Genome-wide association study identifies a potent locus associated with human opioid sensitivity.

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.

Combined Exercise and Education Program: Effect of Smaller Group Size and Longer Duration on Physical Function and Social Engagement among Community-Dwelling Older Adults.

Background: Exercise, education, and social engagement are critical interventions for older adults for a healthy life expectancy and to improve their physical function. Objective: To conduct a combined exercise and education (CEE) program for improved social engagement and physical function of older adults. Design: Based on a short-term program we conducted in our previous study, in this study, the program was conducted for half the number of participants of the earlier study but for a longer duration. Setting: A community of older adults in Ami, Japan, was the setting of the study. Participants: 23 healthy older adults >65 years living in the community were the participants in the study. Interventions: Five 80-minute sessions conducted once in two weeks comprised 60-min exercise instruction and 20-min educational lectures per session on health. We examined the improvement in physical and social engagement before and after participation. Physical function and health-related questionnaire data were collected before and after the program. Results: Data analysis from 15 participants showed improved physical performance but no effect on social engagement. Conclusions: A higher program frequency, rather than program duration, may be vital to improving exercise performance and social engagement and maximizing the effects of high group cohesion in small groups. Further studies are needed to develop more effective interventions to extend healthy life expectancy.

The mechanism of emerging catalytic activity of gold nano-clusters on rutile TiO2(110) in CO oxidation reaction.

This paper reveals the fact that the O adatoms (O(ad)) adsorbed on the 5-fold Ti rows of rutile TiO(2)(110) react with CO to form CO(2) at room temperature and the oxidation reaction is pronouncedly enhanced by Au nano-clusters deposited on the above O-rich TiO(2)(110) surfaces. The optimum activity is obtained for 2D clusters with a lateral size of ∼1.5 nm and two-atomic layer height corresponding to ∼50 Au atoms∕cluster. This strong activity emerging is attributed to an electronic charge transfer from Au clusters to O-rich TiO(2)(110) supports observed clearly by work function measurement, which results in an interface dipole. The interface dipoles lower the potential barrier for dissociative O(2) adsorption on the surface and also enhance the reaction of CO with the O(ad) atoms to form CO(2) owing to the electric field of the interface dipoles, which generate an attractive force upon polar CO molecules and thus prolong the duration time on the Au nano-clusters. This electric field is screened by the valence electrons of Au clusters except near the perimeter interfaces, thereby the activity is diminished for three-dimensional clusters with a larger size.

Cytodiagnosis through use of a z-axis video by volunteer observers: a promising tool for external quality assessment.

OBJECTIVE: This study examined whether cytological diagnosis through the use of a video, which shows the changing depth of focus in the microscopic field, described as a z-axis video, is useful compared with a still image. METHODS: From 17 cytology preparations of fine needle aspiration of the breast, we made six z-axis videos per case. A frame exhibiting the characteristic features was then extracted from each video and saved as a representative still image. One hundred and twenty-eight volunteer cytotechnologists were randomly divided into two groups of video observers and still image observers. The participants were asked to make a diagnosis of benign, indeterminate, suspicious or malignant without having any clinical information other than the age of the patient. Diagnoses were categorized as 'recommended' or 'unacceptable' according to degree of correlation with histology. RESULTS: The number of definitive diagnoses of 'benign' or 'malignant' were increased in video observers, and indeterminate or suspicious categories were decreased (P = 0.013). The distribution of diagnostic categories in three of the 17 cases was significantly different; the distribution in the remaining cases was similar between the two groups. The z-axis video observers may have selected the definite diagnoses with confidence because they observed valuable microscopic findings by 'focusing through observation'. The average number of 'recommended' diagnoses by individual observers was significantly higher in the video observer group than in the still image observer group (P = 0.016). In contrast, the average number of 'unacceptable' diagnoses was significantly lower (P = 0.019). CONCLUSIONS: A z-axis video is easy to obtain and is therefore expected to become a powerful diagnostic modality for the external quality assessment of clinical cytology and even in the field of primary cytodiagnosis.

Sandwich ELISA system for cartilage oligomeric matrix protein in equine synovial fluid and serum.

REASONS FOR PERFORMING STUDY: Measurement of cartilage oligomeric matrix protein (COMP) in serum has potential for diagnosis of equine osteoarthritis (OA), but clinical use is currently limited by the lack of specificity of an inhibition ELISA as well as by baseline increases due to exercise. Improved methods for ELISA with increased antigen specificity and sensitivity are therefore required for reliable measurement. HYPOTHESIS: Measurement of the serum level of COMP by sandwich ELISA allows identification of horses with OA. METHODS: New monoclonal antibodies (mAbs) were elicited against equine cartilage COMP, their epitopes were determined and a sandwich ELISA was developed. The concentrations of COMP in synovial fluid (SF; n=100) and sera (n=100) from OA cases were measured by sandwich ELISA as well as by inhibition ELISA and compared with concentrations in normal joints (n=95) and horses (n=50). RESULTS: Immunoblots of enzymatically cleaved COMP showed that the new mAbs recognised different epitopes located on a 20 kDa fragment between K63 and K238 of the EGF-like repeats. Inhibition ELISA with any mAb detected significantly increased levels of COMP in OA SF compared with normal SF, whereas no significant difference was detected between serum levels of COMP in OA and normal horses. Conversely, sandwich ELISA with the combination of unlabelled 2A11 x biotinylated 11F10 mAbs detected a significant increase in COMP levels in both serum and SF from OA cases compared with levels in normal animals. CONCLUSIONS AND POTENTIAL RELEVANCE: Measurement of serum COMP with sandwich ELISA may be useful in identifying horses with OA.

Inspection of thick welded joints using laser-ultrasonic SAFT.

The detection of defects in thick butt joints in the early phase of multi-pass arc welding would be very valuable to reduce cost and time in the necessity of reworking. As a non-contact method, the laser-ultrasonic technique (LUT) has the potential for the automated inspection of welds, ultimately online during manufacturing. In this study, testing has been carried out using LUT combined with the synthetic aperture focusing technique (SAFT) on 25 and 50mm thick butt welded joints of steel both completed and partially welded. EDM slits of 2 or 3mm height were inserted at different depths in the multi-pass welding process to simulate a lack of fusion. Line scans transverse to the weld are performed with the generation and detection laser spots superimposed directly on the surface of the weld bead. A CCD line camera is used to simultaneously acquire the surface profile for correction in the SAFT processing. All artificial defects but also real defects are visualized in the investigated thick butt weld specimens, either completed or partially welded after a given number of passes. The results obtained clearly show the potential of using the LUT with SAFT for the automated inspection of arc welds or hybrid laser-arc welds during manufacturing.

Characterization of Ca(2+) signaling pathways in human mesenchymal stem cells.

Human mesenchymal stem cells (HMSC) have the potential to differentiate into many cell types. The physiological properties of HMSCs including their Ca(2+) signaling pathways, however, are not well understood. We investigated Ca(2+) influx and release functions in HMSCs. In Ca(2+) imaging experiments, spontaneous Ca(2+) oscillations were observed in 36 of 50 HMSCs. The Ca(2+) oscillations were completely blocked by the application of 10 micro M cyclopiazonic acid (CPA) or 1 micro M thapsigargin (TG). A brief application of 1 micro M acetylcholine (ACh) induced a transient increase of [Ca(2+)](i) but the application of caffeine (10 mM) did not induce any Ca(2+) transient. When the stores were depleted with Ca(2+)-ATPase blockers (CPA or TG) or muscarinic agonists (ACh), store-operated Ca(2+) (SOC) entry was observed. Using the patch-clamp technique, store-operated Ca(2+) currents (I(SOC)) could be recorded in cells treated with ACh or CPA, but voltage-operated Ca(2+) currents (VOCCs) were not elicited in most of the cells (17/20), but in 15% of cells examined, small dihydropyridine (DHP)-sensitive Ca(2+) currents were recorded. Using RT-PCR, mRNAs were detected for inositol 1,4,5-trisphosphate receptor (InsP(3)R) type I, II, and III and DHP receptors alpha1A and alpha1H were detected, but mRNA was not detected for ryanodine receptor (RyR) or N-type Ca(2+) channels. These results suggest that in undifferentiated HMSCs, Ca(2+) release is mediated by InsP(3)Rs and Ca(2+) entry through plasma membrane is mainly mediated by the SOCs channels with a little contribution of VOCCs.

Studies of hypertension-induced vascular hypertrophy in cultured smooth muscle cells from spontaneously hypertensive rats.

Mechanisms of vascular hypertrophy induced by hypertension were studied in cultured aortic smooth muscle cells from spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared with those from normotensive Wistar-Kyoto (WKY) rats. Fetal calf serum-stimulated ornithine decarboxylase (ODC) activity of cultured smooth muscle cells was greater in SHR and SHRSP than in WKY. Beta- but not alpha-adrenergic agonist stimulated ODC activity acutely in cultured smooth muscle cells from WKY, and isoprenaline-induced activation was blocked by the beta-blocker, propranolol, and enhanced by the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine. These results indicate that cultured vascular smooth muscle cells from SHR and SHRSP are more prone to increase the protein synthesis than those from WKY through the trophic induction of ODC activity and that the regulation of ODC activity by catecholamines is mediated through beta-agonistic effect in cultured smooth muscle cells.

Humoral trophic influence on cardiovascular structural changes in hypertension.

Since the early development of structural cardiovascular change in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) indicated the involvement of non-pressure-dependent factors in this process in hypertension, smooth muscle cells (SMC) from the aorta of SHR, SHRSP, and normotensive Wistar-Kyoto rats (WKY) were investigated under tissue culture conditions free from blood pressure and humoral factors in vivo. By the observation of such factors as growth rate and DNA or protein synthesis vascular SMC from these rats with genetic hypertension were proved to have intrinsically greater growth activity independently of blood pressure. Although serum from SHR and SHRSP had no specific stimulative effect on SMC growth, circulating epinephrine may accelerate cardiovascular structural changes because isoproterenol added to the culture media enhanced ornithine decarboxylase (ODC) activity. Moreover, SMC from SHR and SHRSP showed greater thymidine incorporation than those from WKY even in response to lower extracellular Na+ concentration. Local nutritional conditions of SMC, which were proved to have a great effect on the morphology and structure of cultured SMC, may be a basic determinant of the development of hypertension-induced structural vascular changes or lesions.

Polyunsaturated fatty acids induce tight junctions to form in brain capillary endothelial cells.

Tight junctions create a rate-limiting barrier to the diffusion of solutes between vertebrate epithelial cells and endothelial cells. They are also controlled within individual cells by a variety of physiologically relevant signals. We investigated the effects of polyunsaturated fatty acids on the formation of tight junctions in brain capillary endothelial cells, monitoring the transepithelial electrical resistance, and analyzed the expression of occludin messenger RNA. Brain-capillary endothelial cells were grown to confluence on filters and exposed to eicosapentaenoic acids, gamma linolenic acid and linoleic acid. Transepithelial electrical resistance was determined with voltage-measuring electrodes. The messenger RNA expression of occludin was quantitated by real-time quantitative reverse transcriptase-polymerase chain reaction. The basal resistance across monolayers of porcine brain capillary endothelial cells was 83+/-8.1 Omega cm(2). Cells cultured in eicosapentaenoic acids and gamma linolenic acid, but not linolenic acid, displayed a 2.7-fold increase in transepithelial electrical resistance at 10 microM in brain capillary endothelial cells. The expression level of occludin messenger RNA increased markedly immediately after the exposure to eicosapentaenoic acids or gamma linolenic acid. Following an 8 h exposure to exogenous eicosapentaenoic acids or gamma linolenic acid, occludin messenger RNA levels were significantly increased. In addition, the rise in transepithelial electrical resistance induced by eicosapentaenoic acids and gamma linolenic acid was markedly inhibited by the tyrosine kinase inhibitors genistein and PP2 and protein kinase C inhibitor, calphostin C. In contrast, the rise in transepithelial electrical resistance induced by eicosapentaenoic acids and gamma linolenic acid was not inhibited by the PI 3-kinase inhibitor, LY294002. We conclude that eicosapentaenoic acids and gamma linolenic acid increased the transepithelial electrical resistance and the expression of occludin messenger RNA in brain capillary endothelial cells. This gamma linolenic acid and eicosapentaenoic acid induced assembly of tight junction is likely to be regulated by protein kinase C and tyrosine kinase activity.

Angle-resolved photoemission study of insulating and metallic Cu-O chains in PrBa2Cu3O7 and PrBa2Cu4O8

We compare the angle-resolved photoemission spectra of the hole-doped Cu-O chains in PrBa2Cu3O7 (Pr123) and in PrBa2Cu4O8 (Pr124). While, in Pr123, a dispersive feature from the chain takes a band maximum at k(b) (momentum along the chain) approximately pi/4 and loses its spectral weight around the Fermi level, it reaches the Fermi level at k(b) approximately pi/4 in Pr124. Although the chains in Pr123 and Pr124 are approximately 1/4 filled, they show contrasting behaviors: While the chains in Pr123 have an instability to charge ordering, those in Pr124 avoid it and show an interesting spectral feature of a metallic coupled-chain system.

Assessment of in vivo oxidative stress in hypertensive rats and hypertensive subjects in Tanzania, Africa.

Oxidative stress has been reported to be involved in not only cardiovascular diseases but in hypertension, which is a major risk for cardiovascular diseases. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been recognized as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. In the present study, we assessed the oxidative stress in human subjects with hypertension and in hypertensive rats. In stroke-prone spontaneously hypertensive rats at the age of 14 weeks, the excretion of urinary 8-OHdG was significantly (p < 0.05) increased compared with that in age-matched normotensive Wistar-Kyoto rats. Next, we investigated the relationship between oxidative DNA damage and cardiovascular risk factors among Tanzanians aged 46-58 years in a population study carried out in 1998 in at Dar es Salaam, Tanzania, according to the WHO-CARDIAC Study Protocol. Sixty subjects (male/female, 28/32) were selected by SPSS Base 8.0 from those who completed a 24-h urine collection. The 24-h urinary 8-OHdG of the hypertensive subjects (SBP > or =140 mmHg and/or DBP > or =90 mmHg) was significantly (p < 0.05) higher than that of the normotensive subjects (SBP <140 mmHg and DBP <90 mmHg) after adjusting for age and gender (Hypertensives: 17.31 +/- 2.0 ng/mg creatinine, n=38; Normotensives: 10.10 +/- 2.64 ng/mg creatinine, n=22). Oxidative stress was thought to be involved in hypertensive subjects and in hypertensive rats.

Genetic vulnerability of cortical neurons isolated from stroke-prone spontaneously hypertensive rats in hypoxia and oxygen reperfusion.

Severe hypertension and cerebrovascular diseases develop in stroke-prone spontaneously hypertensive rats (SHRSP). Cortical neurons from SHRSP are more vulnerable than those from Wistar Kyoto rats (WKY) to the effects of nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, idebenone, and nilvadipine (a Ca2+ channel blocker) can reduce neuronal damage caused by hypoxia or neurotoxic agents. This study was designed to determine 1) whether cortical neurons from SHRSP are more vulnerable than those from WKY and 2) whether neuronal damage is minimized by the so-called neuroprotective agents in cells exposed to hypoxia and oxygen reperfusion. We demonstrated that 6 to 24 h of hypoxia did not increase cell death in either WKY or SHRSP, whereas 36 h of hypoxia significantly increased cell death in SHRSP (p < 0.01). Furthermore, 6 to 36 h of hypoxia and 1.5 to 5 h of reperfusion heavily damaged cells from both strains of rats, and most cells became apoptotic or necrotic. We also verified that the ability to protect neurons in hypoxia and oxygen reperfusion was as follows: idebenone > insulin-like growth factor-1 (IGF-1) > nilvadipine. These data indicate that oxygen radical generation occurs and the free radicals heavily damage neurons in hypoxia and oxygen reperfusion. SHRSP neurons are weaker than WKY neurons in these conditions. Furthermore, we surmise that idebenone, an antioxidant, decreases free radicals, and IGF-I attenuates p53-mediated apoptosis and thereby prevents cell death. We conclude that antioxidants are more potent than IGF-1 in protecting cortical neurons from damage caused by hypoxia and oxygen reperfusion, although both are very useful in minimizing damage to cortical neurons.

Altered gene expressions during hypoxia and reoxygenation in cortical neurons isolated from stroke-prone spontaneously hypertensive rats.

The expressions of Bcl-2, thioredoxin (TRX) and cytochrome c oxidase III (CO III) mRNAs after hypoxia and reoxygenation (H/R) were examined by quantitative reverse transcription-polymerase chain reaction using cultured cortical neurons isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY). The differences in gene expressions of Bcl-2, TRX and CO III mRNA between SHRSP and WKY were most remarkable at 30 min of oxygen stimulation, and the expressions of these genes were significantly lower in SHRSP compared with those in WKY. These findings pointed out that redox regulatory function and energy metabolism in SHRSP neurons were markedly reduced by oxygen stimulation after hypoxia, and such changes may be involved in neuronal vulnerability.

Reduced production of lactate during hypoxia and reoxygenation in astrocytes isolated from stroke-prone spontaneously hypertensive rats.

Lactate production and expressions of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase (LDH) mRNA after hypoxia and reoxygenation (H/R) were examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using astrocytes in culture isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY). The basal production of lactate in SHRSP was the same as that observed in WKY. In contrast the lactate levels in SHRSP at 1 and 6 h of reoxygenation after hypoxia were significantly lower than those observed in WKY. In addition LDH and MCT1 mRNA expressions in SHRSP were significantly less strong compared with those in WKY during H/R. These findings indicate that decreased production and slow transport of lactate in SHRSP astrocytes are involved in neuronal energy depletion and possibly encourage neuronal damage, although hereditary weakness of cortical neurons is also related to cell death during H/R.

Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroidal products and major circulating steroids in humans. The serum concentrations of DHEA-S are lower in patients with myotonic dystrophy (DM) than normal controls, and possible improvement of myotonia and muscle weakness was recently reported following DHEA-S replacement therapy. However, the molecular mechanism of action of DHEA-S remains unknown. To understand the reported anti-DM action of DHEA-S, we investigated DHEA-S binding in skeletal muscle cells in vitro. We identified two populations of DHEA-S binding sites (Kd = 5-9 microM and 35-40 microM) in C2C12 myocytes. Similar binding sites were also identified in human skeletal muscles. The Kd value of the high-affinity site was within the range of serum concentrations of DHEA-S in adult humans. Our results suggest that DHEA-S might act directly on skeletal muscles under normal physiological conditions in humans.

Ventilatory volume and pressure required for oscillatory ventilation in dogs.

We determined the ventilatory volume and pressure required to maintain a PaCO2 of 40 mmHg in dogs at between 0.5 and 16 Hz. The ventilator used was that incorporating a powerful, specially made loudspeaker to which a sine-wave signal was introduced. A windmill-type flowmeter measured the minute volume. The tidal volume, expressed per kg of body weight, was 16.1 at 0.5 Hz, decreasing linearly with log f, and reaching a value of 6.1 ml/kg at 16 Hz. The minute volume increased 10 times from 0.5 to 16 Hz. The intratracheal pressure was 12 to 13 cmH2O between 0.5 and 2 Hz, rising to 16 at 4 Hz and finally reaching 77.2 cmH2O at 16 Hz. The PaO2 values were always above 500 mmHg when FIO2 was 1.0. The frequency-impedence data were analyzed for R, I and C values. The fitting of the data to an R-I-C series model was good, but the R values obtained were considerably higher than those reported using a smaller amplitude of oscillation.

High-frequency animal ventilator using a loudspeaker and its gas exchange characteristics.

A high-frequency ventilator was designed using a loudspeaker as a piston, driven by a power-amplifier. A sine-wave signal was introduced into the amplifier from an electronic oscillator. The mechanical and gas exchange characteristics of the ventilator were studied in vitro and in dogs. The volume output per stroke, when open to air, was between 100 and 200 ml up to 7 Hz, then gradually decreased as the frequency increased. A Wright respirometer appeared to measure the volume flow fairly accurately up to 14 Hz. The pressure output against a closed volume of 1.1 liters achieved a maximum of 29 mmHg at 7 Hz. It gradually decreased as the frequency was changed from 7 Hz. The loudspeaker worked in such a way that the volume output decreased considerably when it was forced to move against a closed space to generate pressure. Adequate ventilation was achieved in all dogs from 1.4 to 10 Hz. At 14 Hz, the results were variable, and at 20 Hz and above, gross hypoventilation always resulted. The PaO2 values were always over 440 mmHg when 0.8 liter/(kg . min) of oxygen was supplied into the respiratory circuit. A speaker ventilator has the advantage of easy assembly and the possibility of applying various flows by electrical control. Its disadvantages are a lack of power and the difficulty in establishing ventilatory volumes without actual measurement.

PaO2 and intratracheal pressure in oscillatory ventilation in experimental respiratory failure.

In order to study the effect of high frequency ventilation on the pulmonary gas exchange in respiratory failure, we measured the PaO2 and other pulmonary gas exchange parameters for ventilatory rates of 0.5, 1.2, 4.8, and 16 Hz in dogs, to which acute respiratory failure was created by intravenous infusion of oleic acid. Either the mean intratracheal pressure or the end-tidal intratracheal pressure was controlled. A loud-speaker ventilator of our own design was modified so as to enable variation of the intratracheal pressure. Ventilation was measured using an ultrasonic instrument which counts the number of turbulent eddies. The tidal volume was set slightly higher than that was determined for healthy animals, but the resulting PaCO2 values were consistently higher than normal when PaO2 values were low. With the mean intratracheal pressure kept constant at 5, 10, and 15 cm H2O, PaO2 values with the FIO2 of 1 were between 41 and 46 at mPit of 5, 65 and 82 at 10 cm H2O, 278 and 423 at 15 cm H2O. No increase in PaO2 was observed with the increase in respiratory frequencies. If anything, a slight reduction in PaO2 at 8 and 16 Hz was observed, though not statistically significant. With the end-tidal intratracheal pressure constant, PaO2 varied but again correlated well with the mPit.

Multiple space-occupying lesions of the spleen in a case of Gaucher's disease.

A 50-year-old female patient was admitted because of an enormously enlarged spleen and thrombocytopenia. Ultrasonography and magnetic resonance imaging revealed multiple space-occupying lesions in the spleen. She was diagnosed as having Gaucher's disease based on the low level of beta-glucosidase activity in leukocytes and Gaucher's cells present in bone marrow aspirate. Severe hypersplenism necessitated splenectomy. Pathological studies of the excised spleen, including ultrastructural examinations, demonstrated that multiple space-occupying lesions in the spleen were composed of typical Gaucher cells.