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Modulation of the immune response using immunoglobulin fusion proteins has shown great promise for clinical immunotherapy of autoimmune diseases. Alefacept is an immunoglobulin fusion protein composed of the first extracellular domain of human LFA-3 fused to the hinge, C(H)2 and C(H)3 domains of human IgG(1). Alefacept has previously been reported to inhibit T cell proliferation. Here, we analyzed the effects of alefacept on lymphocytes in vitro and characterized the role of autologous NK cells in its mechanism of action. Alefacept, but not a C(H)2 binding mutant of Alefacept, inhibited CD3-induced T cell proliferation only in the presence of live NK cells, consistent with an important role for FcgammaR engagement. Alefacept caused preferential depletion of CD69+CD45R0+CD25+ T cell subsets. Cytotoxicity assays revealed that alefacept, but not the C(H)2 binding mutant, induced NK cell-mediated death of activated T cells and sorting into CD45R0+ and CD45RA+ subpopulations showed that lymphocyte deletion occurred preferentially in the CD45R0+ subset. Activated CD45R0+ cells expressed higher levels of CD2 than CD45R0- cells, providing a possible explanation for the selective targeting of this subset. Our results suggest that selective targeting of CD45R0+ T cells by NK cells represents a potential therapeutic mechanism of action of alefacept.

A midline exploratory laparotomy on a 1-year-old, neutered male, West Highland terrier with a history of lethargy, anorexia, and intermittent vomiting revealed a cranial abdominal cyst. The lining of the excised cyst was histologically identical with that of the small intestine and may have represented an uncommon intestinal malformation.

This Account summarizes techniques for fabrication and applications in biomedicine of microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS). The methods and applications described focus on the exploitation of the physical and chemical properties of PDMS in the fabrication or actuation of the devices. Fabrication of channels in PDMS is simple, and it can be used to incorporate other materials and structures through encapsulation or sealing (both reversible and irreversible).

The mechanism of muscle protein catabolism induced by proteolysis-inducing factor, produced by cachexia-inducing murine and human tumours has been studied in vitro using C(2)C(12) myoblasts and myotubes. In both myoblasts and myotubes protein degradation was enhanced by proteolysis-inducing factor after 24 h incubation. In myoblasts this followed a bell-shaped dose-response curve with maximal effects at a proteolysis-inducing factor concentration between 2 and 4 nM, while in myotubes increased protein degradation was seen at all concentrations of proteolysis-inducing factor up to 10 nM, again with a maximum of 4 nM proteolysis-inducing factor. Protein degradation induced by proteolysis-inducing factor was completely attenuated in the presence of cycloheximide (1 microM), suggesting a requirement for new protein synthesis. In both myoblasts and myotubes protein degradation was accompanied by an increased expression of the alpha-type subunits of the 20S proteasome as well as functional activity of the proteasome, as determined by the 'chymotrypsin-like' enzyme activity. There was also an increased expression of the 19S regulatory complex as well as the ubiquitin-conjugating enzyme (E2(14k)), and in myotubes a decrease in myosin expression was seen with increasing concentrations of proteolysis-inducing factor. These results show that proteolysis-inducing factor co-ordinately upregulates both ubiquitin conjugation and proteasome activity in both myoblasts and myotubes and may play an important role in the muscle wasting seen in cancer cachexia., (comCopyright 2002 Cancer Research UK)

A solid-object printer was used to produce masters for the fabrication of microfluidic devices in poly(dimethylsiloxane) (PDMS). The printer provides an alternative to photolithography for applications where features of > 250 microm are needed. Solid-object printing is capable of delivering objects that have dimensions as large as 250 x 190 x 200 mm (x, y, z) with feature sizes that can range from 10 cm to 250 microm. The user designs a device in 3-D in a CAD program, and the CAD file is used by the printer to fabricate a master directly without the need for a mask. The printer can produce complex structures, including multilevel features, in one unattended printing. The masters are robust and inexpensive and can be fabricated rapidly. Once a master was obtained, a PDMS replica was fabricated by molding against it and used to fabricate a microfluidic device. The capabilities of this method are demonstrated by fabricating devices that contain multilevel and tall features, devices that cover a large area (approximately 150 cm2), and devices that contain nonintersecting, crossing channels.

CR-EAE is a Th1-mediated inflammatory autoimmune demyelinating disease of the CNS and serves as a model of human multiple sclerosis. Our previous studies have shown the protective effect of orally administered lisofylline in the prevention of active and passively induced acute EAE. In our present studies we have examined the efficacy and mechanism of action of lisofylline on CR-EAE. Lisofylline decreased the number and severity of paralytic attacks in mice with relapsing EAE. The reduction of clinical disease correlated with decreased levels of mRNA levels of IFN-gamma but not of mRNA levels of IL-12. These studies suggest that lisofylline may be an effective therapeutic for established Th1 mediated autoimmune disease and that it acts by blocking IL-12R signaling and not IL-12 production in vivo.

Guillain-Barré syndrome is considered to be an immune mediated disorder but the relative role of T cells and antibodies in its pathogenesis is unclear. As gut infection with Campylobacter jejuni is the most common antecedent infection it is possible that gut derived T lymphocytes might play a part in the development of the syndrome. The T cell receptor phenotype (TCR) of a nerve gamma delta T cell line obtained from a sural nerve biopsy taken from a patient with a demyelinating form of GBS was determined using polymerase chain reaction (PCR) and flow cytometry (FACS). This TCR was compared with the phenotype preferentially expressed in the peripheral blood of the same patient. The T cell nerve line was found to express V gamma 8/delta 1 which represents an unusual T cell subset normally found on lymphocytes resident in epithelial tissue such as the gut. The peripheral blood gamma delta T lymphocytes from the patient were of the V gamma 9/delta 2 subset, which is the phenotype predominantly expressed in the peripheral blood of healthy subjects. In conclusion, the presence of this unusual population of V gamma 8/delta 1(+) lymphocytes in nerve would be consistent with a pathogenetic role for gut associated lymphocytes in the pathogenesis of Guillain-Barré syndrome associated with C jejuni.

A single injection of nitric oxide (NO) synthase (NOS) inhibitors prevents the development of persistent hyperalgesia induced by various manipulations, suggesting that NO precipitates long-term changes in nociception. We examined the possibility that inhibition of NOS may also be sufficient to produce long-term decreases in nociceptive assays, such as writhing, that are known to be sensitive to the short-term effects of NOS inhibitors. We characterized short- and long-term effects of NOS inhibitors, N(omega)-nitro-L-arginine (L-NAME) or 7-nitro indazole (7-NI) injected intrathecally (i.t.) in mice on acetic acid-induced writhing. Doses of L-NAME that had no effect on hot plate or tail flick latencies inhibited writhing (0. 01-30 nmol) as well as spinal nNOS activity (5 and 100 nmol) when injected i.t. 60-90 min before testing. Anti-nociception was not mimicked by D-NAME but was prevented by co-administration with the NO precursor, L-arginine. Injection i.t. of 7-NI (30 min), a selective inhibitor of neuronal NOS (nNOS), inhibited NOS activity in the spinal cord and produced anti-nociception, confirming that writhing is sensitive to inhibition of nNOS. Although the acute action of both NOS inhibitors dissipated completely by 3-6 h, a delayed and prolonged inhibition of writhing was again observed 24 h after L-NAME (5-100 nmol), a time when spinal NOS activity was no longer inhibited by L-NAME (5 and 100 nmol) or 7-NI (25 nmol). This novel effect appears to be initiated by the transient inhibition of nNOS as delayed anti-nociception was mimicked by 7-NI at doses (10-100 nmol) that no longer inhibited spinal nNOS (25 nmol) at 24 h. Co-administration with L-arginine prevented the delayed (24 h) anti-nociceptive effects of L-NAME (30 nmol). L-Arginine (30 and 100 nmol) was without effect on nociception when administered alone 60 min or 24 h prior to testing. Together these data indicate that brief changes in the activity of nNOS induce both long- as well as short-term changes in nociception.

Problem: To determine the ontogeny of major histocompatibility complex (MHC) expression and TAP products in mouse embryos., Method of Study: mRNAs encoding MHC and associated molecules were identified by reverse transcriptase-polymerase chain reaction, and the protein products were localized by confocal microscopy., Results: mRNAs encoding class Ia (H-2Db) and class Ib (Q7/9) were present in one-cell embryos, whereas beta 2-microglobulin (beta 2-m) transcripts were not detected until the two-cell stage. Transporter TAP1, but not TAP2, transcripts were detected only in blastocysts. H-2 class Ia (classical) protein was detected on the surface of two-cell embryos, H-2 class Ib (nonclassical) protein was detected on one-cell embryos, and beta 2-m transcripts were detected on eight-cell embryos; TAP1 protein was present at low levels in the cytoplasm from the one-cell stage onward, increasing in expression in blastocysts., Conclusions: In mice, MHC class I mRNAs encoding the heavy chain of H-2- and Q7/9-encoding Qa2 molecules are synthesized soon after conception prior to implantation. Similarly, the nonpolymorphic MHC class I-associated molecule beta 2-m also is expressed before implantation. TAP1, but not TAP2, is first detected at the blastocyst stage, thus preceding the onset of TAP2 in embryonic development.

Homographs and homophones have interesting linguistic properties that make them useful in many experiments involving language. To assist researchers in the elicitation of homophones, this paper presents a set of 93 line-drawn pictures of objects with homophonic names and a set of 108 questions with homophonic answers. Statistics are also included for each picture and question: Picture statistics include name-agreement percentages, dominance, and frequency statistics of depicted referents, and picture-naming latencies both with and without study of the picture names. For questions, statistics include answer-agreement percentages, difficulty ratings, dominance, frequency statistics, and naming latencies for 60 of the most consistently answered questions.

We have measured the level of vascular endothelial growth factor (VEGF) in maternal plasma during normotensive pregnancy and in pregnancies complicated by pre-eclampsia. VEGF was measured using a competitive enzyme immunoassay. Plasma VEGF was significantly elevated (P < 0.0001) in the pre-eclamptic group (median value 32.7 ng mL-1, range 10.3-64.0), compared with the normotensive group (median value 11.7 ng mL-1, range 6.3-24.3). VEGF is a potent regulator of endothelial cell function. The increased level found in women with pre-eclampsia indicates that VEGF may be involved in the maternal endothelial cell dysfunction associated with this condition. An increase in VEGF, a potent regulator of microvascular permeability, may also contribute to the extravasation of plasma proteins and the subsequent development of proteinuria, both characteristic features of pre-eclampsia.

Objective: To measure the mRNA levels of vascular endothelial growth factor and its receptor in the placenta following delivery after uncomplicated pregnancy and after pregnancies complicated by pre-eclampsia., Setting: Rosie Maternity Hospital, Cambridge., Material: Placental biopsies were obtained following delivery by caesarean section in 23 cases of pregnancy presenting at a range of gestational ages with pre-eclampsia. These were compared with biopsies from 20 appropriately matched women with uncomplicated pregnancies., Main Outcome Measure: mRNA levels of vascular endothelial growth factor (VEGF) and its receptor the fins-like tyrosine kinase (flt), were quantified in total RNA isolated from placental biopsies using the RNAse protection assay. The amount of RNA was compared with that of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH), used as a standard. Results were expressed as arbitrary optical density units of VEGF/GAPDH and flt/GAPDH., Results: In both control and pre-eclamptic women regression analysis showed that the level of mRNA encoding VEGF declined significantly with gestational age (P < 0.0001). However, levels of VEGF mRNA were significantly lower in the pre-eclamptic women compared with the control women (P < 0.023)., Conclusions: This study provides evidence of an abnormality of growth factor expression in the placenta during pregnancies complicated by pre-eclampsia. Such placentae exhibit deficient growth and differentiation of terminal villi and reduced fetal capillary branching and reduced levels of VEGF could well account for these morphometric changes. This finding provides a molecular explanation for this abnormal placental development and points to VEGF as a factor in the aetiology of pre-eclampsia and its complications.

Prostacyclin and thromboxane are potent antagonistic regulators of vascular tone and platelet aggregation. In pre-eclampsia, the ratio of their metabolites is decreased. Little is known about the local regulation of intrauterine prostacyclin and thromboxane production in this condition. Placenta and placental bed biopsies were obtained from uncomplicated and pre-eclamptic pregnancies. Prostacyclin synthase (PCS) and thromboxane synthase (TXS) and their mRNA's were localized by immunohistochemistry using monoclonal antibodies and in situ hybridization. Protein and mRNA levels were quantified by immunoblot and RNase protection assay. PCS-like immunoreactivity was found in endothelial cells and leiomyocytes, whereas fetal and maternal macrophages showed positive staining for TXS. Their mRNA was localized to trophoblast and endothelium, and TXS mRNA could also be detected in macrophages. Quantitative analysis showed no significant difference in intrauterine protein or mRNA expression after pre-eclampsia. The prostacyclin and thromboxane production seems to be compartmentalized within the uteroplacental unit. The expression of their synthesizing enzymes might be regulated post-transcriptionally. Additional regulation of prostaglandin production could be metabolically or on the substrate level and requires further elucidation.

The fetal rat muscle nicotinic acetylcholine receptor was expressed in Xenopus oocytes. Using the voltage-clamp technique, the response to a range of agonists was measured, listed in order of (decreasing) activity efficacy: anatoxin > or = epibatidine > acetylcholine > DMPP (1,1-dimethyl-4-phenylpiperazinium) > > cytisine > pyrantel > nicotine > coniine > tubocurare > lobeline. The agonist responses were compared with the steric and electrostatic properties of the molecules, using molecular modelling. Single-channel current were measured in outside-out patches for acetylcholine, nicotine, cytisine, anatoxin and epibatidine. The conductance of the single channels was independent of the type of agonist. The mean open times were characteristic of the agonist applied. Tubocurare, better known for its antagonist properties, was also a partial agonist. Single-channel currents were also observed for tubocurare, and for methyllycaconitine in patches with a very high density of the muscle nicotinic acetylcholine receptor, and these were blocked by alpha-bungarotoxin. The agonist properties of physostigmine, galanthamine and their methyl derivatives were also investigated. The conductance of the channels observed in outside-out patches was similar to that obtained for the classical agonists. The single-channel currents observed for physostigmine, galanthamine and their methyl derivatives were blocked by alpha-bungarotoxin, methyllycaconitine and mecamylamine, in contrast to previously reported studies on neuronal and adult muscle nicotinic acetylcholine receptors.

Vascular endothelial growth factor is a secreted angiogenic growth factor the mRNA of which is present in the placenta. The mRNA encoding the vascular endothelial growth factor receptor, flt, has also been demonstrated in placenta, with trophoblast appearing to be a novel site of flt expression. We investigated the expression of both vascular endothelial growth factor and flt-like immunoreactivity in first trimester and term placentae. In the first trimester, vascular endothelial growth factor immunoreactivity was localized to placental macrophages (Hofbauer cells), and in decidua, to glandular epithelium and maternal macrophages. In the term placenta, vascular endothelial growth factor immunoreactivity was present in extravillous trophoblast and in extracellular material. Flt immunoreactivity was demonstrated on extravillous trophoblast in first trimester and term, and on Hofbauer cells within placental villi. This complex pattern of both vascular endothelial growth factor and flt-like immunoreactivity suggests that vascular endothelial growth factor may be involved not only in the regulation of placental angiogenesis, but also in trophoblast invasion.

The acetylcholine esterase inhibitor (-)-physostigmine has been shown to act as agonist on nicotinic acetylcholine receptors from muscle and brain, by binding to sites on the alpha-polypeptide that are distinct from those for the natural transmitter acetylcholine (Schröder et al., 1994). In the present report we show that (-)-physostigmine, galanthamine, and the morphine derivative codeine activate single-channel currents in outside-out patches excised from clonal rat pheochromocytoma (PC12) cells. Although several lines of evidence demonstrate that the three alkaloids act on the same channels as acetylcholine, the competitive nicotinic antagonist methyllycaconitine only inhibited channel activation by acetylcholine but not by (-)-physostigmine, galanthamine or codeine. In contrast, the monoclonal antibody FK1, which competitively inhibits (-)-physostigmine binding to nicotinic acetylcholine receptors, did not affect channel activation by acetylcholine but inhibited activation by (-)-physostigmine, galanthamine and codeine. The three alkaloids therefore act via binding sites distinct from those for acetylcholine, in a 'noncompetitive' fashion. The potency of (-)-physostigmine and related compounds to act as a noncompetitive agonist is unrelated to the level of acetylcholine esterase inhibition induced by these drugs. (-)-Physostigmine, galanthamine and codeine do not evoke sizable whole-cell currents, which is due to the combined effects of low open-channel probability, slow onset and slow inactivation of response. In contrast, they sensitize PC12 cell nicotinic receptors in their submaximal response to acetylcholine. While the abundance of nicotinic acetylcholine receptor isoforms expressed in PC12 cells excludes identification of specific nicotinic acetylcholine receptor subtypes that interact with noncompetitive agonists, the identical patterns of single-channel current amplitudes observed with acetylcholine and with noncompetitive agonists suggested that all PC12 cell nicotinic acetylcholine receptor subtypes that respond to acetylcholine also respond to noncompetitive agonist. The action of noncompetitive agonists therefore seems to be highly conserved between nicotinic acetylcholine receptor subtypes, in agreement with the high level of structural conservation in the sequence region harboring major elements of this site.

The role of growth factors in pregnancy is a rapidly expanding subject. With the advent of molecular biological techniques more and more detailed information is available to the researcher. This review does not attempt to be exhaustive in its coverage of growth factors in pregnancy, rather it tries to give a brief taste of the possible roles that they may play in pregnancy by considering three specific factors, leukaemia inhibitory factor, colony stimulating factor-1 and vascular endothelial growth factor.

The X-ray crystallographic analysis of porphobilinogen deaminase (hydroxymethylbilane synthase, EC 4.3.1.8) shows the polypeptide chain folded into three domains, (1) N-terminal, (2) central and (3) C-terminal, of approximately equal size. Domains 1 and 2 have a similar overall topology, a modified doubly wound parallel beta-sheet. Domain 3 is an open-faced three-stranded antiparallel beta-sheet, with one face covered by three alpha-helices. The active site is located between domains 1 and 2. The dipyrromethane cofactor linked to cysteine 242 protrudes from domain 3 into the mouth of the cleft. Flexible segments between domains 1 and 2 are thought to have a role in a hinge mechanism, facilitating conformational changes. The cleft is lined with positively charged, highly conserved, arginine residues which form ion pairs with the acidic side chains of the cofactor. Aspartic acid 84 has been identified as a critical catalytic residue both by its proximity to the cofactor pyrrole ring nitrogen and by structural and kinetic studies of the Asp-84-->Glu mutant protein. The active site arginine residues have been altered by site-directed mutagenesis to histidine residues. The mutant proteins have been studied crystallographically in order to reconcile the functional changes in the polymerization reaction with structural changes in the enzyme.

The Health and Nutrition Examination Survey of 1971-75 contains valuable information because it provides unbiased estimates of the state of hearing in the general population. Here, three facets of the subjective aspects of hearing loss are examined: frequent and bothersome tinnitus, ratings of hearing, and general well-being. The period prevalence of frequent, bothersome tinnitus varied with race and gender (13 to 17%) with higher rates among blacks and females. The mean air-conduction thresholds (0.5 to 4 kHz) of those reporting frequent and bothersome tinnitus did not exceed 32 dB HL. Mean audiograms associated with those who rated both ears good, fair, poor, or deaf were significantly different from each other. Mean poorer ear audiograms for those rating one ear as good were significantly better than those for comparable symmetrical ratings. Last, there was no clear, consistent relationship between audiometric thresholds and measures of well-being.

The Health and Nutrition Examination Survey of 1971-75 contains unique hearing data because its design permits generalization to noninstitutionalized civilians in the continental United States. Air-conduction thresholds and their relationships to age, ear, gender, frequency, and race were examined in unscreened 25- to 74-year-olds. Although the observed effects of age, gender, and frequency were expected, three aspects of the results were remarkable. First, there was support for previous observations that older females have poorer low-frequency hearing. Second, there was an ear effect among white males who had poorer 2 and 4 kHz mean thresholds on the left at all ages. Third, there was a pattern of poorer mean thresholds for blacks that was particularly evident in comparisons between black and white females.

Portal hypertension and the development of varices in areas of portosystemic venous anastomoses can lead to dramatic and life-threatening haemorrhage. Varices most commonly occur in the gastro-oesophageal region but ectopic varices can arise at other sites in the gastrointestinal tract. This report describes a patient with massive haemorrhage from duodenal varices. We believe the case highlights the importance of considering ectopic varices as a cause of gastro-intestinal haemorrhage especially when oesophageal varices are absent.

Complaints of diminished hearing or reduced speech discrimination frequently accompany temporomandibular dysfunction. There is no consensus as to the mechanism of their occurrence or the alteration of these symptoms with the treatment. We studied 12 subjects with internal derangement of the temporomandibular joint (treated surgically) and nine subjects with myofascial pain disorder (treated medically), and we found no difference between the groups in pretreatment audiometric findings or in their degree of otologic symptoms. Similarly, there were no differences in posttreatment audiometric measures and there were no significant treatment effects. Furthermore, there was no correlation between subjects' complaints of reduced hearing sensitivity or discrimination and audiometric results. The apparently significant reduction in symptoms experienced by some subjects in the absence of audiometric change suggests the operation of unmeasured factors in their response to treatment.

We previously examined central auditory processing disorders and the effect of age in 1026 64- to 93-yr-olds. Here, we correlated three indices of central auditory processing disorders with age, pure tone averages (PTA) and maximum word recognition scores. With one exception, correlations of indices with PTA equaled or exceeded those with age. With one exception, correlations with word recognition scores were insignificant or smaller than those with age. Although statistically significant, the magnitudes of most effects were small (0.003 less than r2 less than 0.146). However, PTA accounted for approximately 30% of the variability in corrected Staggered Spondaic Word test error scores.

Many healthcare organizations may not fully realize the benefits of standard cost accounting techniques because they fail to routinely report volume variances in their internal reports. If overhead allocation is routinely reported on internal reports, managers can determine whether billing remains current or lost charges occur. Healthcare organizations' use of standard costing techniques can lead to more realistic performance measurements and information system improvements that alert management to losses from unrecovered overhead in time for corrective action.

The relation between central auditory processing disorders (CAPD) and age has been described in selected subjects. However, the prevalence of CAPD in the general population has not been established. We tested 1026, 64- to 93-yr-old members of the Framingham Heart Study cohort with Central Institute for the Deaf W-22 lists (CID W-22) in quiet, the Synthetic Sentence Identification test with ipsilateral competing message (SSI-ICM), and the Staggered Spondaic Word test. The presence or absence of CAPD could be established with at least one of three indices in 1018 subjects. The CID W-22 performance-intensity function rollover index was greater than 0.20 in 1.4% of 1009 subjects. The difference between maximum CID W-22 and SSI-ICM (0 dB message-to-competition ratio) scores was greater than 20% in 18.2% of 816 subjects. The Staggered Spondaic Word category was moderately, severely, over-corrected moderately, or over-corrected severely abnormal in 10.7% of 941 subjects (using 12-59-yr-olds' norms and adjusting scores when appropriate). Abnormal results on any one index occurred in 22.6% of the subjects. Thus, we conclude that the prevalence of CAPD in the elderly is less common than previous studies would suggest. Furthermore, although the rate of CAPD increased with age, age accounted for no more than 15% of the variability of any of the three indices. Therefore, its presence is dominated by factors other than chronological age.

In an attempt to establish the overall role played by percutaneous transluminal angioplasty in the treatment of critical ischaemia we studied 101 consecutive patients (110 limbs) who presented to one vascular unit over an 18 month period with this diagnosis. All patients underwent assessment with Doppler waveform analysis and arteriography and decisions about further management were made jointly by the surgical team and vascular radiologist. Results showed that only 24/110 limbs (22%) had lesions that were suitable for treatment with angioplasty alone. In addition one patient underwent angioplasty in conjunction with a distal bypass. Forty-one of the 110 limbs (37%) underwent reconstructive surgery, 18/110 (16%) primary amputation and 26/110 (24%) conservative treatment. Of those 24 limbs undergoing angioplasty, four were technically unsuccessful, and six were technically successful but without clinical improvement and all required alternative treatment. Only 12/110 limbs (11%) showed clinical improvement during their admission following angioplasty. We conclude that although angioplasty can be used successfully to treat critical ischaemia the overall numbers of patients who are suitable for treatment and who gain benefit from it is small.

This study reports one unit's experience of the value of computed tomography (CT) in the evaluation of 24 patients with large cervical and retrosternal goitres. Of these patients, 17 were thought clinically to have symptoms of tracheal compression, but the CT demonstrated significant narrowing in only 12 cases. In the other five patients, surgery was deferred and other causes for their symptoms sought and treated. Seven patients were asymptomatic and CT failed to reveal any evidence of tracheal compression in six. In the remaining patient, however, CT revealed gross narrowing and urgent surgery was performed. When compared with CT, chest/thoracic inlet radiographs were misleading in 48% of patients, with tracheal narrowing being overestimated and underestimated. We conclude that CT gives useful information about tracheal compression in patients with large multinodular goitres, and is more accurate than chest/thoracic inlet radiographs.

Pure-tone audiometry was done on 1475 persons on two occasions 6 years apart by the same audiologist in the same facility. The age of the subjects ranged from 58 to 88 years at the initial testing and 63 to 95 at the second. The average 6-year threshold change ranged from 1 to 8 dB at 250-6 kHz and 10-15 dB at 8 kHz. The differences in thresholds fell into two patterns, one for low frequencies (250-1 kHz) and the other for high frequencies (4-8 kHz). For the lows, thresholds worsened at an increasing rate with increasing age independent of the initial hearing level, and women's thresholds worsened more than men's. For the highs, the rate of threshold change decreased with age and with the initial threshold at rates that did not differ between genders. Using a change in PTA (0.5, 1, 2 kHz) of greater than 10 dB as a criterion, significant worsening occurred in the right ear in 8.5%, in the left ear in 13.5%, and in both ears of 4.1% of the subjects over the 6 year period. The rate of significant worsening increased with age. Although hearing loss increased with age, age alone accounted for less than 10% of the variance. Therefore, factors that co-vary with age may be responsible. The difference in phenomena between the low frequencies and the highs suggests that two different processes are occurring. Hair-cell degeneration is the most likely cause for the change in the high frequencies. Strial atrophy or other intracochlear processes may be the cause of the low frequency changes.

Many studies have documented the decline in auditory function with age. We broaden that data base in this the first of a series of reports emanating from the auditory testing of the Framingham cohort during biennial exam 18. The results of the auditory questionnaire, hearing sensitivity, acoustic compliance measures, and word recognition tests obtained from 1662 men and women in their 60th through 90th decades are presented. Pure-tone thresholds increased with age but the rate of change with age did not differ by gender even though men had poorer threshold sensitivity. Maximum word recognition ability declined with age more rapidly in men than in women and was poorer in men than in women at all ages. Acoustic compliance and middle ear pressure did not vary with gender or age. Acoustic reflex thresholds to a contralateral stimulus at 1 kHz increased slightly with age, more in women than in men; ipsilateral acoustic reflex thresholds did not vary with age or gender. Hearing aids were being used in only 10% of subjects likely to benefit from amplification.

Four patients receiving continuous ambulatory peritoneal dialysis presented with scrotal or labial oedema but no detectable cough impulse. Two of the patients later developed clinical evidence of inguinal hernia, and in the other two inguinal hernias were found at operation. These cases suggest that genital oedema occurring in a patient receiving continuous ambulatory peritoneal dialysis is a sign of a small inguinal hernia which may not be detectable clinically.

This study was undertaken to measure the degree of high-frequency sensorineural hearing loss following mastoid surgery. Twenty-five patients undergoing mastoidectomy procedures were tested preoperatively, less than 2 days postoperatively, and at 30 days postoperatively using the Tonndorf Audimax 500 high-frequency audiometer. Electrostimulation thresholds in 1-kHz intervals, from 1 to 20 kHz, were measured, and the highest detectable frequency was determined to within 0.1 kHz. Surgical drilling time was recorded. Average drilling time was 51 minutes. A significant temporary threshold shift was observed, measurable at multiple frequencies, less than 48 hours after mastoidectomy. There was no clinically significant change in electrostimulation thresholds (measured in 1-kHz increments, from 1 to 16 kHz) preoperatively to 30 days postoperatively. A statistically significant average loss of 0.89 kHz in the highest frequency producing a measurable response was noted (p less than 0.05). Determinations of the highest measurable frequency may be the most sensitive measure of surgically-induced, high-frequency sensorineural hearing changes.

An introduction to cost-accounting systems for pharmacy managers is provided; terms are defined and examples of specific applications are given. Cost-accounting systems determine, record, and report the resources consumed in providing services. An effective cost-accounting system must provide the information needed for both internal and external reports. In accounting terms, cost is the value given up to secure an asset. In determining how volumes of activity affect costs, fixed costs and variable costs are calculated; applications include pricing strategies, cost determinations, and break-even analysis. Also discussed are the concepts of direct and indirect costs, opportunity costs, and incremental and sunk costs. For most pharmacy department services, process costing, an accounting of intermediate outputs and homogeneous units, is used; in determining the full cost of providing a product or service (e.g., patient stay), job-order costing is used. Development of work-performance standards is necessary for monitoring productivity and determining product costs. In allocating pharmacy department costs, a ratio of costs to charges can be used; this method is convenient, but microcosting (specific identification of the costs of products) is more accurate. Pharmacy managers can use cost-accounting systems to evaluate the pharmacy's strategies, policies, and services and to improve budgets and reports.

Proctocolectomy (PC) with small bowel resection may lead to profuse ileostomy diarrhoea which can be difficult to treat. The effect of a recently developed long acting somatostatin analogue (SMS 201-995) on ileostomy output was investigated in 5 patients who had undergone PC and ileal resection (median 120 cm) and who suffered severe diarrhoea (4-7 litres/24 h). Gastric emptying, transit of a standard meal through the small bowel and the amounts of nutrients excreted were simultaneously determined during double blind infusion of SMS (25 micrograms/h) and placebo (isotonic saline 125 ml/h). SMS 201-995 significantly reduced ileostomy output (P less than 0.05) and water excretion (P less than 0.05) and prolonged small bowel transit time (P less than 0.05). Whilst having little effect on gastric emptying, or on the excretion of glucose or nitrogen, fat excretion was significantly increased (P less than 0.05). In two patients subcutaneous administration of SMS 201-995 (50 micrograms b.d.) has maintained a reduced ileostomy output for 4 and 6 months respectively.

The relationship between middle ear disease and eustachian tube function was studied in 24 children with persistent otitis media with effusion and with pressure-equalization tubes in place using the pressure system of an impedance bridge. Five measurements of function were correlated with a child's age and six indexes of disease. The highest multiple correlation squared accounted for only 27% of the variability in results, indicating that knowledge of tubal function by this technique has little useful correlation with other indicators of disease.