Pharmacological characterization of the receptor mediating the adrenergic inhibition of responses to substance P in the cingulate cortex

The excitatory responses of neurones in the anterior cingulate cortex of the rat to iontophoretically applied substance P (SP) are reduced by noradrenaline (NA) applied iontophoretically or released from noradrenergic pathways. In order to determine the receptor involved in this inhibitory effect we have studied the effects of a number of receptor-specific adrenergic agonists and antagonists on responses of cingulate neurones to SP in rats anaesthetized with chloral hydrate. Low iontophoretic currents (0-15 nA) of NA, adrenaline and the beta-agonist, clenbuterol, all strongly reduced responses to SP. Isoprenaline was also effective but less consistently so, although problems were experienced with its iontophoretic release from micropipettes. The alpha 1-agonists, phenylephrine and methoxamine were also able to reduce responses to SP. However, this reduction required higher iontophoretic currents (15-60 nA) and was associated with depressant effects on baseline firing rate. The alpha 2-agonist clonidine was only weakly active at high currents and this too was associated with depression of baseline firing. Similar weak effects were noted with dopamine. The inhibitory effects of NA on SP responses were convincingly blocked or reversed by the beta-antagonist, practolol, but not by the alpha 1-antagonist, prazosin. The reduction of SP responses by phenylephrine was also blocked by practolol but unaffected by prazosin. Finally, reduction of SP excitations by activation of the coeruleocortical pathway was also blocked by practolol applied iontophoretically to the cortical cells. These results are consistent with the hypothesis that the effect of NA on SP responsiveness in the cingulate cortex is mediated by beta-adrenoreceptors.     

Long-term effects of cochlear implants in children.

OBJECTIVE: Since 1987, when the use of multichannel cochlear implants was initiated in children, candidacy has expanded; many thousands of children have received these devices, and results have revealed a wide range of performance. However, few long-term studies exist on a large population of these children. There have been concerns expressed that cochlear implant function might degrade over time, that devices and electrodes might migrate and extrude in the growing child, or that there might even be a deleterious effect of long-term stimulation of the cochlear nerve. The purpose of this study was to explore the long-term effects of implantation as a function of performance over time, reimplantation, and educational factors. STUDY DESIGN AND SETTING: We studied 81 children who received implants at a major academic medical center and were followed for 5 to 13 years. RESULTS: Results revealed significant gains in speech perception, use of oral language, and ability to function in a mainstream environment. There was no decrease in performance over time and no significant incidence of device or electrode migration or extrusion, and device failure did not cause a deterioration in long-term outcome. CONCLUSIONS: Multichannel cochlear implants in children provide perception, linguistic, and educational advantages, which are not adversely affected by long-term electrical stimulation.     

Should the membranous labyrinth be destroyed because of vertigo?

The purpose of this article is to determine if any change has occurred in the role labyrinthectomy plays in the therapeutic armamentarium of members of the American Neurotologic Society. Questionnaires were sent to all members and 42% of these were returned. Analysis of the questionnaires suggests that labyrinthectomy still remains an important tool in the surgical management of vertigo, although it is less frequently employed now than 10 years ago. This seems to be the consequence of increased valuation of even minimal levels of residual hearing.     

Value of grading squamous cell carcinoma of the head and neck.

We report a series of 3,294 patients with squamous cell carcinoma of the head and neck seen by one of us between 1963 and 1990. Two thousand and seven patients had a histologically proven and graded, but previously untreated, squamous cell carcinoma of the mucosal surfaces of the head and neck. These tumors had been graded previously by many different pathologists in many different hospitals, both in the United Kingdom and the United States, as well as continental Europe, over this period. Of the host factors both sex and age were associated with differentiation: 34% of patients less than age 50 had a well-differentiated tumor compared with 44% greater than age 50; 32% of women had a poorly differentiated tumor compared with 26% of men. General condition had no correlation with degree of differentiation. Site was closely associated with grading: well-differentiated tumors were more common in the mouth and larynx and poorly differentiated tumors in the pharynx. Furthermore, of poorly differentiated tumors, 19% arose from areas normally lined by keratinized squamous epithelium, 22% from a nonkeratinized area, 36% from respiratory epithelium, and 45% from areas normally covered by lymphoid epithelium. T stage had no significant correlation with differentiation. However, 46% of patients with poorly differentiated tumors had a nodal metastasis at presentation compared with only 28% of well-differentiated tumors. Distant metastases at presentation were found in 3.4% of poorly differentiated tumors compared with 1.8% of well-differentiated tumors. The survival fell significantly from 33% for well-differentiated tumors to 27% for poorly differentiated tumors. The recurrence rate at the primary site rose from 25% for well-differentiated tumors to 27% for poorly differentiated tumors, and recurrence in the lymph nodes rose from 26% to 30%. Both differences were just significant.     

Tissue characterization of symptomatic and asymptomatic disc herniations by quantitative magnetic resonance imaging

The purpose of this investigation was to determine differences in tissue composition of symptomatic and asymptomatic disc herniations as reflected in T₁ and T₂ relaxation times (quantitative magnetic resonance investigation of the lumber spine. The longitudinal and transverse magnetic rlaxation times (T₁ and T₂, respectively) were calculated from a set of 20 images obtained with five single-slice/multi-echo sequences at different repetition time values on a commercial whole-body system (1.5 T). Twenty-two symptomatic and asymptomatic disc herniations could be matched according to age, gender, disc level, and the extent of herniation (protrusion or extrusion) and were compared with regard to T₁ and T₂ relaxation times. Symptomatic disc herniations exhibited significantly (p_T1 < 0.04 and p_T2 < 0.003) shorter T₁(ΔT₁:–182.1 milliseconds, ?15%) and T₂(ΔT₂: ?11.0 milliseconds, ?21%) relaxation times than matched asymptomatic herniations. Symptomatic disc herniations also exhibited more advanced disc degeneration as graded by Pearce's criteria (p < 0.01). These results suggest that symptomatic and morphologically matched asymptomatic disc herniations differ with regard to disc matrix composition.     

The interaction of endothelin receptor responses in the isolated perfused rat lung

To gain more insight into the complex pulmonary interactions of endothelins (ET), we studied airway and vascular responses to endothelins in isolated perfused rat lungs in the presence of the novel ET_B-receptor antagonist BQ788. In particular we focused on airway responses and on prostacyclin release. The effectiveness of BQ788 in our system was shown by its ability to concentration-dependently prevent vasoconstriction (IC₅₀ 0.1μM), bronchoconstriction (IC₅₀ 0.1μM) and prostacyclin production (IC₅₀<0.1μM) induced by the ET_B-receptor agonist IRL1620 (1nmol). Airway responses to ET-1: ET-1-induced bronchoconstriction was aggravated by BQ123 (1 or 8μM), while BQ788 pretreatment (1 or 8μM) showed no significant effect. Simultaneous treatment with 8μM BQ123 and BQ788 attenuated the ET-1-induced bronchoconstriction. Vascular responses to ET-1: ET-1 (1nmol)-induced vasoconstriction was potentiated by BQ788 (1 or 8μM), but attenuated by the ET_A-receptor antagonist BQ123 (1μM). In the presence of BQ788 diminished amounts of the stable prostacyclin metabolite 6-keto-PGF_1α were detected in the perfusate. Simultaneous treatment with 8μM BQ123 and BQ788 completely prevented the ET-1-induced vasoconstriction. Conclusions: Both ET_A- and ET_B-receptors contribute to ET-1-induced vasoconstriction and bronchoconstriction. The ET-1-induced vasoconstriction is attenuated by stimulation of ET_B-receptors, a response that is partly mediated by prostacyclin. Due to the mutual interactions between ET_A- and ET_B-receptors, simultaneous inhibition of both receptors is required to prevent the deleterious effects of ET-1 on lung functions. Received: 17 October 1996 / Accepted: 16 May 1997     

Autoregulation by eicosanoids of human Kupffer cell secretory products. A study of interleukin-1, interleukin-6, tumor necrosis factor-alpha, transforming growth factor-beta, and nitric oxide.

OBJECTIVE: Methods employed previously to analyze the secretory behavior of rodent Kupffer cells (KC) were used to examine the human KC's secretory response to lipopolysaccharide (LPS). SUMMARY BACKGROUND DATA: As the resident hepatic macrophage, the KC resides at the interface between the portal and systemic circulations. Consequently, this cell may play an integral role in the immune response to antigens and bacteria in the sinusoid. Study of cytokine production by the KC has relied predominantly on the rat as the source of these cells. Whether human KCs respond similarly to rat KCs after LPS stimulation has been a matter of speculation. METHODS: Kupffer cells obtained from seven human livers were tested under conditions identical to those used to study rat KCs. Kupffer cells rested for 12 hours after isolation were stimulated with LPS (2.5 micrograms/mL). Arginine concentration in the culture medium varied from 0.01 to 1.2 mM. To examine the role of eicosanoids, parallel culture wells received indomethacin (10 microM). Culture supernatants were assayed for interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), prostaglandin E2 (PGE2), and nitric oxide. RESULTS: Similar to the rat KC, LPS-stimulated human KCs released IL-1, IL-6, TNF-alpha, TGF-beta, and PGE2. However, unlike rat KCs, nitric oxide could not be detected, regardless of whether the human KCs were exposed to LPS, interferon-gamma (INF-gamma), or LPS + IFN-gamma. Similar to rat KCs, indomethacin prevented PGE2 release while significantly upregulating TNF-alpha, IL-1, and IL-6, but not TGF-beta, consistent with an autoregulatory control of eicosanoids over proinflammatory cytokines. As has been shown in the rat, physiologic levels of L-arginine (0.01 mM) significantly enhanced LPS-induced PGE2 secretion relative to the response in medium containing standard L-arginine concentration (1.2 mM); however, unlike the rat KC, the human's cytokine response to LPS was not downregulated by this enhanced PGE2 release. CONCLUSIONS: Although many functional features are shared by rat and human KCs, significant differences do exist. Such discrepancies reinforce the need to proceed with caution when generalizing from the results obtained in other species to human physiology.     

Hypoosmolare Hyponatri?mie als Leitsymptom bei Hypothyreose

Zusammenfassung Anamnese und Diagnostik: Ein 75-jähriger Patient wies neben unspezifischen anamnestischen Symptomen (Appetitverlust, Merkfähigkeitsstörung und Muskelschwäche) klinisch diskrete Beinödeme, abgeschwächte Muskeleigenreflexe und eine deutliche Gedächtnisstörung auf. Aufgrund einer euvolämischen, laborchemisch hypoosmolaren Hypoatriämie und eines Urinnatriums im Normbereich wurde als Arbeitsdiagnose von einem Syndrom der inadäquaten ADH-Sekretion (SIADH) ausgegangen. Während sich weder in der Anamnese noch in den folgenden Untersuchungen eine dem SIADH zugrunde liegende Pathologie eruieren ließ, ergab sich in den weiteren Laboruntersuchungen der Befund einer ausgeprägten Hypothyreose. Die Hyponatriämie bei Hypothyreose spiegelt eine Komponente der renalen Funktionsstörung bei Schilddrüsenhormonmangel wider. Therapie und Verlauf: Nach Flüssigkeitsrestriktion und Hormonsubstitution erreichte der Patient schnell normale Natriumwerte und zeigte eine deutliche Besserung seiner kognitiven Fähigkeiten. Schlussfolgerung: Als Schlussfolgerung aus dieser Kasuistik wird Zurückhaltung bei der Diagnose eines SIADH empfohlen, bevor nicht eine sorgfältige Untersuchung des Nebennieren- und Schilddrüsenhormonstatus erfolgt ist. Abstract Case History and Diagnosis: A 75-year-old male patient presented with a history of anorexia, muscle weakness, and increasing memory loss. He had mild pedal edema and decreased deep tendon reflexes. As the laboratory tests showed hypoosmolar hyponatremia and urinary sodium within the normal range, a syndrome of inappropriate ADH secretion (SIADH) was presumed. While neither the medical history nor any of the diagnostic procedures revealed any underlying pathology explaining the SIADH, laboratory tests showed significant hypothyroidism. Hypothyroid states are associated with significant changes in renal function, one of which is hypoosmolar hyponatremia. Treatment and Course: Treatment included fluid restriction and hormone substitution and resulted in a quick correction of the hyponatremia and a clear improvement of the patient's cognitive function. Conclusion: It is concluded that the diagnosis of SIADH should only be made after thorough investigation of the adrenal and thyroid hormone status.