Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients.

STUDY QUESTION: What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome? SUMMARY ANSWER: Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation. WHAT IS KNOWN ALREADY: Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias. STUDY DESIGN, SIZE, DURATION: Systematic mutation screening and genome-wide copy-number analysis of 62 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization. MAIN RESULTS AND THE ROLE OF CHANCE: Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome. LIMITATIONS, REASONS FOR CAUTION: The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions. WIDER IMPLICATIONS OF THE FINDINGS: Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation. Most importantly, this is the first report documenting possible oligogenicity of non-syndromic hypospadias. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; by the Grant-in-Aid from the Japan Society for the Promotion of Science; by the Grants from the Ministry of Health, Labour and Welfare, from the National Center for Child Health and Development and from the Takeda Foundation. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Beamline AR-NW12A: high-throughput beamline for macromolecular crystallography at the Photon Factory.

AR-NW12A is an in-vacuum undulator beamline optimized for high-throughput macromolecular crystallography experiments as one of the five macromolecular crystallography (MX) beamlines at the Photon Factory. This report provides details of the beamline design, covering its optical specifications, hardware set-up, control software, and the latest developments for MX experiments. The experimental environment presents state-of-the-art instrumentation for high-throughput projects with a high-precision goniometer with an adaptable goniometer head, and a UV-light sample visualization system. Combined with an efficient automounting robot modified from the SSRL SAM system, a remote control system enables fully automated and remote-access X-ray diffraction experiments.

Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.

The first known human case of heme oxygenase-1 (HO-1) deficiency is presented in this report. The patient is a six-year-old boy with severe growth retardation. He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin. An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage. Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material. Iron deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production. An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. Sequence analysis of the patient's HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele. Growth retardation, anemia, iron deposition, and vulnerability to stressful injury are all characteristics observed in recently described HO-1 targeted mice. This study presents not only the first human case of HO-1 deficiency but may also provide clues to the key roles played by this important enzyme in vivo.

X-ray phase imaging of biological soft tissue using a direct-sensing x-ray HARP tube camera.

A HDTV camera having a direct-sensing x-ray high-gain avalanche rushing amorphous photoconductor (HARP) tube was used, for the first time, to acquire x-ray phase maps. The tube can achieve a high sensitivity as a result of the avalanche multiplication process in the HARP target. A beryllium plate, rather than a glass plate, was used as the face plate of the tube to minimize the loss of x-rays due to absorption, and a 15 microm thick HARP target was directly formed on it. In the experiment, the x-ray phase shifts produced by a rat liver were measured using synchrotron x-rays (lambda = 0.0766 nm) and a triple Laue-case (LLL) x-ray interferometer. Interference patterns produced by the sample were observed with the direct-sensing x-ray HARP tube camera. A voltage of 1300 V was applied to the HARP target to give an output signal gain of two. The camera was operated in 1125 scanning-line mode, and real-time images were stored on a workstation at a rate of 30 images/s with an image format of 960 (H) x 1100 (V) pixels. A phase-map image of the sample was successfully obtained using the fringe scanning method and phase unwrapping. The observed phase shifts ranged from 50 degrees to 200 degrees . Trees of blood vessels in the rat liver were clearly depicted without using a contrast agent. The spatial resolution of the x-ray camera was estimated to be better than 35 microm in the vertical direction and 100 microm in the horizontal direction.

The relationship between serum levels of interleukin-6 and thyroid hormone in children with acute respiratory infection.

To determine whether monocyte-derived humoral factors such as tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and IL-6 modulate serum thyroid hormone levels in infectious disorders, we measured serum levels of these monocyte-derived products, T3, T4, and C-reactive protein (CRP) in 59 out-patients with acute respiratory infection, aged 5 months to 15 yr (mean +/- SD, 5.7 +/- 4.2 yr). To minimize individual variation in their clinical and nutritional conditions, we selected out-patients with fever lasting for at least 3 days who had no severe disturbance of food intake. Serum T3 concentrations tended to be low in these subjects; 3 (5.1%) had levels below 1.2 nmol/L, L, and 13 (22.0%) had levels below 1.5 nmol/L. Serum T3 levels in 22 patients with elevated IL-6 (> 15 pg/mL) were significantly lower than those in 19 patients with normal IL-6 (< or = 5 pg/mL; T3, 1.7 +/- 0.4 vs. 2.2 +/- 0.6 nmol/L; P < 0.05). The serum IL-6 concentration was correlated inversely with the serum T3 level (r = -0.324; P = 0.012) as well as the T3/T4 ratio (r = -0.279; P = 0.032). Furthermore, a significant negative correlation was observed between CRP (induced mainly by IL-6) and T3 (r = -0.408; P = 0.001) or the T3/T4 ratio (r = 0.302; P = 0.020). On the other hand, TNF alpha was measurable in only 9 of 59 patients, and there was no correlation between TNF alpha and levels of thyroid hormone, CRP, or IL-6. Serum IL-1 beta was weakly detected in only 1 patient. On follow-up study of 10 of these patients, the serum T3 and T3/T4 ratio increased significantly with a reciprocal decrease in IL-6 and CRP during convalescence. No remarkable change in the serum T4 level was observed in our study. Our data suggest that the euthyroid sick syndrome is relatively common in children with acute respiratory infection, and IL-6 appears to mediate this syndrome in infectious disorders.

Effects of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 on type I iodothyronine 5'-deiodination in rat thyroid cell line, FRTL-5.

Using a functioning rat thyroid cell line (FRTL-5), we studied the effects of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) on thyroidal type I iodothyronine 5'-deiodination (I-5'-deiodination) and on the expression of I-5'-deiodinase (I-5'-D) mRNA. After 24 h incubation in medium containing 0.5 microM rT3 with a tracer amount of [125I]rT3, radioactivity of released 125I- was counted. Deiodination in live FRTL-5 cells was enhanced about three times from the basal level by the addition of TSH and was inhibited markedly by propylthiouracil and dose dependently by T4. These results suggest the suitability of this model for investigating I-5'-deiodination in live thyroid tissue. Basal and TSH-induced I-5'-deiodination were significantly inhibited by 100 ng/liter of IL-1 beta and IL-6, and the inhibitory effect of TNF-alpha was seen over 1 microgram/liter. I-5'-deiodination was restored by removal of the cytokines. TSH-induced cAMP production and (Bu)2cAMP-induced I-5'-deiodination were also inhibited by the cytokines. Catalase, dexamethasone, and indomethacin did not abolish the inhibitory effects of the cytokines. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a marked suppression of I-5'-D mRNA expression by IL-1 beta and IL-6. We conclude that these cytokines inhibit the thyroidal type I I-5'-deiodination in the order of potency IL-1 beta > IL-6 >> TNF-alpha, probably by decreasing the I-5'-D mRNA level.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of matrix metalloproteinase-2 in head and neck squamous cell carcinoma: studies of clinical samples and in vitro cell lines co-cultured with fibroblasts.

We undertook this present study to investigate the activation of matrix metalloproteinase-2 (MMP-2) in human head and neck squamous cell carcinomas (HNSCC) tissues and cell lines. Gelatinolytic activities of active MMP-2 were significantly higher in carcinoma samples than in normal portions. Furthermore, the activation ratio of proMMP-2 significantly correlated with cervical lymph node metastasis. In vitro studies revealed an HNSCC cell line, HEp-2, to produce neither the pro form nor the active form of MMP-2, but human fibroblasts were found to produce proMMP-2. However, coculture of HEp-2 cells with fibroblasts resulted in the production of not only proMMP-2 but also activeMMP-2 in the culture medium. Northern blot analysis revealed a stronger expression of membrane-type 1 matrix metalloproteinase (MT1-MMP),which is a specific activator of MMP-2, mRNA in HEp-2 cells than in fibroblasts. These results suggest the activation of proMMP-2 as an important event in the process of HNSCC metastasis. They also suggest MMP-2 is secreted in its pro form by stromal fibroblasts surrounding the cancer cells and activated by MT1-MMP localized on the cancer cells.

Follicle-stimulating hormone promotes the growth of human epithelial ovarian cancer cells through the protein kinase C-mediated system.

We have previously described that follicle-stimulating hormone (FSH) stimulated the growth of human epithelial ovarian cancer tissues and cells. In order to determine the signaling pathway on FSH action in ovarian cancer, we used an epithelial ovarian cancer cell line (HRA line) which constitutively FSH receptors (FSHRs). FSH significantly increased cell proliferation (230.1 +/- 20.5%, P < 0.05) and (3)H-thymidine uptake (443.5 +/- 35.1%, P < 0.01). 1-(5-Isoquinolinesulfonyl)-2-methyipiperazine (H7, 1 5 nM), staurosponine (STR, 5 nM) and calphostin C (5 nM), specific protein kinase C (PKC) inhibitors, significantly suppressed the FSH-stimulated cell growth (120.2-140.2%, P < 0.05) and (3)H-thymidine uptake (140.5-173.9%, P < 0.05), whereas N-(2-guanidinoethyl)-5-isoquinoline-sulfon-amide (HA1004, l5 nM), which is a derivant of H7 and inhibits most of protein kinases except PKC, showed no effect on the FSH-stimulated cell growth and (3)H-thymidine uptake. A pretreatment with 12-0-tetradecanoylphorbol-13 acetate (TPA, 100 ng/ml) or STR (20 nM) significantly suppressed the subsequent FSH-stimulated cell growth (TPA; 152.3 +/-10.3%, STR; 160.4 +/- 15.9%, P < 0.05) and (3)H-thymidine uptake (TPA; 250.4 +/-18.3%, STR; 208.7 +/- 15.9%, P < 0.05). STR abolished the suppression of TPA preincubation on the subsequent FSH-stimulated cell growth and (3)H-thymidine uptake. HRA cells constitutively expressed PKCalpha but not PKCbeta nor PKCgamma. The levels of either expression of PKCalpha protein and mRNA were significantly amplified by FSH. These data suggest that stimulation of PKCalpha transcription is involved in the FSH-stimulated cell growth and DNA synthesis in epithelial ovarian cancer cells.

Matrix metalloproteinase expression in cultured human gastric wall fibroblasts--interactions with Helicobacter pylori isolated from patients with ulcers.

BACKGROUND: Matrix metalloproteinases (MMPs), enzymes capable of degrading collagens and other extracellular matrix components, have been implicated in gastric ulcer formation. However, the effect on MMP expression of Helicobacter pylori, also implicated in these lesions, has not been studied to our knowledge. AIM: To seek links between H. pylori and MMP expression likely to affect gastric ulcer formation. After fibroblasts from human gastric wall were cocultured with H. pylori. concentrations of MMP-1 and -2 in the medium were determined by enzyme-linked immunosorbent assays. RESULTS: Whereas MMP-1 was not detected in media from fibroblasts or H. pylori culture alone, MMP-1 was detected in cocultures (P<0.01). Similar amounts of MMP-2 were detected in medium from fibroblasts cultured alone and with H. pylori. No MMP-2 production by H. pylori cultured alone was detected. CONCLUSIONS: MMP-1 appears to be important in gastric ulcer pathogenesis, and MMP-1 induction by H. pylori may impede gastric ulcer healing.

Crystallization and preliminary X-ray analysis of cytochrome c-554 from Nitrosomonas europaea.

Cytochrome c-554 from Nitrosomonas europaea was crystallized by the batch method utilizing ammonium sulfate as the precipitant. The crystals belong to the space group, P21, with unit cell dimensions of a = 64.8 A, b = 44.7 A, c = 78.7 A, and beta = 99.0 degrees. The crystals diffracted X-rays beyond 2.5 A resolution.

Apoptosis in adenoma and early adenocarcinoma of the colon.

Twenty-six specimens of tubular adenoma and 7 specimens of adenocarcinoma in adenoma of the colon were examined to evaluate apoptosis between adenoma and early adenocarcinoma. Cell proliferation and cell death seemed to be balanced in adenoma with mild and moderate atypia, but unbalanced in adenoma with severe atypia and cancer. Apoptosis was considered to be suppressed at cancer in some cases. However, a number of apoptosis increased at cancer in other cases. Necrosis was seen only in cancer areas. The ratio of cells simultaneously stained by anti-Ki-67 antibody (MIB-1) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labeling (TUNEL) tended to be high from adenoma with moderate atypia to cancer, suggesting the unstableness of DNA. It is possible that cancer cells having highly unstable DNA easily underwent apoptosis as well as necrosis, accidentally. The p53 protein was positive only in cancer areas of three cases. One of these three showed decreased apoptosis in a cancer area, but the other two cases showed increased apoptosis. Furthermore, certain numbers of cancer cells were double-stained by p53 immunohistochemistry and TUNEL. These results suggest that the p53 protein may contribute to suppress apoptosis in the last stage of carcinogenesis of the colonic adenocarcinoma, but other factors including extrinsic stimulation may cause apoptosis despite the mutation of p53 protein.

Distribution and expression of mRNAs for the proto-oncogenes c-fos and c-jun in bone cells in vivo.

In this study we assessed the expression and localization of the proto-oncogenes c-fos and c-jun in normal bone so as to gain more insight into the role of these proto-oncogenes in bone tissue. Femurs of 4-week-old rats were examined by non-radioactive in situ hybridization. cDNA probes for c-fos- and c-jun-labeled digoxygenin were produced by Polymerase Chain Reaction (PCR). C-fos and c-jun exhibited similar distribution in growth plate and bone tissue. Expression of c-fos and c-jun mRNAs in growth plate was observed in the proliferative zone and partly in the upper layer of the hypertrophic zone. In spongy bone, high expression of c-fos and c-jun mRNAs was observed in the osteoblast cytoplasm. However, there was little expression in bone lining cells. In the bony trabeculae, slight expression of c-fos and c-jun was observed in the premature osteocytes situated close to the bone surface, but no expression was detected in osteocytes that possessed relatively large lacunae in the center of the trabeculae. C-fos and c-jun were also slightly expressed in osteoclasts. These data strongly suggest that c-fos and c-jun are involved in regulating chondrocyte proliferation as immediate early genes, and may also be involved in the gene expression of bone matrix proteins as transcription factor (AP-1) in vivo. In addition, the fact that strong expression was observed in osteoblasts but hardly any expression at all in bone lining cells seems to suggest that these genes are also involved in osteoblast activation.

Head movements and neck muscle activities associated with the jaw movement during mastication in the rabbit authors.

Rhythmical head movements and neck muscle activities associated with the masticatory jaw movement were investigated in rabbits. In natural mastication, head movements and neck muscle activities showed a rhythmical feature synchronized with jaw movement. During cortically induced rhythmical jaw movements, some neck muscle showed rhythmical activity induced by biting a wooden stick. Neck muscles may contribute to the rhythmical head movement after loading the tooth with food.

Effects of food consistency on the modulatory mode of the digastric reflex during chewing in freely behaving rabbits.

Effects of food consistency on the mode of the phase-linked modulation in the digastric reflex amplitude were examined in naturally chewing rabbits. Two test foods with different textures (bread as a soft food, pellet as a hard food) were used. The digastric reflex was elicited by electrical stimulation (10 train pulses at 2 kHz) of the inferior alveolar nerve. The amplitude of the digastric reflex measured was divided into three categories depending on the chewing phases in which the stimulus was delivered and each value was compared with the control response obtained when the animal was resting. The reflex was strongly inhibited in the jaw-opening phase and no difference was observed in the inhibitory effect between the foods. In the jaw-closing phase, larger digastric reflexes than those in the opening phase were elicited with both foods. This was the case in both the fast-closing and slow-closing phases. Reflex amplitude was significantly larger during chewing of the hard food than the soft food and, thereafter, inhibition of the reflex was observed only during chewing of the soft food in the closing phase. The results suggest the following: (1) food consistency may affect the central mechanism which regulates the digastric reflex and (2) the reflex may contribute to the regulation of masticatory force during chewing particularly hard food.

Effect of dilazep dihydrochloride against ischemia and reperfusion-induced disruption of blood-brain barrier in rats: a quantitative study.

The effect of dilazep dihydrochloride (dilazep) against ischemia and reperfusion-induced disruption of blood-brain barrier (BBB) was quantitatively investigated in Slc:Wistar strain rats using Evans blue dye as a BBB destruction indicator. The forebrain of sham-operated animal had a small amount of the dye. A treatment of 3.5-h ischemia plus 2-h reflow extravasated the dye into the brain and markedly increased the dye content as compared with that of sham group (P less than 0.01 vs. sham group). Continuous infusion (i.v.) of dilazep during cerebral ischemia dose-dependently reduced the increase of the dye content, and a significant reduction was found at 3 mg/kg/h (P less than 0.05 vs. control group). Evans blue dye extravasation after ischemia was also greatly reduced in saline-perfused brains by the treatment with dilazep. Dilazep has been reported to inhibit edema formation in cerebral ischemia model of spontaneously hypertensive rats. These results suggest that dilazep prevents the ischemic damage of BBB, which may contribute to reduction of the brain edema.

Molecular analysis of peroxisomal beta-oxidation enzymes in infants with Zellweger syndrome and Zellweger-like syndrome: further heterogeneity of the peroxisomal disorder.

The biosynthesis of enzymes of peroxisomal beta-oxidation was investigated in an attempt to elucidate the mechanism of deficiencies of proteins of these enzymes in 3 infants with Zellweger syndrome and in a baby with Zellweger-like syndrome with clinical and biochemical findings consistent with Zellweger syndrome except that the peroxisomes were detected electronmicroscopically. Enzyme proteins of peroxisomal beta-oxidation, acyl-CoA oxidase, bifunctional protein and 3-ketoacyl-CoA thiolase were hardly detectable, in both syndromes. Total hepatic RNA extracted from the liver of one patient with each syndrome and three controls was translated in a rabbit reticulocyte lysate protein-synthesizing system in the presence of [35S]methionine. Translatable mRNAs for all of the peroxisomal beta-oxidation enzymes were detected in both patients at much the same levels seen in the controls. Pulse labelling and chase experiments of fibroblasts from the control revealed that the 72 kDa subunit of acyl-CoA oxidase was first synthesized, after which the 52 kDa and 21 kDa subunits were processed from the 72 kDa subunit. In the patient with Zellweger syndrome, little of the 52 kDa and 21 kDa subunits of acyl-CoA oxidase were synthesized. The mature form of peroxisomal 3-ketoacyl-CoA thiolase was also not processed from its precursor form, in this patient. We consider that Zellweger-like syndrome is a new variant form of a peroxisomal disorder in which biogenesis of peroxisomes is intact, while in contrast, the biogenesis of peroxisome is considered to be defective in those with Zellweger syndrome. Multiple defects of enzymes of beta-oxidation in Zellweger-like syndrome are assumed to be caused by a defect of transport or localization of these enzymes. Our molecular analyses indicate that the enzymes of peroxisomal beta-oxidation are synthesized in patients with Zellweger and Zellweger-like syndrome but that these enzymes are not processed normally and are degraded rapidly.

Cervical spinal cord infarction after surgery for a pineal region choriocarcinoma in the sitting position: case report.

OBJECTIVE AND IMPORTANCE: Spinal cord injury is one of several devastating complications after operation in the sitting position. Young patients exhibiting extraordinary growth spurts demonstrate a higher risk for this complication. CLINICAL PRESENTATION: We describe a 7-year-old male patient with a pineal region choriocarcinoma in whom a cervical spinal cord infarction (C5-T1) developed as an acute complication after operation in the sitting position. Preoperatively, high serum levels of human chorionic gonadotropin (5867.7 mIU/ml) and somatomedin-C (704 ng/ml) and an extreme growth velocity in height (16 cm/yr) were noted. CONCLUSION: It is assumed that, in addition to head flexion, the abnormal skeletal growth spurt resulting from an excessive secretion of human chorionic gonadotropin from a tumor was a possible predisposing factor for this complication. To prevent this complication, surgeons need to pay great attention to head positioning, especially in a young patient experiencing an active growth spurt.

Morphological analysis of pancreatic endocrine cells in newborn animals delivered by experimental diabetic rats.

Rats with mildly impaired glucose tolerance (MIGT) were prepared by the administration of streptozotocin and subsequent islet-isotransplantation. Of pups born to these rats, 65% exhibited macrosomia that weighed over 6.8 g (average weight of control pups was 5.96 g). The morphological changes in the endocrine pancreas in pups born of MIGT and normal control rats were studied using immunohistochemical methods and quantitative morphological analysis. In macrosomic pups, the percentages of pancreatic tissue devoted to islet areas and B cell areas were significantly higher than in control pups. The percentage of pancreas devoted to A cell areas was also higher in macrosomic than normal pups, while the ratio of A/B cell areas was in normal range. In non-macrosomic pups born to MIGT rats, the percentages of pancreas devoted to islet tissues, B cell, and A cell areas were each lower than these in macrosomic pups. Moreover, increase in the proportions of islet and B cell areas in the pancreatic tissue in pups born of MIGT mothers was linearly correlated with increase in birthright. There were no significant differences in D cell area as a proportion of pancreas among macrosomic, non-macrosomic and control pups. These findings suggest that insulin secreted from B cells play important roles in the control of fetal growth.

Photosensitive drug eruption induced by flutamide.

We describe a 68-year-old man who showed a photosensitive drug eruption induced by flutamide. The minimal erythema dose with ultraviolet A light was reduced to 2 J/cm2 under administration of flutamide, which recovered to over 16 J/cm2 after cessation of the medication, without changing the reactivity to ultraviolet B. The absorption spectrum of flutamide was not altered after ultraviolet A irradiation, suggesting that flutamide is photostable with regard to ultraviolet A. In addition, bovine serum albumin was not covalently photocoupled with flutamide under ultraviolet A. Thus, flutamide seems to have low potency to act as a photohapten, and it is likely that a non-photohaptenic mechanism operates in this photosensitivity or its active metabolite may work as a photosensitizer.

Laparoscopic wedge resection of gastric submucosal tumors.

Minimally invasive surgery has revolutionized the treatment of gastrointestinal tumors. Submucosal tumors (SMTs) of the stomach can be resected using laparoscopic techniques. Between 1993 and 1997, laparoscopic wedge resection was performed in 34 patients with an SMT of the stomach. The tumors ranged from 8 to 60 mm in diameter. All surgical margins were clear. The average operative time was 131 minutes. Most of the patients began eating on the first postoperative day and were discharged within 5 to 7 days. Histopathologic examination of the tumors showed gastrointestinal stromal tumor (n = 14), ectopic pancreas (n = 7), leiomyosarcoma (n = 4), schwannoma (n = 3), carcinoid (n = 2), leiomyoma (n = 2), an inflammatory lesion caused by parasites (n = 1), and cyst (n = 1). No recurrences were observed over the 5-year follow-up period. A solid SMT of the stomach larger than 20 mm in diameter can be treated using laparoscopic wedge resection.