Effect of remifentanil on plasma propofol concentration and bispectral index during propofol anaesthesia.

BACKGROUND: Propofol and remifentanil are commonly administered together in clinical anaesthesia, but the effect of remifentanil on the plasma concentration of propofol has yet to be established. The aim of the present study was to investigate the effect of remifentanil on plasma propofol concentrations (Cp) in the absence of surgical stimulation. METHODS: Thirty-eight patients undergoing elective gynaecologic surgery were randomly assigned to receive one of the three remifentanil doses (0, 0.5, or 1.0 µg kg⁻¹ min⁻¹). Anaesthesia was induced by a target-controlled infusion of propofol. After tracheal intubation, saline or remifentanil infusion was administered for 15 min. Mean arterial pressure (MAP), heart rate (HR), and bispectral index (BIS) were recorded and cardiac index (CI), blood volume, and indocyanine green disappearance ratio (K-ICG) were measured using a dye densitogram analyser before and 15 min after saline or remifentanil infusion. Cp was measured using high-performance liquid chromatography. RESULTS: HR, K-ICG, and BIS were significantly decreased in the remifentanil 0 µg kg⁻¹ min⁻¹ group. The decrease in MAP, HR, CI, and K-ICG was significantly lower in the remifentanil 0.5 and 1.0 µg kg⁻¹ min⁻¹ groups compared with the remifentanil 0 µg kg⁻¹ min⁻¹ group. Cp was significantly increased after remifentanil administration, but this had no influence on BIS. CONCLUSIONS: Remifentanil reduced the CI and increased the Cp, which may be related to a decrease in the K-ICG, but had no significant effect on the BIS.

Eosinophilic bronchiolitis indicating eosinophilic airway disease with overexpression of carcinoembryonic antigen in sinus and bronchiole: case report.

The present case showed eosinophilic bronchiolitis and sinusitis with an overexpression of carcinoembryonic antigen (CEA) in lung and sinus and an elevation of serum CEA level, both of which were improved by oral steroid therapy. A 54-year-old asthmatic woman had developed a shortness of breath on exertion, and the chest X-ray revealed diffuse centrilobular shadows. Her serum CEA level had increased gradually. Eosinophil infiltration and overexpression of CEA were demonstrated in both the lung and sinus by immunohistochemistry. Both the lung and sinus lesions, and the serum CEA level were improved by oral steroid therapy. No evidence of tumor was found by extensive examination. From this case, eosinophilic bronchiolitis was considered to be an airway disease like "eosinophilic sinobronchiolitis" through the common pathophysiology of CEA, and serum CEA level was a good marker of disease condition.

Rocuronium dose-dependently suppresses the spectral entropy response to tracheal intubation during propofol anaesthesia.

BACKGROUND: The Entropy Module anaesthesia monitor displays two spectral entropy-based indices, response entropy (RE) and state entropy (SE). The difference between RE and SE (RE-SE), which mainly reflects electromyography activation, is thought to indicate the adequacy of antinociception. Little is known, however, about the effects of neuromuscular blocking agents on the RE-SE. We investigated the effects of rocuronium on the RE-SE response to tracheal intubation. METHODS: Forty-four patients were randomly assigned to receive one of four rocuronium doses (0.3, 0.6, 0.9, and 1.2 mg kg(-1)). Anaesthesia was induced by propofol target-controlled infusion. Rocuronium was administered 2 min after anaesthesia induction. Tracheal intubation was performed 7 min after anaesthesia induction. Arterial pressure, heart rate (HR), bispectral index (BIS), RE, SE, and patient movement were recorded. RESULTS: All EEG-derived indices (BIS, RE, SE, and RE-SE) increased after tracheal intubation. The maximum increase in the indices after tracheal intubation was significantly suppressed by an increase in the rocuronium dose. Patient movement after tracheal intubation was suppressed by an increase in the rocuronium dose. All indices were higher in patients who moved during or after tracheal intubation than in those who did not move. Rocuronium dose did not affect the mean arterial pressure or HR in response to tracheal intubation. CONCLUSIONS: The RE-SE response to tracheal intubation was suppressed by increasing the rocuronium dose. Estimates of nociception using RE-SE should be interpreted carefully in different states of muscle paralysis during general anaesthesia.

Influence of hypobaric hypoxia on bispectral index and spectral entropy in volunteers.

BACKGROUND: Hypoxia has been shown to change electroencephalogram parameters including frequency and amplitude, and may thus change bispectral index (BIS) and spectral entropy values. If hypoxia per se changes BIS and spectral entropy values, BIS and spectral entropy values may not correctly reflect the depth of anaesthesia during hypoxia. The aim of this study was to examine the changes in BIS and spectral entropy values during hypobaric hypoxia in volunteers. METHODS: The study was conducted in a high-altitude chamber with 11 volunteers. After the subjects breathed 100% oxygen for 15 min at the ground level, the simulated altitude increased gradually to the 7620 m (25,000 ft) level while the subjects continued to breathe oxygen. Then, the subjects discontinued to breath oxygen and breathed room air at the 7620 m level for up to 5 min until they requested to stop hypoxic exposure. Oxygen saturation (SpO2), heart rate, 95% spectral edge frequency (SEF), BIS, response entropy (RE), and state entropy (SE) of spectral entropy were recorded throughout the study period. RESULTS: Of the 11 subjects, seven subjects who underwent hypoxic exposure for 4 min were analysed. SpO2 decreased to 69% at the 7620 m level without oxygen. However, SEF, BIS, RE, and SE before and during hypoxic exposure were almost identical. CONCLUSION: These data suggest that hypoxia of oxygen saturation around 70% does not have a strong effect on BIS and spectral entropy.

Effect of cervical sympathetic trunk transection on renal sympathetic nerve activity in rats.

Stellate ganglion blockade (SGB) with a local anesthetic increases muscle sympathetic nerve activity in the tibial nerve in humans. However, whether this sympathetic excitation in the tibial nerve is due to a sympathetic blockade in the neck itself, or due to infiltration of a local anesthetic to adjacent nerves including the vagus nerve remains unknown. To rule out one mechanism, we examined the effects of cervical sympathetic trunk transection on renal sympathetic nerve activity (RSNA) in anesthetized rats. Seven rats were anesthetized with intraperitoneal urethane. RSNA together with arterial blood pressure and heart rate were recorded for 15 min before and 30 min after left cervical sympathetic trunk transection. The baroreceptor unloading RSNA obtained by decreasing arterial blood pressure with administration of sodium nitroprusside was also measured. Left cervical sympathetic trunk transection did not have any significant effects on RSNA, baroreceptor unloading RSNA, arterial blood pressure, and heart rate. These data suggest that there was no compensatory increase in RSNA when cervical sympathetic trunk was transected and that the increase in sympathetic nerve activity in the tibial nerve during SGB in humans may result from infiltration of a local anesthetic to adjacent nerves rather than a sympathetic blockade in the neck itself.

Effect of landiolol on bispectral index and spectral entropy responses to tracheal intubation during propofol anaesthesia.

BACKGROUND: beta1-Adrenoceptor antagonists suppress the haemodynamic and arousal responses to tracheal intubation. The Entropy Module shows two spectral entropy-based indices, response entropy (RE) and state entropy (SE). The difference between RE and SE (RE-SE) may reflect nociception during general anaesthesia. In the present study, we investigated the effect of landiolol on entropy indices in response to tracheal intubation. METHODS: A total of 60 patients were randomly assigned to receive saline (Group S), remifentanil (Group R), or landiolol (Group L). Anaesthesia was induced by propofol target-controlled infusion. Two minutes after the induction of anaesthesia, infusion with vecuronium bromide and remifentanil, landiolol, or saline was initiated. Tracheal intubation was performed 7 min after anaesthesia induction. Arterial pressure, heart rate (HR), bispectral index (BIS), and entropy indices were recorded. RESULTS: In Group S, RE increased significantly after tracheal intubation, but there was no significant increase in BIS or SE. These increases in RE were abolished in Groups R and L. RE-SE increased significantly after tracheal intubation in Group S, whereas no increase in RE-SE was observed in Groups R and L. Increases in mean arterial pressure and HR after tracheal intubation were suppressed in Groups R and L compared with Group S. CONCLUSIONS: RE increased in response to tracheal intubation, whereas BIS and SE did not. Landiolol and remifentanil suppressed the increase in RE after tracheal intubation with significant inhibition of RE-SE difference.

Effectiveness of Bortezomib in a Patient With Acute Rejection Associated With an Elevation of Donor-Specific HLA Antibodies After Small-Bowel Transplantation: Case Report.

BACKGROUND: A significant association between donor-specific antibody (DSA) and graft rejection has recently been documented. However, confirmed strategy has not been established for DSA-associated rejection after intestinal transplantation (ITx). CASE REPORT: A 20-year-old male patient with chronic intestinal obstruction caused by hypoganglionosis of the entire intestine underwent cadaveric donor ITx with grafting performed on 232 cm of the small intestine, cecum, and a part of the ascending colon. On post-operative day (POD) 14, a histological evaluation showed an acute rejection of indeterminate grade. The patient had severe acute rejection on POD 16, which prompted us to administer bolus steroids and polyclonal anti-thymocyte antibody, along with baseline maintenance immunosuppression. The histopathological findings of the graft indicated typical acute cellular rejection, although C4d was positive. We then detected donor-specific HLA antibody. The patient initially responded well to the therapy and showed decreased histological rejection signs. However, the refractory low-grade rejection persisted in the graft. During this period, the patient showed increased levels of DSA, and we speculated that the persistent rejection was associated with DSA; thus, bortezomib was administered at this stage as a salvage therapy. This rejection was thereafter successfully controlled without severe adverse effect. Twenty-three months after ITx, the patient is currently alive with complete enteral autonomy. CONCLUSIONS: A case of acute graft rejection followed by a marked elevation of DSA is presented. In this particular case, a modified treatment protocol using bortezomib in addition to the typical immunosuppressive agents was effective.

Effect of enzyme digestion on anionic sites and charge-selective permeability of dermo-epidermal junction.

To study components of anionic sites on the lamina densa of the dermo-epidermal junction (DEJ) and to assess the effect of removal of sialic acid or glycosaminoglycans on its charge-selective permeability, epidermal sheets, whose dermis had been removed by treatment with dithiothreitol, were digested with heparitinase, chondroitinase ABC, hyaluronidase, or neuraminidase. They were then stained with polyethyleneimine for demonstration of the anionic sites or incubated in a medium containing native anionic ferritin for tracer experiments. The anionic sites were completely removed after heparitinase digestion. Although the numerical density of the sites was not altered, their electron density was decreased after chondroitinase ABC digestion. The other enzymes had no effect on the sites. In the tracer experiments, heparitinase or neuraminidase increased the number of tracer molecules penetrating into the lamina lucida of the epidermal sheet, while the other enzymes had no effect on it. These data indicate that heparan sulfate, which is a main component of the anionic sites, plays an important role in the charge-selective permeability of the DEJ, whereas chondroitin sulfate, which seems to be contained in the sites, does not, probably because of its small amount. These data also indicate that sialic acid, which is not a main component of the anionic sites demonstrated with the cationic probe, has a role in the permeability function.

Charge-selective permeability of dermo-epidermal junction: tracer studies with cationic and anionic ferritins.

To investigate quantitatively the charge-selective permeability of the basement membrane (BM) of the dermo-epidermal junction (DEJ), tracer experiments using anionic and cationic ferritins were performed on an epidermal sheet, whose lamina densa was exposed on the dermal surface; its dermis was removed with forceps after the treatment of newborn rat skin with 10 mM dithiothreitol. The lamina densa and epidermal components of the sheets were electron microscopically well preserved, and anionic sites were ultrastructurally demonstrated on both the dermal and epidermal aspects of the lamina densa in the DEJ as clusters of cationic ferritins (CF) [isoelectric point (pI) greater than 9.5] or polyethyleneimine particles, indicating that the epidermal sheets were suitable for study of permeability. In tracer experiments, a large number of CF (pI 8.0-9.4) passed the lamina densa and formed clusters on both aspects of the lamina densa and in the intercellular space. The number of native anionic ferritins (NF) (pI 4.1-4.6) passing it was apparently much smaller than that of CF. When the epidermal sheets were pre-treated with protamine sulfate to neutralize the negative charges in the tissue, the number of NF penetrating the lamina densa was significantly larger than the number of those in the untreated sheet. These results indicate that the BM of the DEJ plays a role in a charge-selective filtration, although it is not as selective a barrier as the glomerular basement membrane.

Immunohistochemical alterations in basement membrane components of squamous cell carcinoma.

To investigate alterations in the basement membrane (BM) in squamous cell carcinoma (SCC), we investigated 20 tumors. Four had the cytologic characteristics of Bowen's disease (SCC-BD) and 16 did not have them (SCC-NB). Tumors were studied immunohistochemically by double immunofluorescent staining by using mouse monoclonal antibodies to the core protein of heparan sulfate proteoglycan (HSPG) and chondroitin 6-sulfate glycosaminoglycan (Ch6S) as well as rabbit antiserum to laminin (LN) and type IV collagen (C-4). In well-differentiated and highly keratinized SCC-NB, LN, C-4, and HSPG could be detected in the tumor nest BM and showed no loss of continuity, but they were largely lost in poorly differentiated and poorly keratinized SCC-NB. This suggests that poorly differentiated SCC-NB cause greater enzymatic degradation of BM components than well-differentiated SCC-NB. Ch6S was detected in parts of the BM of SCC-BD, but it was absent in all SCC-NB examined. It appears that SCC-NB have lost the ability to synthesize Ch6S, and that SCC-BD degrade Ch6S although they continue to produce it. Thus, it appears that in SCC the BM is qualitatively different from that of normal epidermis, and that SCC-BD can be distinguished from SCC-NB by the Ch6S content of the BM.

Histologic and cell kinetic studies of hair loss and subsequent recovery process of human scalp hair follicles grafted onto severe combined immunodeficient mice.

To establish a model for studying human scalp hair, individually isolated hair follicles were grafted onto back skin of severe combined immunodeficient mice. Histologic changes and cell kinetics in the hair loss and subsequent recovery process were investigated. In the dystrophic stage (from day 7 to 30), all the hair shafts became dystrophic and were shed. Thickening and corrugation of vitreous membrane, apoptosis, and regression of the lower part were observed in the grafted hair follicles. 5-bromo-2'-deoxy-uridine-labeled cells were not detected in the lower end of the follicles, and keratin 19-positive cells appeared there. At the end of this stage their lower part was maximally retracted, secondary germ remained beneath the bulge, and the vitreous membrane disappeared. In the regeneration stage (from day 30 to 50), the same histologic findings as those at the end of the dystrophic stage were observed. The keratin 19-positive cells in the secondary germ, however, were replaced with keratin 19-negative and 5-bromo-2'-deoxy-uridine-labeled cells. Then, differentiation into an inner root sheath and a hair shaft began, and apoptosis was terminated. In the stable growth stage (from day 40 to at least 150), the grafted follicles were immunohistochemically and light microscopically identical with the normal anagen hair follicles except for the presence of melanin incontinence. These findings suggest that the grafted hair follicles entered into dystrophic catagen, subsequently dystrophic telogen, then returned to normal anagen follicles, and that stem cells or their close progeny in the secondary germ play an important part in the recovery process.

Paraneoplastic pemphigus associated with bronchiolitis obliterans.

Paraneoplastic pemphigus (PNP) is an autoantibody-mediated mucocutaneous blistering disease associated with underlying neoplasms. Autoantibodies of PNP bind to the plakin family of cytoplasmic proteins and desmogleins of cell-surface target antigens. We describe a 36-year-old female patient with PNP who had non-Hodgkin's lymphoma, and who developed bronchiolitis obliterans and died of respiratory failure. Autopsy findings confirmed luminal narrowing of bronchioles by scarring, which is a histopathologic features of bronchiolitis obliterans. After the onset of respiratory failure, the reaction of autoantibodies against the plakins detected by immunoprecipitation at the onset of PNP disappeared with negative immunofluorescence within the bronchial epithelium. It is thought that autoantibodies against some of these antigens play a role in causing acute inflammation of the respiratory epithelium. In treating PNP, the possibility of the patient developing the lethal complication bronchiolitis obliterans should be kept in mind. Furthermore, prevention of the initial autoantibody-mediated injury to the respiratory epithelium should be an important treatment goal.

Proliferation of macrophage-lineage cells in the bone marrow, severe thymic atrophy, and extramedullary hematopoiesis of possible donor origin in an autopsy case of post-transplantation graft-versus-host disease.

A case of proliferation of CD68-positive macrophage-lineage cells in the bone marrow accompanied by severe thymic atrophy associated with graft-versus-host disease (GVHD) in a boy given allogeneic bone marrow transplantation (BMT) is reported. A 7-year-old boy was treated for posthepatitic severe aplastic anemia by BMT from his HLA-identical, mixed lymphocyte reaction-negative sister. After the transplantation his peripheral blood group converted to the donor type. However, the patient suffered from acute and chronic GVHD and slowly progressive anemia, and he died of multiple organ failure 21 months after BMT. At the autopsy diffuse and monotonous proliferation of CD68-positive macrophage-lineage cells was found to be replacing the blood-forming cells in the bone marrow. The thymus was almost empty of T lymphocytes, and remaining strands of extremely atrophic epithelial cells showed focal cystic change. Extramedullary hematopoiesis was found in the spleen. Analyses of microsatellite markers suggested the hematopoietic cells in the spleen to be of donor origin.

Primary aldosteronism treated by trilostane (3 beta-hydroxysteroid dehydrogenase inhibitor).

The practicability and tolerability of trilostane, a competitive inhibitor of 3 beta-hydroxysteroid-delta 5-dehydrogenase, for the therapy of primary aldosteronism was assessed in 1 patient with aldosterone-producing adenoma (APA) and 3 subjects with idiopathic adrenal hyperplasia (IHA). Trilostane afforded reduction of plasma levels of aldosterone, progesterone, deoxycorticosterone, 17-OH progesterone, cortisol, delta 4-androstenedione, and urinary excretion of 17-hydroxycorticosteroid. Conversely, circulating levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, and urinary excretion of 17-ketosteroids were increased following this drug therapy. Suppression of mineralo- or glucocorticoid biosynthesis was accompanied by an increase in plasma renin activity. One patient with APA or 3 subjects with IHA showed slight or remarkable improvement of hypertension and hypokalemia. Based on these findings, efficacy and tolerability of trilostane appear to aid in the treatment of IHA.

Establishment and characterization of a clear-cell sarcoma (malignant melanoma of soft parts) cell line.

A clear cell sarcoma (CCS) cell line, designated as NCS-1, was established in monolayer culture from a xenograft line originating from a metastatic CCS. Marked karyotypic aberrations and tumorigenicity in nude mice revealed the malignant derivation of the NCS-1 cell line. These cells contained abundant glycogen and were amelanotic by light microscopy. By electron microscopy, however, melanosomes in various developmental stages were seen, and some of them were partially melanized. The electron microscopic dopa reaction revealed the presence of tyrosinase activity. Enzyme-linked immunoadsorbent assay revealed that NCS-1 cells expressed a 75-kDa glycoprotein which was identified as a marker of highly differentiated melanoma cells. From these results, NCS-1 cells were found to retain both cytochemical and morphological properties of CCS. Application of NCS-1 cells to a panel of monoclonal antibodies recognizing melanocytic differentiation antigens showed that they corresponded approximately to highly differentiated melanoma cells. In conclusion, the present study strongly supports the close relationship between CCS and malignant melanoma.

Two-dimensional electrophoretic analysis of human hair keratins, especially hair matrix proteins.

Human hair keratins are composed of hair fibrous proteins (HFP) forming 10-nm filaments and nonfilamentous cysteine-rich hair matrix proteins (HMP); these proteins are highly cross-linked by disulfide bonds. In order to obtain high-resultional separation of HFP and HMP by two-dimensional polyacrylamide gel electrophoresis according to isoelectric point (IP) in the first dimension and molecular weight (MW) in the second dimension, these proteins were converted to S-carbamoylmethylated (SCam) derivatives with nonionizable iodoacetamide; this treatment hardly modified the electrophoretic mobility. SCam-HFP were separated into polypeptides with MW 41.5-59 kD (IP pH 5.1-6.8). SCam-HMP were subdivided into two groups; 14 polypeptides of acidic HMP with MW 15-28 kD (IP pH 5.0-7.0) and 12 polypeptides of basic HMP with MW 18.5-28 kD (IP pH 7.8-8.8). Variation in electrophoretic patterns among hair samples obtained from 15 persons in four Japanese families was found in acidic HMP, but not in HFP in basic HMP. The present method appears to be very suitable for the biochemical analysis of human hair keratins, especially HMP of nonfilamentous proteins.

3D-MR mammography-guided breast conserving surgery after neoadjuvant chemotherapy: clinical results and future perspectives with reference to FDG-PET.

BACKGROUND: Three dimensional MR Mammography (3D-MRM) can detect tumor extension more accurately than mammography or ultrasound. There are two shrinkage patterns observed by 3D-MRM after neoadjuvant chemotherapy. Concentric shrinkage is a good indication for breast conserving surgery. On the other hand, a dendritic pattern was represent ductal spread. Therefore, we developed MRM guided mapping to aid BCS for tumors showing a dendritic pattern. METHODS: Fifteen patients consisting of 8 stage II (T > 3.5 cm) cases and 7 stage IIIa cases aged 39 to 61 years (mean 47-8 years) were treated with AT neoadjuvant chemotherapy with the aim of performing breast conserving surgery. All patients were examined by 3D-MRM before and after neoadjuvant chemotherapy. Breast conserving surgery indications were determined by tumor volume reduction and shrinkage patterns on 3D-MRM. Supine position mapping using MRM was performed for dendritic type tumors. FDG-PET was simultaneously performed for one case with bilateral breast cancer. RESULTS: Breast conserving surgery was performed for 13 of the 15 cases. One case underwent re-operating and mastectomy because of a positive margin. One case had microscopically positive margin and received boost radiation. Therefore, 11 of 15 cases (73.3%) underwent BCS and achieved negative margins under MRM guidance. PET scanning can detect residual tumor and occult metastasis but it is not suitable for mapping because of its spatial resolution. CONCLUSIONS: 3D-MRM is a useful modality to select appropriate cases for breast conserving surgery after neoadjuvant chemotherapy. FDG-PET can also detect residual tumor or occult metastasis but it may not be suitable for mapping. Because both examinations have potential, further evaluation of their clinical efficacy is necessary.

Gonadotropin therapy in males with hypogonadotropic hypogonadism: factors affecting induction of spermatogenesis after gonadotropin replacement.

Sixteen patients with hypogonadotropic hypogonadism received gonadotropin replacement therapy. Two patients treated with HCG alone showed induction of spermatogenesis 2 and 12 months after the start of treatment. Three subjects receiving combination therapy showed sperm appearance 6-28 months after treatment. The patients showing sperm appearance, whose testicular volume was > or = 4 ml, showed a higher sperm count and impregnated their partners, although no relationship was found between pretreatment testicular volume and sperm appearance. The response to HCG test correlated with sperm appearance after gonadotropin therapy. Sperm appearance was not observed in any subject except for one who showed no response to luteinizing hormone-releasing hormone (LH-RH) test and none of the patients without response of FSH to LH-RH demonstrated any induction of spermatogenesis. In conclusion, the responses to LH-RH test and possibly to HCG test could predict the induction of spermatogenesis after gonadotropin replacement therapy, and a large testicular volume is associated with post-treatment fertility.

Relationship between zinc concentrations in seminal plasma and various sperm parameters.

The zinc concentration in seminal plasma from 98 infertile male patients and 8 fertile males was measured. The zinc concentration of the seminal plasma in azoospermic and oligoasthenozoospermic patients was significantly lower than that in the other groups (each, p<0.05 ). The seminal plasma zinc concentration in asthenozoospermic males was significantly higher than that in any other group (p<0.05). There was a positive correlation of zinc concentration with sperm concentration (r=0.33, p<0.05) and with sperm motility (r=0.22, p<0.05), while there was no correlation with sperm morphology. A correlation between zinc concentration and plasma testosterone concentration was observed (r=0.24, p<0.05). It is concluded that excessively high zinc concentration is apparently related to defective motility in asthenozoospermic patients, even though adequate seminal plasma content of the element is required for normal sperm function.

Volume change of the prostate and seminal vesicles in male hypogonadism after androgen replacement therapy.

Before and after androgen replacement therapy prostatic and seminovesicular volume was estimated by means of transrectal ultrasonography in 13 hypogonadal men. Volume of the prostate (p less than 0.001) and seminal vesicles (p less than 0.01) significantly increased after treatment with testosterone enanthate. However, the plasma level of testosterone remained abnormally low. These results indicate that volume determination of the prostate and seminal vesicles by means of transrectal ultrasonography is suitable for evaluating the adequacy of androgen replacement therapy in male hypogonadism.