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Headaches secondary to sinonasal anatomic abnormalities continue to remain a difficult entity to diagnose and to manage. This retrospective study analyzed the outcome of care for 34 patients who presented with headaches as one of their primary sinonasal complaints and were subsequently found to have contact points between the nasal septum and one or more turbinates on nasal endoscopy and/or computed tomography scan. Following functional endoscopic sinus surgery to relieve the contact points, these patients were interviewed regarding preoperative and postoperative intensity and frequency of the headaches and the overall response of the chronic sinusitis and headaches to surgery, after a mean follow-up period of 13.9 months. After surgery, reduction in intensity and frequency of headaches was experienced in 91% and 85% of the patients, respectively. This investigation demonstrates that surgical management of contact point headaches can make a significant impact on the headache symptomatology in children and adults. [ABSTRACT FROM AUTHOR]

Posterior laryngeal clefts (PLCs) are described in the literature as rare laryngeal abnormalities. The authors believe type I clefts are much more common than previously reported. In two busy pediatric tertiary care centers, such clefts are the second most common congenital laryngeal finding at rigid endoscopy, second only to laryngomalacia. PLCs frequently present with symptomatology that can be attributed to other common disease processes and are often undiagnosed unless the surgeon maintains a high index of suspicion and specifically examines the posterior glottis by palpation during microlaryngoscopy. This report presents a series of 41 patients with type I PLCs, reviews their subtle and often confusing presenting signs and symptoms, and describes a simple yet reliable method of diagnosis. [ABSTRACT FROM AUTHOR]

Nasal irrigations have been used for centuries without any scientific data to determine efficacy. For 10 years, the senior author has used buffered hypertonic saline nasal irrigation for patients with acute/chronic sinusitis and for those having undergone sinus surgery. A simple study was undertaken using volunteers without any significant sinonasal disease. Patients served as their own control using a saccharin clearance test before any nasal irrigation was used. Patients then used one of two solutions to irrigate their nose-buffered normal saline or buffered hypertonic saline-and were then retested. On a separate day, the control test was repeated, followed by irrigation with the alternate solution and a second saccharin clearance test. The outcome showed buffered hypertonic saline nasal irrigation to improve mucociliary transit times of saccharin, while buffered normal saline had no such effect. [ABSTRACT FROM AUTHOR]

Zeolites contain extraframework cations that are exchangeable under favorable aqueous conditions; this is the fundamental feature for their application in water purification and necessary to produce cation forms for other applications such as catalysis. Optimization of the process is common, but there is little fundamental understanding based on real-time experiments of the mechanism of exchange for most zeolites. The sodium and potassium forms of zeolite chabazite selectively uptake Cs + by ion exchange, leading to its application in removing radioactive 137 Cs + from industrial nuclear waste streams, as well as from contaminated environments in the aftermath of the Fukushima and Three Mile Island accidents. In this study, in situ synchrotron powder X-ray diffraction patterns have been collected on chabazite as it undergoes Cs-ion exchange. Applying Rietveld refinement to these patterns has revealed the time-resolved structural changes that occur in the zeolite as exchange progresses, charting the changes in the spatial distribution of the extraframework cations and water molecules in the structure during the reaction. Ultimately, a detailed mechanistic understanding of how this dynamic ion-exchange reaction occurs has been obtained., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Down syndrome (DS) is the most common chromosomal disorder in humans. DS is associated with increased prevalence of several ocular sequelae, including characteristic blue-dot cerulean cataract. DS is accompanied by age-dependent accumulation of Alzheimer's disease (AD) amyloid-β (Aβ) peptides and amyloid pathology in the brain and comorbid early-onset Aβ amyloidopathy and colocalizing cataracts in the lens. Quasi-elastic light scattering (QLS) is an established optical technique that noninvasively measures changes in protein size distributions in the human lens in vivo. In this cross-sectional study, lenticular QLS correlation time was decreased in adolescent subjects with DS compared to age-matched control subjects. Clinical QLS was consistent with alterations in relative particle hydrodynamic radius in lenses of adolescents with DS. These correlative results suggest that noninvasive QLS can be used to evaluate molecular changes in the lenses of individuals with DS., Competing Interests: Declaration of competing interest Goldstein (Cognoptix, Rebion); Hunter (Rebion, Luminopia). None of the reported entities contributed financial support for or had access to results from this study. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Ltd.)

A cubic tin(II) germanate, α-Sn 6 GeO 8 (space group F 4̅3 m , a = 10.52521(2) Å, and Z = 4), has been synthesized by both regular hydrothermal and microwave-assisted hydrothermal methods, and the crystal structure of this material has been solved by Rietveld refinement of synchrotron powder X-ray diffraction (PXRD) data. The crystal structure is analogous to α-Sn 6 SiO 8 and is therefore related to the zinc blende structure comprising a face-centered cubic array of [Sn 6 O 8 ] 4- anionic clusters with Ge 4+ cations occupying half of the tetrahedral holes. Variable-temperature PXRD has revealed that tin(II) germanate has high thermal stability: remaining stable at 950 K and mostly decomposing over the range 984-1034 K. The tin(II) germanate has been further characterized by X-ray fluorescence (XRF), Raman, and diffuse reflectance (DR) UV-vis spectroscopies. In addition, variable-temperature PXRD studies have revealed the formation of a tetragonal tin(II) silicate polymorph, γ-Sn 6 SiO 8 (space group I 4̅, a = 7.30414(6) Å, c = 10.53731(6) Å, and Z = 2), at temperatures below 170 K. The crystal structure of γ-Sn 6 SiO 8 has been elucidated by Rietveld refinement. While a transition to a tetragonal polymorph is observed upon cooling α-Sn 6 SiO 8 , no corresponding transition is observed for α-Sn 6 GeO 8 , which retains its cubic structure over the probed temperature range.

The human zinc transporter ZnT8 provides the granules of pancreatic β-cells with zinc (II) ions for assembly of insulin hexamers for storage. Until recently, the structure and function of human ZnTs have been modelled on the basis of the 3D structures of bacterial zinc exporters, which form homodimers with each monomer having six transmembrane α-helices harbouring the zinc transport site and a cytosolic domain with an α,β structure and additional zinc-binding sites. However, there are important differences in function as the bacterial proteins export an excess of zinc ions from the bacterial cytoplasm, whereas ZnT8 exports zinc ions into subcellular vesicles when there is no apparent excess of cytosolic zinc ions. Indeed, recent structural investigations of human ZnT8 show differences in metal binding in the cytosolic domain when compared to the bacterial proteins. Two common variants, one with tryptophan (W) and the other with arginine (R) at position 325, have generated considerable interest as the R-variant is associated with a higher risk of developing type 2 diabetes. Since the mutation is at the apex of the cytosolic domain facing towards the cytosol, it is not clear how it can affect zinc transport through the transmembrane domain. We expressed the cytosolic domain of both variants of human ZnT8 and have begun structural and functional studies. We found that (i) the metal binding of the human protein is different from that of the bacterial proteins, (ii) the human protein has a C-terminal extension with three cysteine residues that bind a zinc(II) ion, and (iii) there are small differences in stability between the two variants. In this investigation, we employed nickel(II) ions as a probe for the spectroscopically silent Zn(II) ions and utilised colorimetric and fluorimetric indicators for Ni(II) ions to investigate metal binding. We established Ni(II) coordination to the C-terminal cysteines and found differences in metal affinity and coordination in the two ZnT8 variants. These structural differences are thought to be critical for the functional differences regarding the diabetes risk. Further insight into the assembly of the metal centres in the cytosolic domain was gained from potentiometric investigations of zinc binding to synthetic peptides corresponding to N-terminal and C-terminal sequences of ZnT8 bearing the metal-coordinating ligands. Our work suggests the involvement of the C-terminal cysteines, which are part of the cytosolic domain, in a metal chelation and/or acquisition mechanism and, as now supported by the high-resolution structural work, provides the first example of metal-thiolate coordination chemistry in zinc transporters.

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo. We used quasi-elastic light scattering (QLS) to measure age-dependent signals in lenses of healthy human subjects. Age-dependent QLS signal changes detected in vivo recapitulated time-dependent changes in hydrodynamic radius, protein polydispersity, and supramolecular order of human lens proteins during long-term incubation (~1 year) and in response to sustained oxidation (~2.5 months) in vitro. Our findings demonstrate that QLS analysis of human lens proteins provides a practical technique for noninvasive assessment of molecular aging in vivo., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Zinc is an essential element for all forms of life, and one in every ten human proteins is a zinc protein. Zinc has catalytic, structural and signalling functions and its correct homeostasis affects many cellular processes. Zinc deficiency leads to detrimental consequences, especially in tissues with high demand such as skeletal muscle. Zinc cellular homeostasis is tightly regulated by different transport and buffer protein systems. Specifically, in skeletal muscle, zinc has been found to affect myogenesis and muscle regeneration due to its effects on muscle cell activation, proliferation and differentiation. In relation to skeletal muscle, exercise has been shown to modulate zinc serum and urinary levels and could directly affect cellular zinc transport. The oxidative stress induced by exercise may provide the basis for the mild zinc deficiency observed in athletes and could have severe consequences on health and sport performance. Proteostasis is induced during exercise and zinc plays an essential role in several of the associated pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The crystal structure of a novel cubic tin(II) silicate, Sn 6 SiO 8 (space group F 4̅3 m , a = 10.40708(2) Å, and Z = 4), synthesized by microwave-assisted hydrothermal synthesis has been solved by Rietveld refinement of the powder X-ray diffraction (PXRD) data. The structure, analogous to zinc blende, comprises a face-centered-cubic array of [Sn 6 O 8 ] 4- anions, with Si 4+ occupying half of the tetrahedral holes. The tin(II) silicate has been further characterized by variable-temperature PXRD, demonstrating stability of the structure and resistance to Sn II oxidation up to ∼600 °C, when the compound begins to thermally decompose.

A significant aspect of the control of cellular zinc in eukarya is its subcellular re-distribution. One of the four human vesicular zinc transporters, ZnT8, supplies the millimolar zinc concentrations of insulin granules in pancreatic β-cells, affecting insulin processing, crystallisation and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc and/or channels zinc to the transport site in the transmembrane domain (TMD). A common variant W325R in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. To investigate the differences between the two protein variants, we purified and biophysically characterised both variants of the ZnT8 CTD [R325 variant of ZnT8 CTD (aa267-369) (ZnT8cR) and W325 variant of ZnT8 CTD (aa267-369) (ZnT8cW)]. The domains fold independently of the TMD. Remarkably, the ZnT8cW variant (diabetes protection in the full-length protein) is less thermostable than the ZnT8cR variant (diabetes risk in the full-length protein). The ZnT8cW monomers associate with higher affinity. Both CTD variants bind zinc with a stoichiometry that differs from bacterial homologues, emphasising the limitation of the latter as models for the structure and function of the human proteins. The relatively small but reproducible differences between the two ZnT8 CTD variants begin to provide a molecular basis for the different diabetes susceptibility caused by the full-length ZnT8 proteins., (© 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding ε-sarcoglycan (ε-SG); the mouse homolog of this gene is Sgce. Paternally-inherited Sgce heterozygous knockout (Sgce KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of Sgce KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out., Methodology/principal Findings: The protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in Sgce KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in Sgce KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in Sgce KO mice without altering DAT and D1R. Sgce KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates., Conclusion/significance: The results suggest ε-SG may have a role in the regulation of D2R expression. The loss of ε-SG results in decreased striatal D2R, and subsequently leads to increased discharge of dopamine which could contribute to the behavioral impairment observed in DYT11 dystonia patients and in Sgce KO mice. The results suggest that reduction of striatal D2R and enhanced striatal dopamine release may contribute to the pathophysiology of DYT11 M-D patients.

In rat, injection of the specific cholinotoxin, 192 IgG-saporin, into the medial septum results not only in a selective cholinergic denervation of hippocampus, but in an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion, into the hippocampus. A similar process, in which peripheral noradrenergic axons invade hippocampus, may also occur in Alzheimer's disease. Since apoptotic cell death has been demonstrated in the selective neuronal loss found in Alzheimer's disease, the aim of this study was to measure apoptotic protein expression and DNA fragmentation in hippocampal sympathetic ingrowth and cholinergic denervation. Western blot, TdT-mediated dUTP nick end labeling, and oligo ligation techniques were used. Choline acetyltransferase activity and norepinephrine concentrations were also measured. As seen in our previous results, an increase in apoptotic markers was induced by cholinergic denervation alone (medial septum lesion + ganglionectomy), while hippocampal sympathetic ingrowth (medial septum + sham ganglionectomy) reduced or normalized apoptotic effects to control group levels. A decrease in choline acetyltransferase activity was also found in the dorsal hippocampus of hippocampal sympathetic ingrowth and cholinergic denervation groups. An increase in norepinephrine concentration was found in hippocampal sympathetic ingrowth but not in cholinergic denervation group. Results of this study suggest that cholinergic denervation is responsible for most of the proapoptotic responses, while hippocampal sympathetic ingrowth produces a protective effect in the process of programmed cell death in rat dorsal hippocampus. This effect may be a secondary to an altered relationship between norepinephrine-acetylcholine.

In this study, the effect of intraseptal injection of specific cholinotoxin 192-IgG saporin (SAP) +/- intraperitoneal injection of N-[chloroethyl]-N-ethyl-2-bromobenzylamine (DSP-4) (noradrenergic fiber neurotoxin) was examined in rat hippocampus. Medial septal lesions resulted not only in selective cholinergic denervation of hippocampus (Medial septal lesion + ganglionectomy; SAP + Gx) but also in hippocampal sympathetic ingrowth (IG) of adrenergic fibers (Medial septal lesion + sham ganglionectomy; SAP + IG). Saporin-induced septal lesions produced a significant reduction in hippocampal choline acetyltransferase activity in all tested groups (SAP + IG +/- DSP-4 and SAP + Gx +/- DSP-4), and an increase in noradrenaline concentration in the SAP + IG group. Visualization of noradrenergic fibers by histofluorescence revealed a mixture of fine and thick varicosities in the SAP + IG but only fine fibers in control and SAP + Gx animals. SAP + IG + DSP-4 lesions produced significant reduction in noradrenaline concentration in all groups with a concomitant decrease in visualization of central noradrenergic fibers in dorsal and ventral hippocampus. Treatment of SAP + IG animals with DSP-4 left mostly thick fibers, probably derived from peripheral sympathetic ingrowth. No fluorescence was seen in either the control + DSP-4 or SAP + Gx + DSP-4 animals. Apoptotic-like changes, using in situ oligonucleotide ligation techniques, were also assessed. Proapoptotic changes were seen in the SAP + Gx +/- DSP-4 group as compared to CON +/- DSP-4 groups. SAP + IG regardless of DSP-4 treatment protected hippocampal cells from apoptotic cell death when compared to positive control and SAP + Gx +/- DSP-4 groups. In summary, elevated noradrenaline concentration following specific cholinergic denervation probably reflects compensatory hippocampal ingrowth originating from the peripheral sympathetic system which may be responsible for neuroprotective effects, i.e., antiapoptosis-like effect. Since cholinergic and noradrenergic systems are known to be involved in Alzheimer's disease and related cognitive function, knowing how these neurotransmitters work after specific lesions may be of importance as an animal model of Alzheimer's disease and as a potential target for Alzheimer's disease drug therapies.

Background: Studies have reported an increase in median Lipoprotein (Lp) (a) in patients with high molecular weight (HMW) apolipoprotein (apo) (a) isoforms and renal impairment. Some studies identify Lp (a) levels as a risk factor for vascular disease in renal failure whilst others have demonstrated an association with apo (a) isoform type and vascular disease., Methods: A total of 239 patients at end-stage renal failure (ESRF) were studied prior to the initiation of dialysis. Blood was taken for Lp (a) levels and apo (a) isoforms. Clinical vascular disease (CVD) was assessed on the basis of clinical history and Rose questionnaire. The control group for Lp (a) levels consisted of 228 healthy volunteers., Results: Despite a higher median Lp (a) level in those with HMW isoforms, 30% of patients had Lp (a) levels <10 mg/dl. Overall, 49% patients were identified as having CVD. Diabetes, smoking history and Lp (a) levels were significantly associated with CVD in logistic regression analysis, although when patients with low molecular weight (LMW) and HMW isoforms were analysed separately, Lp (a) levels were not significantly associated with CVD in those with LMW isoforms. The rates of CVD in those with HMW isoform and low Lp (a) levels were significantly lower than those with HMW isoforms and elevated Lp (a) levels, 34 vs 57% (P < 0.01)., Conclusions: Although median Lp (a) levels in those patients at ESRF with HMW isoforms are higher than controls, in a third of such patients Lp (a) levels remain relatively low. These patients have lower rates of CVD than those with high levels of Lp (a).

Background: Total homocysteine (tHcy) and lipoprotein(a) [Lp(a)] levels have been recognized as risk factors for vascular disease. The combination of elevated tHcy and Lp(a) levels may be particularly atherogenic, although no study has examined the prevalence of the combination of both risk factors in patients with chronic renal impairment., Methods: One hundred ninety-seven patients with renal impairment were studied. Patients had glomerular filtration rate (GFR) measured by clearance of chromium 51-labeled EDTA. Blood was obtained for the determination of tHcy, Lp(a), and apolipoprotein(a) [apo(a)] isoform levels., Results: Patients were divided into five groups according to GFR. Mean tHcy levels in the five groups were as follows: GFR less than 10 mL/min, 30.2 +/- 9.8 (SD) micromol/L; GFR of 10 to 20 mL/min, 26.6 +/- 10.5 micromol/L; GFR of 20 to 30 mL/min, 23.9 +/- 8.6 micromol/L; GFR of 30 to 45 mL/min, 22.2 +/- 8.6 micromol/L; and GFR of 45 to 75 mL/min, 18.2 +/- 9.1 micromol/L compared with control levels of 12.7 +/- 4.6 micromol/L. There was a progressive increase in median Lp(a) levels with declining renal function: median Lp(a) levels for those with a GFR less than 10 mL/min were 37.1 mg/dL (range, 0.6 to 156.0 mg/dL); GFR of 10 to 20 mL/min, 30.3 mg/dL (range, 2.6 to 163.7 mg/dL); GFR of 20 to 30 mL/min, 26.1 mg/dL (range, 0.0 to 164.0 mg/dL); GFR of 30 to 45 mL/min, 20.9 mg/dL (range, 0.0 to 99.8 mg/dL), and GFR of 45 to 75 mL/min, 16.8 mg/dL (range, 2.1 to 81.0 mg/dL) compared with control values of 12.5 mg/dL (range, 0.0 to 88.7 mg/dL)., Conclusion: Defining hyperhomocysteinemia as tHcy levels greater than the 90th percentile of controls and elevated Lp(a) level as greater than 30 mg/dL, the frequency of the combination increased with declining renal function. Fifty-eight percent of patients with a GFR less than 10 mL/min had both hyperhomocysteinemia and elevated Lp(a) levels, and even in patients with mild renal impairment, 20% of patients had both risk factors present., (Copyright 2002 by the National Kidney Foundation, Inc.)

Cholinergic denervation of the hippocampal formation, via medial septal lesions, induces peripheral noradrenergic fibers, originating from the superior cervical ganglion, to grow into the hippocampus. We have previously reported that cholinergic denervation and hippocampal sympathetic ingrowth differentially affect guanosine-5'-O-(3-thiotriphosphate)- as well as guanosine-5'-O-(3-thiotriphosphate) + carbachol-stimulated polyphosphoinositide hydrolysis, suggesting an alteration in G proteins and/or the entire receptor complex. To examine the type of G protein which may be involved in these effects, rat dorsal hippocampal membranes were preincubated with pertussis toxin in the presence of guanosine-5'-O-(3-thiotriphosphate) and guanosine-5'-O-(3-thiotriphosphate) + carbachol. Pertussis toxin reduced guanosine-5'-O-(3-thiotriphosphate) in all groups, while guanosine-5'-O-(3-thiotriphosphate) + carbachol-stimulated phosphoinositide hydrolysis was reduced in controls and animals without sympathetic ingrowth but not in animals with hippocampal sympathetic ingrowth. This suggests that pertussis toxin-sensitive G proteins may be involved in the mediation of phosphoinositide hydrolysis. To confirm this hypothesis, membranes were preincubated with antibodies to Galphao and Gq/11. The Go antibody significantly decreased guanosine-5'-O-(3-thiotriphosphate) in all groups, while guanosine-5'-O-(3-thiotriphosphate) +carbachol-stimulated phosphoinositide hydrolysis was reduced only in hippocampal sympathetic ingrowth. Impairment of guanosine-5'-O-(3-thiotriphosphate) and carbachol-stimulated phosphoinositide hydrolysis was also decreased in all groups when preincubated with Gq/11 antibody. To determine whether hippocampal sympathetic ingrowth or cholinergic denervation altered the concentration of various G proteins, immunoblotting methodology was utilized. Gq/11 concentrations were found to be equivalent among groups. The density of Go1, Go2, and Go3 isoforms was significantly increased in the cholinergic denervation, while in the hippocampal sympathetic ingrowth only group Go3 was significantly increased. When assessed as total Go protein, density was increased significantly only in the cholinergic denervation group. Overall, these results suggest that hippocampal sympathetic ingrowth and cholinergic denervation induce alterations in phosphoinositide hydrolysis through both the Gq/11 and the Go proteins and that the coupling between muscarinic receptor and G protein is the possible site which affects changes in phosphoinositide turnover. Our results also suggest that cholinergic denervation and hippocampal sympathetic ingrowth may mediate phosphoinositide hydrolysis through an effect on different isoforms of the same G protein., (Copyright 2000 Academic Press.)

An immunoblotting method using prefrontal cortical and hippocampal membranes from control and Alzheimer disease postmortem brains was employed to detect three subtypes of Galphao protein. In the membranes from control subjects, the density of Galphao1 in hippocampus and cortex was the highest, whereas the density of Galphao2 was the lowest and that of Galphao3 was intermediate. In the Alzheimer disease membranes from hippocampus, the density of total Galphao and all three subtype forms was not changed significantly when compared with control values. There were statistically significant alterations in Galphao in cortical membranes from Alzheimer disease when compared with controls. The density of Galphao1 was decreased by approximately 85%, density of Galphao3 was decreased by approximately 95%, and total Galphao density was decreased by approximately 84% of control value. However, Galphao2 density was decreased by approximately 44% but was found not to be statistically different from controls.

Following cholinergic denervation of the hippocampus by medial septal lesions, an unusual neuronal reorganization occurs in which peripheral adrenergic fibers arising from the superior cervical ganglia grow into the hippocampus (hippocampal sympathetic ingrowth). We have reported previously that cholinergic denervation and hippocampal sympathetic ingrowth differentially affected cholinergically stimulated phosphoinositide hydrolysis, concentration and affinity of muscarinic receptors, Go-protein level and protein kinase C activity. To complete these studies, we determined whether cholinergic denervation and hippocampal sympathetic ingrowth influenced phospholipase C and protein kinase C expression in dorsal hippocampal membranes and cytosol. Using immunoblotting methods, the results showed that the 100,000 mol. wt subunit of phospholipase Cbeta was increased in the membrane fraction in the hippocampal sympathetic ingrowth group by 45% compared to controls and the 150,000 mol.wt subunit was increased by 75% and 59% compared to controls and cholinergic denervation, respectively. For protein kinase C detection, immunoblots were prepared using antibodies selective for "classical" protein kinase C members (alpha, beta, gamma) and for the "novel" protein kinase C subfamily members (delta, &theta;). Membrane protein kinase Cbeta was decreased in hippocampal sympathetic ingrowth by 35% compared to controls and by 41% compared to cytosolic hippocampal sympathetic ingrowth. Membrane protein kinase Cbeta was decreased in cholinergic denervation by 28% compared to controls. When compared to membranes from controls and the cholinergic denervation group, and to cytosolic fractions from the hippocampal sympathetic ingrowth groups, respectively, the following membrane protein kinase isoforms were found to be decreased by hippocampal sympathetic ingrowth: gamma by 55%, 40% and 57%; delta by 91.5%, 70% and 120%; theta; by 95%, 100% and 86%.In conclusion, our results may indicate the connection between the previously reported differential influence of hippocampal sympathetic ingrowth and cholinergic denervation on cholinergically stimulated phosphoinositol hydrolysis. The "normalization" of phosphoinositol hydrolysis found in hippocampal sympathetic ingrowth may be due to the increase in phospholipase Cbeta expression in hippocampal sympathetic ingrowth membrane fractions. Since the activation of protein kinase C is known to block phosphoinositol hydrolysis, hippocampal sympathetic ingrowth "normalization" of phosphoinositol hydrolysis may result from a reduction in protein kinase expression in hippocampal sympathetic ingrowth membranes.

Objective: The cause of pediatric chronic sinusitis is multifactorial, but nasal edema appears to be the initial pathologic step. The objective of this study is to evaluate gastronasal reflux as a possible cause of pediatric sinusitis., Methods: Thirty children with chronic sinusitis were believed to be appropriate candidates for functional endoscopic sinus surgery. Children were evaluated retrospectively for their response to reflux therapy with regard to their sinus symptoms and avoidance of sinus surgery., Results: Two of the 30 children were eventually excluded because they were taken to surgery for the specific purpose of contact point release. Chart review at 24-month follow-up indicated that 25 of the 28 children (89%) avoided sinus surgery., Conclusion: After reflux treatment, the number of children requiring sinus surgery was dramatically reduced. The results of this preliminary pediatric study indicate that gastronasal reflux should be evaluated and treated before sinus surgical intervention.

Prior to endonasal endoscopic advances for the treatment of sinus disease, surgical results for aviators with recurrent sinus barotrauma (RSB) were inconsistent. Between 1988 and 1992, 54 aviators, who were permanently or temporarily grounded, underwent functional endoscopic sinus (FES) surgery in an attempt to return them to active flying status. Follow-up in the immediate postoperative period revealed that 98% of these aviators returned to active flight duty. A questionnaire was mailed to each of these aviators to compare their preoperative and long-term postoperative symptoms and determine their current flying status. Long-term follow-up time ranged from 20 to 72 mo with average of 48 mo. Of the aviators who responded to the survey, 92% have continued their flying duties and do not report difficulties with RSB. We conclude that FES surgery is effective in the short- and long-term management RSB in aviators.

Botryomycosis is a chronic bacterial granulomatous disease often involving the skin and subcutaneous tissue. Head and neck involvement is rare. Botryomycosis presents with clinical and histological features similar to actinomycosis or mycetoma, but the causative organism is usually Staphylococcus aureus. Microscopically the organisms appear to be encapsulated in granules, which are thought to protect them from the effects of standard courses of antibiotics. Botryomycosis usually requires surgical intervention for cure. Major debilitating surgery has been required for most patients, because the infection has been unresponsive to seemingly appropriate medical therapy. We present an 8-month-old male with periorbital botryomycosis. Surgical specimens for diagnosis were obtained, but complete resection would have created debilitating functional and cosmetic defects. The lesion failed to respond to nafcillin alone or combination therapy with hyperbaric oxygen, but showed slow, steady improvement with long-term clindamycin. The patient has been disease free for more than 4 years, with minimal scarring and no functional impairment. Prolonged medical therapy for botryomycosis may be a viable alternative to the traditionally recommended surgical resection, thereby reducing cosmetic and functional morbidity.

Our laboratory has been utilizing the model of hippocampal sympathetic ingrowth, which has been suggested to occur in Alzheimer's disease, to investigate the effects of cholinergic denervation and hippocampal rearrangements. After cholinergic denervation by medial septal lesions, peripheral sympathetic fibres originating from the superior cervical ganglia grow into the rat hippocampus. This hippocampal sympathetic ingrowth can be prevented by superior cervical ganglionectomy. We examined the long-term effects of these treatments on muscarinic receptors by comparing [3H]quinuclidinyl benzilate binding in rat dorsal hippocampus four and 12 weeks post lesion. Four groups of animals were employed, including controls (sham lesion+sham ganglionectomy), animals with ingrowth (medial septal lesion+ sham ganglionectomy), animals with cholinergic denervation alone (medial septal lesion+ ganglionectomy), and ganglionectomy alone (sham lesion+ganglionectomy) animals. In dorsal hippocampus four weeks post lesion, binding affinity was similar among all groups, while muscarinic receptor number was increased in ingrowth animals as compared to both the control (P<0.0002) and ganglionectomy animals (P<0.01). By 12 weeks, receptor affinity was significantly decreased in ingrowth (P<0.0001) and cholinergic denervation (P<0.0003) groups, and receptor number remained significantly elevated in ingrowth animals as compared to control (P<0.01), ganglionectomy (P<0.02) and cholinergic denervation (P<0.01) groups. The decrease in muscarinic receptor affinity may provide some insight into the ineffectiveness of cholinomimetic therapies in Alzheimer's disease, in that agonist efficacy would be reduced at the receptor.

The quality of life of patients with end-stage renal disease (ESRD) has become an area of intensive investigation because of the high costs of renal-replacement therapy (dialysis or renal transplantation) and the rising prevalence of renal failure. Studies comparing quality of life of patients using different forms of renal-replacement therapy are flawed by deficiencies in study design, such as lack of randomisation. Nevertheless, in both retrospective and prospective studies, transplantation has been shown to offer the highest levels of functional ability, employment and subjective quality of life. After case-mix adjustment, there is little difference between peritoneal dialysis and haemodialysis in terms of quality-of-life (QOL) outcomes. Vocational rehabilitation is an important aim of therapy; for patients below retirement age, pre-dialysis education and counselling are important in maintaining employment. The elderly comprise the fastest-growing group of dialysis recipients; multiple comorbidities add to functional impairment in these patients. Subjective quality of life remains surprisingly high in many elderly patients, despite poor objective quality of life. The quality of life of patients with diabetes mellitus and ESRD is lower than that of nondiabetic patients with ESRD. For selected patients with insulin-dependent diabetes mellitus, combined renal and pancreatic transplantation offers the advantage of freedom from insulin injections. Unfortunately, available evidence suggests only small improvements in quality of life with combined transplantation versus kidney-only transplantation, probably because many patients have developed multiple diabetic complications by the time of transplantation. Epoetin alfa (erythropoietin) has been shown to improve quality of life in a number of trials. The optimal target haematocrit is a subject of controversy, but on current evidence, a target of 34 to 37% is reasonable. The degree of improvement in quality of life must be balanced against the additional costs of achieving a higher haematocrit. Further study is necessary to clarify the optimal target haematocrit for epoetin alfa therapy, as well as the possible effects of nutritional support, growth hormone in paediatric patients, and combined renal and pancreatic transplantation in improving quality of life.

The etiology of respiratory failure associated with Stevens-Johnson syndrome may be multifactorial, including upper airway involvement, pneumothorax/pneumomediastinum, and direct involvement of the respiratory mucosa. Respiratory failure from direct involvement of the respiratory mucosa is relatively uncommon. We describe a 9-year-old boy who had respiratory failure associated with Mycoplasma pneumoniae-induced Stevens-Johnson syndrome. Bronchoscopic examination of the airways revealed sloughed mucosa, ulcerative lesions, and inspissated secretions indicative of lower airway involvement with Stevens-Johnson syndrome. Although the mainstay of therapy is supportive care with controlled ventilation, rigid bronchoscopy with bronchoalveolar lavage to clear the airways of the debris was an invaluable adjunct to this patient's care.

Laryngotracheoesophageal (LTE) clefts are rare anomalies of the airway. Surgical correction has been performed in all cases reported in the literature for clefts diagnosed during life. Posterior laryngeal clefts (PLC) are defined as minor (type I) to severe (type IV), with types III and IV being further described as LTE clefts. Type I clefts have been observed with an increased frequency of up to 6% of all pediatric direct laryngoscopies performed at a tertiary pediatric referral hospital. These can be managed medically and seldom require surgical correction. A case is presented of a boy whose initial diagnosis of LTE cleft (PLC type III) was made at age 7 years. His presenting complaints were chronic airway symptoms without airway distress. He developed only two episodes of pneumonia. Surgical correction was not performed. This young athlete has been followed for more than 6 years without significant problems. This appears to be the only case found in the literature of the successful management of a LTE cleft that has not required surgical correction. Photographic documentation and suggestions on endoscopic diagnosis are presented.

Following cholinergic denervation of the hippocampal formation, via medial septal lesions, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus. In previous studies, we have found that hippocampal sympathetic ingrowth and cholinergic denervation alone (animals with concurrent medial septal lesions and superior cervical ganglionectomy) alter phosphoinositide turnover and muscarinic cholinergic receptors in such a way as to suggest an alteration in coupling between the muscarinic cholinergic receptors and phosphoinositol turnover. To test this hypothesis we examined the effect of hippocampal sympathetic ingrowth and cholinergic denervation on phospholipase C activity, G-protein function and the whole receptor complex by measuring the amount of phosphoinositide hydrolysed in hippocampal membranes of the rat. Neither hippocampal sympathetic ingrowth nor cholinergic denervation was found to alter phospholipase C activity when activated by increasing concentrations of Ca2+. In dorsal hippocampus, cholinergic denervation, when compared to hippocampal sympathetic ingrowth and controls, was found to decrease the amount of phosphoinositol hydrolysed when stimulated with the GTP analog, guanosine-5'-O-(3-thiotriphosphate). When guanosine-5'-O-(3-thiotriphosphate) plus carbachol (1 mM) was utilized to stimulate the entire receptor complex, phosphoinositol hydrolysis was found to be decreased in the cholinergic denervation group as compared to both hippocampal sympathetic ingrowth and control groups. This effect was maximum at 3 microM guanosine-5'-O-(3-thiotriphosphate). These results suggest that both hippocampal sympathetic ingrowth and cholinergic denervation affect the efficiency of coupling between the muscarinic cholinergic receptors and phosphoinositol turnover, with cholinergic denervation decreasing and hippocampal sympathetic ingrowth "normalizing" efficiency. Further, they suggest that the G-protein is the site at which hippocampal sympathetic ingrowth and cholinergic denervation mediate their effects. The results of these experiments are also discussed within the context of recent findings demonstrating G-protein abnormalities in Alzheimer's disease.

Acute epiglottitis is a well-described life-threatening disease. Since the generalized use of the Haemophilus influenzae type B (HIB) vaccine, presentations of this disorder have decreased dramatically in children. Presentations of this and other acute epiglottic swelling can vary remarkably and may easily be misdiagnosed by physicians who have little or no experience with the acutely obstructed airway. Early suspicion and a proper evaluation is mandatory to prevent a life-threatening crisis. Six patients are presented with unusual presentations of acute epiglottic swelling from differing etiologies; these include the following: case 1, recurrent epiglottitis; case 2, chronic epiglottitis; case 3, traumatic epiglottitis; case 4, caustic ingestion; and cases 5 and 6, simultaneous infection of family members. Because the incidence of acute epiglottitis is decreasing, it has become rare at most institutions. To help primary care and emergency room physicians, a formal written protocol should be available at medical facilities that might be faced with patients presenting with acute airway obstruction. An "acute airway obstruction protocol" used successfully for the last decade is offered. Use of such a written document might be life-saving for patients with impending upper airway obstruction. The otolaryngologist is a key member of the recommended multidisciplinary team.

Hippocampal sympathetic ingrowth (HSI), a form of neuronal plasticity, is induced by medial septal lesions and consists of the sprouting of peripheral sympathetic fibers, arising from the superior cervical ganglion, into the dentate gyrus and CA3 region of the hippocampus. HSI has been previously shown to alter learned and spontaneous behaviors, phosphatidyl inositide hydrolysis, and the antagonist binding kinetics of both muscarinic cholinergic receptors and phorbol ester receptors. We now report that sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C (PKC) following septohippocampal denervation of the rat hippocampus. Further, no changes were found in alpha, beta or gamma PKC isoenzymes among experimental groups, suggesting that the group A PKC isoforms do not mediate the observed changes in activity and phorbol ester binding.

The posterior ethmoid air cells and the sphenoid sinuses have a complex anatomy that is surrounded by vital structures. To more easily protect these structures, three approaches are presented that make pediatric sphenoidotomy a safer procedure. The approaches include measuring the distance from the anterior nasal spine to the anterior and surgical posterior faces of the sphenoid sinus intraoperatively and comparing these to the patient's height and age, the use of the "ridge" to ensure a safe entry into the sphenoid, and, in patients where isolated sphenoid disease is present, the use of a powered instrument to enlarge the sphenoid ostium. The availability of measurements relating the height of the patient to the location of the sphenoid sinus, the use of the "ridge," and the use of powered instrumentation, should help the surgeon enter the sphenoid with greater confidence and achieve a more effective result.

Otitis media and sinusitis are common pediatric diagnoses and share common features that are described in this article. Although the anatomy, physiology, and disease processes are not identical, knowledge of the basic pathophysiology of middle ear disease often enables a clinician to have a useful working understanding of sinus disease. Recognizing these similarities provides a better understanding of their pathophysiology and treatment.

Powered instrumentation is now available for a variety of sinonasal procedures in children. Microdebriders with continuous suction at the operative site allow increased precision for complex procedures that often were difficult in small, fragile, pediatric noses. These instruments can be used for functional endoscopic sinus surgery in children and for such procedures as benign and malignant sinonasal or base of skull tumors, choanal atresia, complicated adenoidectomies, dacrocytorinostomies, septal spurs, and recurrent respiratory papillomatosis. These instruments can remove mucosa, neoplastic tissue, cartilage, thin bony septations, nasal debris, and blood under continuous endoscopic visualization. Edematous mucosa is not stripped, but trimmed and preserved, allowing much more rapid postoperative healing because exposed bone is avoided.

This article portrays the anatomy of the ethmoid bone and lateral nasal wall in a detailed, but easily digested form. Understanding the anatomy of the lateral wall of the nose is the cornerstone of competent paranasal sinus surgery.

Chronic sinusitis in children who do not have other underlying medical problems is a medically treatable disease, and surgery is not required often. Allergies, environmental factors, and gastroesophageal reflux are the three most important contributing causes of chronic sinusitis in children. Chronic sinusitis is not a primary infectious disease.

Maxillary sinus disease often is exacerbated by a laterally displaced uncinate process that functionally obstructs the infundibulum and the natural ostium. The drainage pathway may be adequate during periods of wellness but with the introduction of nasal edema, the ostium/infundibulum interface is inadequate, thus preventing acceptable ventilation and drainage. Incomplete removal of the most anterior uncinate can keep the surgeon from identifying the natural ostium. Failure to relieve any obstruction from this important opening, with simultaneous creation of an MMA that does not include the natural ostium of the maxillary sinus, leads to the missed ostium sequence and continued sinus disease.

Objective: To review the clinical features, associated congenital abnormalities, management, and morbidity of infants presenting with posterior laryngeal and laryngotracheal clefts., Design: Case series., Setting: Great Ormond Street Hospital for Sick Children NHS Trust, London, England., Patients: Consecutive sample of 44 patients presenting with posterior laryngeal and laryngotracheal clefts between December 10, 1979, and January 30, 1992., Main Outcome Measures: Clinical features, incidence of surgery, and associated morbidity and mortality related to different types of airway cleft., Results: The main presenting features were stridor and aspiration, which were more evident with the more extensive clefts. Twenty-five patients (56%) had associated congenital abnormalities. Fourteen patients (32%) were treated conservatively. Sixteen patients (36%) underwent primary endoscopic surgical repair. Eight patients (18%) underwent primary repair via an anterior laryngofissure; and six patients (14%) underwent primary repair via a lateral pharyngotomy. Eight patients (18%) required revision surgery, two (4%) of them on more than one occasion. Ten patients (23%) required fundoplication to control gastroesophageal reflux. Six patients (14%) died., Conclusions: The identification of an airway cleft requires a high index of suspicion. Morbidity and mortality are reduced by securing the airway, controlling gastroesophageal reflux, and using a multidisciplinary pediatric team. We recommend the anterior laryngofissure because of the ease of surgical access.

Twenty-nine consecutive patients with cystic fibrosis were offered functional endoscopic sinus surgery. Twenty-six of these patients underwent surgery. A symptom questionnaire was obtained from the patient or parent before surgery. At the end of the study this symptom questionnaire was again administered to the same individual, and 21 completed it. There were 14 male and 7 female patients, with a mean age of 12.3 years and a median age of 8.7 years. Mean follow-up was 34.3 months. Results for the following symptoms were significant: nasal airway obstruction was improved (p < 0.0002), olfactory function was improved (p < 0.0037), purulent nasal discharge was decreased (p < 0.001), and activity level was increased (p < 0.001). Other parameters are also reported in the text. In summary, this study prospectively studies the effects of functional endoscopic sinus surgery on symptoms in patients with cystic fibrosis. The study points out several significant areas of symptom improvement and supports the selective use of functional endoscopic sinus surgery in patients with cystic fibrosis. Indications for surgery are provided.

After cholinergic denervation of the hippocampus, via medial septal (MS) lesions, peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. In this study, we sought to determine the effect of hippocampal sympathetic ingrowth (HSI) on the M2 subtype of muscarinic cholinergic receptors, by examining the membrane binding of [3H]AF-DX 384 in hippocampal tissue from control rats, rats with HSI and rats with MS lesions + concurrent ganglionectomy (CD group). In dorsal hippocampus, Kd was found to be increased while Bmax was decreased in the CD group as compared with both the HSI and control group which did not differ from one another. In ventral hippocampus, Kd was found to be increased while Bmax was decreased in the CD group when compared only with the control group. These results suggest that sympathetic ingrowth, which has its greatest concentration in dorsal hippocampus, can 'normalize' the M2 receptor in hippocampus.

Following cholinergic denervation of the hippocampus by medial septal (MS) lesions, an unusual neuronal reorganization occurs in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus (hippocampal sympathetic ingrowth; HSI). Previously, we have found that with MS lesions, animals with (the HSI(+) group) and without (HSI(-) group) ingrowth differed in carbachol stimulated PI hydrolysis, in PKC activity, and in muscarinic cholinergic receptors (mAChR). In this study, performed in hippocampal slices obtained four weeks after MS lesions, we utilized the hydrophilic muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) and hydrophobic muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) in the presence of either 4-alpha-phorbol or phorbol 12,13-dibutyrate (PDBu) to determine the effect of MS lesions with and without ingrowth on PKC-mediated mAChR internalization. In the presence of PDBu, a group effect was observed in [3H]NMS binding, with control groups > HSI(+) group > HSI(-) group. However, [3H]QNB binding was similar across groups. These results suggest that the cholinergic denervation of the hippocampus enhances the internalization of mAChRs, which is modified in the presence of HSI.

Following cholinergic denervation of the hippocampus by medial septal lesions, and unusual neuronal reorganization occurs, in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. Previously, we have found that both hippocampal sympathetic ingrowth (HSI) and cholinergic denervation (CD), alone, altered the total number and affinity of muscarinic cholinergic receptors (mAChR). In this study, we utilized the muscarinic antagonist [3H]Pirenzepine, in combination with membrane radioligand binding techniques, to determine the effects of HSI and CD on hippocampal M1 and M1 + M3 mAChR subtypes, 4 weeks after MS lesions. In both the dorsal and ventral hippocampus, HSI was found to markedly diminish the number of M1 AChRs, while CD was found to increase the number of M1 AChRs. Neither treatment affected the affinity of the M1 AChR. However, when M1 + M3 binding was assessed, CD was found to decrease the affinity in both hippocampal regions, without altering the number of receptors. Neither affinity nor number of M1 + M3 receptors was altered by HSI. The results of this study suggest that both cholinergic denervation and hippocampal sympathetic ingrowth uniquely affect hippocampal muscarinic receptors.

Cholinergic denervation of the hippocampus by medial septal (MS) lesions results in the ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglia, into the hippocampus. To determine the effect of hippocampal sympathetic ingrowth (HSI) [3H]-QNB (L-quinuclidinyl [benzilic-4,4(n)] binding was assessed in the dorsal and ventral hippocampus four weeks after MS lesions. In dorsal hippocampus, HSI was found to significantly increase the number (Bmax) of [3H]-QNB binding sites and to normalize the decrease in affinity found in animals with MS lesions plus ganglionectomy (i.e., no ingrowth). In ventral hippocampus, HSI was found to normalize the increased number of binding sites and decreased affinity found in animals with MS lesions without ingrowth. No effect on either Kd or Bmax was found in animals that had undergone ganglionectomy with sham MS lesions. These results suggest that HSI can induce changes in hippocampal muscarinic cholinergic receptors.

The relationship between cystic fibrosis (CF) and sinus disease has been appreciated since at least 1959. Unfortunately the standard methods used to treat sinus disease have been very unrewarding in the CF patients. We evaluated the long-term results achieved on 17 patients with CF that underwent FES surgery between July 1988 and January 1991. This group consisted of 16 pediatric and 1 adult patients with previously diagnosed CF, documented chronic sinus disease and nasal polyposis that had failed long-term maximal medical management. The patients, or their parents, were contacted and asked to rate the severity and frequency of their symptoms associated with chronic sinus disease, pre- and postoperatively. The specific symptoms evaluated were nasal obstruction, nasal discharge, postnasal drip, halitosis and cough. In addition, we attempted to measure the number of hospitalizations and the presence and frequency of headaches. We were able to show that, while there was no change in the relative health of patients as measured by the number of hospitalizations, there was a significant improvement in the quality of life. There was a marked decline in the frequency of nasal obstruction, nasal discharge and postnasal drip and a high level of patient satisfaction with the procedure. No changes were seen in the frequency or nature of the cough, halitosis or headache.