripheral baroreceptors, produce a brief and selective cessation in the spontaneous activity of vasopressin-secreting cells in the hypothalamic supraoptic nucleus. This response appears to require the noradrenergic innervation of the diagonal band of Broca. The present study evaluated whether injections of norepinephrine into the diagonal band of Broca affect the spontaneous activity of supraoptic vasopressin-secreting neurons. Extracellular recordings were obtained from antidromically identified supraoptic neurons in pentobarbital anesthetized rats using a transpharyngeal approach. Injections of 200 nl of 10 microM norepinephrine into the diagonal band of Broca region arrested the spontaneous activity of 80% (12/15) of vasopressin-secreting neurons but only 7% (1/14) of oxytocin secreting-neurons demonstrated a comparable decrease in excitability. Vehicle injections did not influence the activity of any of the neurons tested. These results are consistent with the hypothesis that the baroreceptor-sensitivity of vasopressin neurons is mediated by a noradrenergic mechanism in the diagonal band of Broca.

Membrane properties of organum vasculosum lamina terminalis neurons recorded in vitro.

Intracellular recordings of organum vasculosum lamina terminalis (OVLT) neurons were obtained from superfused explants of rat hypothalamus. Most (32 of 34) OVLT neurons displayed a low threshold spike response during depolarizing pulses applied from holding membrane potentials negative to -70 mV. In 17 of 34 cells, electrical stimulation of the supraoptic nucleus area evoked antidromic responses. In 20 of the 34 cells, 8 of which were antidromically driven, identical stimuli also revealed either excitatory (n = 12) or inhibitory (n = 5) or mixed (n = 3) postsynaptic potentials. Axonal projections to the ipsilateral supraoptic nucleus were confirmed afterwards using reconstruction of Lucifer yellow-filled cells. A 10-40 mosmol/kgH2O increase in the osmolality of the superfusion media by addition of NaCl or mannitol prompted a membrane depolarization of 2-10 mV in each of nine OVLT neurons tested. These results indicate that OVLT neurons project to the supraoptic nucleus and possess intrinsic properties capable of influencing their excitability. Because neurons in OVLT depolarize consequent to elevations in media osmolality, the OVLT may provide a means by which hyperosmotic stimuli influence neuroendocrine function.

Catecholamine depletion of the diagonal band reduces baroreflex inhibition of supraoptic neurons.

In the rat, neurons in the diagonal band of Broca (DBB) participate in baroreceptor-induced depression of spontaneous activity of vasopressin neurons in the supraoptic nucleus (SON). The present study examined the role of the catecholaminergic innervation of the DBB in this response. Male rats were anesthetized with pentobarbital (50 mg/kg ip) and stereotaxically injected in the DBB with either vehicle (2 microliters), 6-hydroxydopamine (6-OHDA; 4 micrograms/2 microliters), or 6-OHDA preceded 20 min earlier by desimipramine (25 mg/kg ip), a norepinephrine uptake inhibitor. Two weeks later, the rats were reanesthetized and a transpharyngeal approach was used for extracellular recording from SON neurons. In vehicle-injected controls, baroreceptor stimulation produced by brief increases in blood pressure from metaraminol injections (10 micrograms/10 microliters iv) transiently arrested the spontaneous activity of 24 of 24 phasically active neurons tested. Sixty-three percent of the vasopressin neurons were not affected by comparable increases in blood pressure in 6-OHDA-treated rats, and the norepinephrine content of the DBB was significantly reduced. In experiments with desimipramine-pretreated rats, 92% of the vasopressin neurons were silenced by increases in blood pressure while the norepinephrine content of the DBB was not affected. Thus the noradrenergic innervation of DBB appears to participate in the baroreceptor sensitivity of SON vasopressinergic neurons.