[Head and neck hamartomas: 10 years of experience at the Charité--University Medical Center Berlin]. / Hamartome im Kopf-Hals-Bereich: 10 Jahre Erfahrung an der Charité--Universitätsmedizin Berlin.

BACKGROUND: Head and neck tumors are rare entities in neonates. Hamartomas are benign congenital neoplasms. To date, there is a lack of sufficient epidemiological data concerning hamartomas in the field of otorhinolaryngology. MATERIALS AND METHODS: We retrospectively analyzed experiences at the Charité over the past 10 years in an ICD-10-based manner. Our otorhinolaryngology department maintains close cooperation with the level 1 perinatal center on our campus. RESULTS: The authors identified 3 patients suffering from fibrous hamartomas. This corresponds to an incidence of 2-3/30,000 newborns. The clinical aspects and courses are described in detail. Experiences with the management of hamartomas obstructing the upper aerodigestive tract are described. CONCLUSION: Head and neck hamartomas are very rare malformations. They possess the ability to cause otorhinolaryngological emergencies in newborns. Interdisciplinary management and histological assessment are mandatory. Anmerkung.

The impact of psychiatric patient boarding in emergency departments.

Objectives. Studies have demonstrated the adverse effects of emergency department (ED) boarding. This study examines the impact of resource utilization, throughput, and financial impact for psychiatric patients awaiting inpatient placement. Methods. The authors retrospectively studied all psychiatric and non-psychiatric adult admissions in an Academic Medical Center ED (>68,000 adult visits) from January 2007-2008. The main outcomes were ED length of stay (LOS) and associated reimbursement. Results. 1,438 patients were consulted to psychiatry with 505 (35.1%) requiring inpatient psychiatric care management. The mean psychiatric patient age was 42.5 years (SD 13.1 years), with 2.7 times more women than men. ED LOS was significantly longer for psychiatric admissions (1089 min, CI (1039-1140) versus 340 min, CI (304-375); P < 0.001) when compared to non-psychiatric admissions. The financial impact of psychiatric boarding accounted for a direct loss of ($1,198) compared to non-psychiatric admissions. Factoring the loss of bed turnover for waiting patients and opportunity cost due to loss of those patients, psychiatric patient boarding cost the department $2,264 per patient. Conclusions. Psychiatric patients awaiting inpatient placement remain in the ED 3.2 times longer than non-psychiatric patients, preventing 2.2 bed turnovers (additional patients) per psychiatric patient, and decreasing financial revenue.

The selective beta1-adrenoceptor antagonist nebivolol is a potential oestrogen receptor agonist with neuroprotective abilities.

BACKGROUND AND PURPOSE: Nebivolol, a selective beta(1)-adrenoceptor antagonist mediating rapid vasodilating effects, is used clinically to treat hypertension. Recently, it was reported that nebivolol also acts as an oestrogen receptor (ER) agonist. To investigate the neuroprotective potential of oestrogens, we assessed the oestrogenic effects of nebivolol in several in vitro neuronal models. EXPERIMENTAL APPROACH: Human neuroepithelioma SK-N-MC cells stably transfected with human ER alpha and beta, and mouse N2A neuroblastoma cells expressing human APP695(SWE)[N2Aswe, stably transfected with the Swedish mutation form of the Alzheimer-associated amyloid precursor protein (APPswe, K670M/N671L)] were incubated with different concentrations of nebivolol and 17beta-oestradiol (E2) for 24-48 h. ER activation was detected in a specific reporter assay, and ER-dependent gene expression was measured by quantitative real-time PCR (qRT PCR). Furthermore, cell survival rates were determined, and oxidative stress was induced by hydrogen peroxide and paraquat. Amyloid beta protein precursor (APP) processing was investigated, and the cleavage fragments sAPPalpha and Abeta were quantified via alpha-, beta- and gamma-secretase activity assays. Alterations of secretase expression levels were determined by qRT PCR. KEY RESULTS: Nebivolol induces oestrogen-dependent gene transcription, and protects neuronal cells against oxidative stress even at low and physiological concentrations (10(-8) M). Moreover, nebivolol modulates processing of APP in mouse neuronal N2Aswe cells by increasing alpha-secretase activity, ultimately leading to enhanced release of soluble non-amyloidogenic sAPPalpha. CONCLUSIONS AND IMPLICATIONS: We showed that nebivolol acts as ER agonist in neuronal cell lines, and suggest oestrogen-like neuroprotective effects mediated by nebivolol.

Antiepileptic drugs and the developing brain.

Epilepsy is the most common neurological disorder in young humans. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters and second messenger systems constitute molecular targets of AEDs. The same targets regulate brain processes essential both for propagation of seizures and for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain development in undesired ways. Here we review mechanisms of action of AEDs, examine clinical evidence for their adverse effects in the developing human brain, and present studies on cognitive and behavioral effects in animal models. Furthermore, we discuss mechanisms responsible for adverse effects of AEDs in the developing mammalian brain, including interference with cell proliferation and migration, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.

From structural biochemistry to expression profiling: neuroprotective activities of estrogen.

Estrogens are neuromodulatory and neuroprotective hormones. Chemically, estrogens are steroid compounds and unfold most of their activities through the activation of nuclear receptors that bind to specific target genes and control their transcription. Two subtypes of estrogen receptors are known (estrogen receptor alpha and estrogen receptor beta) and they are expressed throughout the body including the CNS and in particular the brain. We employed large scale DNA-chip-analysis to display the gene expression pattern differentially regulated by both estrogen receptor subtypes in human neuronal cells. We identified different gene families regulated by estrogen receptors that complement the knowledge about the estrogen receptor target genes. Some of these genes may serve neuroprotective functions and may therefore mediate the overall neuroprotective activities of estrogens. In addition to estrogen receptor-dependent neuroprotective effects, estrogen (17beta-estradiol) itself is a compound with a phenolic structure that may display also direct and estrogen receptor-independent antioxidant activities which may be important for the defense against oxidative stress. In summary estrogen can display a wide range of neuroprotective activities through different types of mechanisms and we are only understanding part of the molecular control of these activities which may help to develop neuropreventive strategies against neurodegenerative diseases in the future.

Nephrolithiasis.

This article covers the diagnosis and management of renal colic. New imaging modalities will be reviewed using evidence-based medicine. The disposition of the patient with renal colic will be addressed. Additionally, special groups with nephrolithiasis will be discussed.

Estrogen induces a rapid secretion of amyloid beta precursor protein via the mitogen-activated protein kinase pathway.

The female sex hormone estrogen (17beta-estradiol; E2) may function as a neurohormone and has multiple neuromodulatory functions in the brain. Its potent neuroprotective activities can be dependent and independent of estrogen receptors (ERs). In addition, E2 influences the processing of the amyloid beta precursor protein (APP), one central step in the pathogenesis of Alzheimer's disease. Here, we show: (a) that physiological concentrations of E2 very rapidly cause an increased release of secreted nonamyloidogenic APP (sAPPalpha) in mouse hippocampal HT22 and human neuroblastoma SK-N-MC cells; and (b) that this effect is mediated through E2 via the phosphorylation of extracellular-regulated kinase 1 and 2 (ERK1/2), prominent members of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, we show that the activation of MAPK-signaling pathway and the enhancement of the sAPP release is independent of ERs and could be induced by E2 to a similar extent in neuronal cells either lacking or overexpressing a functional ER.

Intracellular domains of mouse connexin26 and -30 affect diffusional and electrical properties of gap junction channels.

To evaluate the influence of intracellular domains of connexin (Cx) on channel transfer properties, we analyzed mouse connexin (Cx) Cx26 and Cx30, which show the most similar amino acid sequence identities within the family of gap junction proteins. These connexin genes are tightly linked on mouse chromosome 14. Functional studies were performed on transfected HeLa cells stably expressing both mouse connexins. When we examined homotypic intercellular transfer of microinjected neurobiotin and Lucifer yellow, we found that gap junctions in Cx30-transfected cells, in contrast to Cx26 cells, were impermeable to Lucifer yellow. Furthermore, we observed heterotypic transfer of neurobiotin between Cx30-transfectants and HeLa cells expressing mouse Cx30.3, Cx40, Cx43 or Cx45, but not between Cx26 transfectants and HeLa cells of the latter group. The main differences in amino acid sequence between Cx26 and Cx30 are located in the presumptive cytoplasmic loop and C-terminal region of these integral membrane proteins. By exchanging one or both of these domains, using PCR-based mutagenesis, we constructed Cx26/30 chimeric cDNAs, which were also expressed in HeLa cells after transfection. Homotypic intercellular transfer of injected Lucifer yellow was observed exclusively with those chimeric constructs that coded for both cytoplasmic domains of Cx26 in the Cx30 backbone polypeptide chain. In contrast, cells transfected with a construct that coded for the Cx26 backbone with the Cx30 cytoplasmic loop and C-terminal region did not show transfer of Lucifer yellow. Thus, Lucifer yellow transfer can be conferred onto chimeric Cx30 channels by exchanging the cytoplasmic loop and the C-terminal region of these connexins. In turn, the cytoplasmic loop and C-terminal domain of Cx30 prevent Lucifer yellow transfer when swapped with the corresponding domains of Cx26. In chimeric Cx30/Cx26 channels where the cytoplasmic loop and C-terminal domains had been exchanged, the unitary channel conductance was intermediate between those of the parental channels. Moreover, the voltage sensitivity was slightly reduced. This suggests that these cytoplasmic domains interfere directly or indirectly with the diffusivity, the conductance and voltage gating of the channels.

The female sex hormone oestrogen as neuroprotectant: activities at various levels.

The female sex hormone oestradiol (oestrogen) is a steroidal compound that binds to specific intracellular receptors which act as transcription factors. Oestrogen displays many of its effects by the classical mode of action through receptor binding, transactivation and binding to consensus oestrogen response elements on DNA. Although the primary role of oestrogen as an ovarian steroid was thought to be the regulation of sex differentiation and maturation, since oestrogen receptors are expressed in a variety of other tissues besides sex organs, oestrogen is believed to exert multiple activities in several target sites throughout the body, including the nervous system. In the brain oestrogens have multiple activities. Potential neuroprotective functions of oestrogens are being intensively studied and it is becoming increasingly clear that oestrogens are (1) neuroprotective hormones acting via oestrogen receptor-dependent pathways at the genomic level and (2) neuroprotective steroidal structures acting independently of the activation of specific oestrogen receptors. One striking activity of the molecule oestradiol is its intrinsic antioxidant activity which makes it a potential chemical shield for neurons. Nerve cells frequently encounter oxidative challenges during the normal physiology, but also under pathophysiological conditions. Oxidative stress has been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. It is important to stress that the antioxidant neuroprotective activity of oestrogens is independent of oestrogen receptor activation, since oestrogen derivatives and aromatic alcohols that do not bind to oestrogen receptors share the same antioxidant neuroprotective activity. Although this effect of oestrogens can clearly be separated from oestrogen receptor binding, oestrogens may interact with intracellular signalling pathways, such as the mitogen activated protein kinase, cyclic AMP pathways, and with the activity of the redox-sensitive transcription factor NF-kappa B.

Neuroprotective activities of estrogen: an update.

For many molecules, which have been found first in a certain tissue and with a certain activity in the body, multiple activities have been discovered decades later. The steroidal compound estrogen (estradiol) is certainly such a molecule. What was first described as the female sex hormone is now well acknowledged as a central neuroactive and neuromodulatory molecule. One important aspect of estrogen's effects on neurons is its neuroprotective activity. Cellular and molecular studies underline powerful neuroprotective functions of estrogen which are characterized by long-term "classical" genomic effects as well as by rapid activities depending on estrogens interaction with neuronal membranes and intracellular signal transduction pathways. In addition, estrogen has been shown to bear an intrinsic antioxidant structure that lies in the phenolic moiety of the steroidal compound. This antioxidant activity of estrogen and estrogen-derivatives may provide an antioxidant "chemical shield" for neurons and may complement other neuroprotective activities of estrogen and therefore also mediate some of the beneficial effects of estrogen replacement with respect to Alzheimer's Disease. Although, investigated for decades estrogen and its receptors may still hold many surprises that remain to be identified. With the advent of novel genomic techniques, the neuronal target genes of estrogen will be identified in the future.

Biophysical properties of mouse connexin30 gap junction channels studied in transfected human HeLa cells.

1. Human HeLa cells expressing mouse connexin30 (Cx30) were used to study the electrical properties of Cx30 gap junction channels. Experiments were performed on cell pairs with the dual voltage-clamp method. 2. The gap junction conductance (gj) at steady state showed a bell-shaped dependence on junctional voltage (Vj; Boltzmann fit: Vj,0 = 27 mV, gj,min = 0.15, z = 4). The instantaneous gj decreased slightly with increasing Vj. 3. The gap junction currents (Ij) declined with time following a single exponential. The time constants of Ij inactivation (taui) decreased with increasing Vj. 4. Single channels exhibited a main state, a residual state and a closed state. The conductances gammaj,main and gammaj,residual were 179 and 48 pS, respectively (pipette solution, potassium aspartate; temperature, 36-37 degrees C; extrapolated to Vj = 0 mV). 5. The conductances gammaj,residual and gammaj,main showed a slight Vj dependence and were sensitive to temperature (Q10 values of 1.28 and 1.16, respectively). 6. Current transitions between open states (i.e. main state, substates, residual state) were fast (< 2 ms), while those between an open state and the closed state were slow (12 ms). 7. The open channel probability (Po) at steady state decreased from 1 to 0 with increasing Vj (Boltzmann fit: Vj,0 = 37 mV; z = 3). 8. Histograms of channel open times implied the presence of a single main state; histograms of channel closed times suggested the existence of two closed states (i.e. residual states). 9. We conclude that Cx30 channels are controlled by two types of gates, a fast one responsible for Vj gating involving transitions between open states (i.e. residual state, main state), and a slow one correlated with chemical gating involving transitions between the closed state and an open state.

Pediatric case of accidental oral overdose of methotrexate.

Methotrexate is a chemotherapy antimetabolite, folic acid antagonist, that inhibits the enzyme dihydrofolate reductase resulting in decreased levels of tetrahydrofolate in the cells. This in turn blocks synthesis of thymidylate, a nucleotide necessary for DNA synthesis. It is readily absorbed from the gastrointestinal tract. Toxicity from overdose can affect multiple organ systems including bone marrow, liver, intestinal tract, kidneys, lungs, skin, and blood vessels, resulting in death in severe cases. Methotrexate is widely used to treat neoplastic disease, dermatologic disorders (psoriasis), and rheumatologic disorders (severe rheumatoid arthritis). As its indications for use increase, more accidental overdoses can be expected. We present the treatment and clinical course of one such case, that of a 2-year-old who accidentally took her grandmother's arthritis pills. Her initial serum level was 10 times greater than that needed to cause toxicity. She was treated with gastric lavage, activated charcoal, leucovorin rescue, and ICU admission. Her clinical course was unremarkable, and the only evidence of toxicity was a mild elevation in a liver-associated enzyme that resolved without any clinical sequela. Leucovorin at a dose equal to or greater than the possible ingestion should be given as soon as possible in methotrexate overdoses.

Molecular cloning and functional expression of the mouse gap junction gene connexin-57 in human HeLa cells.

A new mouse connexin gene has been isolated that codes for a connexin protein of 505 amino acid residues. Based on the predicted molecular mass of 57.115 kDa, it has been designated connexin-57. Similar to most other mouse connexin genes, the coding region of connexin-57 is not interrupted by introns and exists in the mouse genome as a single-copy gene. Within the connexin family, this new gene shows highest sequence identity to porcine connexin-60 in the alpha group of connexins. The connexin-57 gene was mapped to a position on mouse chromosome 4, 30 centimorgans proximal to a cluster of previously mapped connexin genes. Low levels of connexin-57 mRNA were detected in skin, heart, kidney, testis, ovary, intestine, and in the mouse embryo after 8 days post coitum, but expression was not detected in brain, sciatic nerve or liver. In order to analyze gene function, the connexin-57 coding region was expressed by transfection in human HeLa cells, where it restored homotypic intercellular transfer of microinjected neurobiotin. Heterotypic transfer was observed between HeLa connexin-57 transfectants and HeLa cells, expressing murine connexin-43, -37, or -30.3. Double whole-cell voltage clamp analyses revealed that HeLa-connexin-57 transfectants expressed about 10 times more channels than parental HeLa cells. Voltage gating by transjunctional and transmembrane voltages as well as unitary conductance ( approximately 27 picosiemens) were different from intrinsic connexin channels in parental HeLa cells.

Human gap junction protein connexin31: molecular cloning and expression analysis.

We have isolated and characterized a human genomic clone containing the complete coding region of connexin31 (Cx31). Similar to rodent Cx31, the coding region of human Cx31 is completely contained within the second exon and consists of 810 nucleotides. The deduced human Cx31 polypeptide consists of 270 amino acids with a predicted molecular mass of 30.818 kDa. Its sequence is most similar to mouse Cx31 (82.6% identical amino acids) and rat (83.0% identical amino acids), but shows considerably fewer potential sites of phosphorylation. After Northern blot hybridization, two Cx31 transcripts of 2.2 and 1.8 kb were detected in total RNA of the human keratinocyte cell line HaCaT and two transcripts of 2.2 and 1.9 kb in total RNA of E6/E7 transfected human keratinocytes (HEK cells). Using affinity-purified rabbit antibodies to mouse Cx31, immunofluorescence analysis demonstrated relatively weak expression of human Cx31 in HaCaT and HEK cells. The Cx31 gene exists as a single copy gene in the human genome and was mapped to the chromosomal region 1p34-p36 by analyzing human-mouse somatic cell hybrids.

Tension hydrothorax due to ventriculopleural shunting.

Tension hydrothorax is rare, with few cases reported in the literature dating back to the late 1960s. We report a case of tension hydrothorax in a patient with a ventriculopleural shunt who improved dramatically after thoracentesis. The discussion includes a brief review of ventriculopleural shunts and pleural physiology.

Painless acute aortic dissection presenting as left lower extremity numbness.

Acute aortic dissection may have variable presentations, making the diagnosis clinically challenging. Acute neurologic syndromes secondary to dissection of the aorta are uncommon. However, including aortic dissection in the differential diagnosis is imperative. This report describes the first reported case of an acute thoracic aortic dissection presenting with the chief complaint of unilateral lower extremity numbness. Peripheral ischemic neuropathy as the result of vascular occlusion is uncommon. The pathophysiology and clinical manifestations of ischemic neuropathies in the setting of acute aortic dissection are discussed.

Ultrasound versus radiography in the detection of soft-tissue foreign bodies.

STUDY OBJECTIVE: To determine the usefulness of ultrasound and radiography in detecting foreign bodies in soft-tissue models closely duplicating puncture-wound trauma and hand anatomy. METHODS: In this randomized, blinded descriptive study, two radiologists independently evaluated 120 chicken thighs for foreign bodies with the use of standard two-view radiography and 7.5-MHz transducer ultrasonography. All chicken thighs were manipulated with hemostats to ensure uniform tissue damage. In 60 thighs, one foreign body had been inserted (10 each: gravel, metal, glass, cactus spine, wood, and plastic). RESULTS: The sensitivity of ultrasound in detecting gravel was 40%, that for metal was 45%, that for glass was 50%, that for cactus spine was 30%, that for wood was 50%, and that for plastic was 40%. The overall sensitivity, specificity, and false-negative and false-positive rates for ultrasound were 43%, 70%, 50%, and 30%, respectively. No individual foreign body had an ultrasound detection rate of 50%. Radiography detected foreign bodies generally considered radiopaque (gravel, glass, metal) 98% of the time, but it never detected bodies considered radiolucent (wood, plastic, cactus spine). The false-negative and false-positive rates for radiography were 50% and 1.6%, respectively. CONCLUSION: Ultrasound detection of foreign bodies by skilled operators in this animal model revealed poor sensitivity and specificity. Radiographic detection was highly sensitive for foreign bodies considered radiopaque. Our data suggest that ultrasound should not be relied on to rule out the possibility of a retained foreign body in the distal extremities.