Cholelithiasis prevalence and risk factors in individuals with severe or profound intellectual and motor disabilities.

BACKGROUND: The prevalence and risk factors of cholelithiasis in individuals with severe or profound intellectual and motor disabilities (SPIMD) are poorly characterised. Thus, we aimed to investigate the prevalence and risk determinants of cholelithiasis in a cohort with SPIMD under medical care in a residential facility. METHODS: We categorised 84 patients in a residential hospital for persons with SPIMD into groups: those with (Group CL) and without (Group N) cholelithiasis. Gallstones were detected via computed tomography, ultrasonography or both. We evaluated gastrostomy status, nutritional and respiratory support, constipation, and bladder and kidney stones. Data were significantly analysed using univariate and multivariate logistic regression analyses. RESULTS: The prevalence rate of cholelithiasis in our SPIMD cohort was 27%. There were no significant differences in sex, age, weight, height, or Gross Motor Function Classification System between the two groups. However, more patients received enteral nutrition (39.13% vs. 6.56%; P = 0.000751) and were on ventilator support (56.52% vs. 19.67%; P = 0.00249) in Group CL than in Group N. Enteral nutrition [odds ratio (OR) 10.4, 95% confidence interval (CI) 1.98-54.7] and ventilator support (OR 20.0, 95% CI 1.99-201.0) were identified as independent risk factors for the prevalence of cholelithiasis in patients with SPIMD. CONCLUSIONS: Patients with SPIMD demonstrated an increased prevalence of cholelithiasis, with a notable association between nutritional tonic use and respiratory support. Therefore, to emphasise the need for proactive screening, it is crucial to devise diagnostic and therapeutic strategies specific to patients with SPIMD. Further investigation is essential to validate our findings and explore causative factors.

Randomized clinical trial of extensive intraoperative peritoneal lavage versus standard treatment for resectable advanced gastric cancer (CCOG 1102 trial).

BACKGROUND: A survival benefit of extensive intraoperative peritoneal lavage (EIPL) has been reported in patients with gastric cancer with positive peritoneal cytology. The hypothesis of this study was that EIPL may reduce peritoneal recurrence in patients with advanced gastric cancer who undergo surgery with curative intent. METHODS: This was an open-label, multi-institutional, randomized, phase 3 trial to assess the effects of EIPL versus standard treatment after curative gastrectomy for resectable gastric cancer of T3 status or above. The primary endpoint was disease-free survival (DFS); secondary endpoints were overall survival, peritoneal recurrence-free survival and incidence of adverse events. RESULTS: Between July 2011 and January 2014, 314 patients were enrolled from 15 institutions and 295 patients were analysed (145 and 150 in the EIPL and no-EIPL groups respectively). The 3-year DFS rate was 63·9 (95 per cent c.i. 55·5 to 71·2) per cent in the EIPL group and 59·7 (51·3 to 67·1) per cent in the control group (hazard ratio (HR) 0·81, 95 per cent c.i. 0·57 to 1·16; P = 0·249). The 3-year overall survival rate was 75·0 (67·1 to 81·3) per cent in the EIPL group and 73·7 (65·9 to 80·1) per cent in the control group (HR 0·91, 0·60 to 1·37; P = 0·634). Peritoneal recurrence-free survival was not significantly different between the two groups (HR 0·92, 0·62 to 1·36; P = 0·676). No intraoperative complications related to EIPL were observed. CONCLUSION: EIPL did not improve survival or peritoneal recurrence in patients who underwent gastrectomy for advanced gastric cancer. Registration number: 000005907 (http://www.umin.ac.jp/ctr/index.htm).

ANTECEDENTES: Se ha descrito que un lavado peritoneal extenso intraoperatorio (extensive intraoperative peritoneal lavage, EIPL) proporciona un beneficio en la supervivencia en pacientes con cáncer gástrico con citología peritoneal positiva. La hipótesis de este estudio era que el EIPL podría disminuir la recidiva peritoneal en pacientes con cáncer gástrico avanzado sometidos a cirugía con intención curativa. MÉTODOS: Ensayo clínico fase 3, abierto, multicéntrico y aleatorizado para evaluar los efectos de un lavado peritoneal extenso intraoperatorio (EIPL) frente a tratamiento estándar tras gastrectomía curativa por cáncer gástrico ≥T3 resecable. La variable de resultado primaria fue la supervivencia libre de enfermedad (disease-free survival, DFS), y las variables de resultado secundarias fueron la supervivencia global (overall survival, OS), la supervivencia libre de recidiva peritoneal y la incidencia de efectos adversos. RESULTADOS: Entre julio de 2011 y enero de 2014, se reclutaron 314 pacientes de 15 instituciones y se analizaron los datos de 295 pacientes (145 en el grupo con EIPL y 150 en el grupo sin EIPL). La DFS a los 3 años fue 63,9% (i.c. del 95% 55,5-71,2) en el grupo con EIPL y 59,7% (i.c. del 95% 51,3-67,1) en el grupo control (cociente de riesgos instantáneos, hazard ratio, HR 0,81 (i.c. del 95% 0,57-1,16), P = 0,249). La OS a los 3 años fue 75,0% (i.c. del 95% 67,1-81,3) en el grupo con EIPL y 73,7% (i.c. del 95% 65,9-80,1) en el grupo control (HR 0,91 i.c. del 95% 0,60-1,37), P = 0,634). No se observaron diferencias estadísticamente significativas entre los dos grupos en la supervivencia libre de recidiva peritoneal (P = 0,676, HR 0,92 (i.c. del 95% 0,62-1,36). No se observaron complicaciones intraoperatorias relacionadas con EIPL. CONCLUSIÓN: El EIPL no mejoró la supervivencia o la recidiva peritoneal en pacientes sometidos a gastrectomía por cáncer gástrico avanzado.

Randomized clinical trial of duct-to-mucosa pancreaticogastrostomy versus handsewn closure after distal pancreatectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a major cause of morbidity after distal pancreatectomy. The aim of this study was to investigate whether duct-to-mucosa pancreaticogastrostomy of the pancreatic stump decreased clinical POPF formation compared with handsewn closure after distal pancreatectomy. METHODS: This multicentre RCT was performed between April 2012 and June 2014. Patients undergoing distal pancreatectomy were assigned randomly to either duct-to-mucosa pancreaticogastrostomy or handsewn closure. The primary endpoint was the incidence of clinical POPF. Secondary endpoints were rates of other complications and length of hospital stay. RESULTS: Some 80 patients were randomized, and 73 patients were evaluated in an intention-to-treat analysis: 36 in the pancreaticogastrostomy group and 37 in the handsewn closure group. The duration of operation was significantly longer in the pancreaticogastrostomy group than in the handsewn closure group (mean 268 versus 197 min respectively; P < 0·001). The incidence of clinical POPF did not differ between groups (7 of 36 versus 7 of 37; odds ratio (OR) 1·03, 95 per cent c.i. 0·32 to 3·10; P = 1·000). The rate of intra-abdominal fluid collection was significantly lower in the pancreaticogastrostomy group (6 of 36 versus 21 of 37; OR 0·15, 0·05 to 0·45; P < 0·001). There were no statistically significant differences in the rates of other complications or length of hospital stay. CONCLUSION: Duct-to-mucosa pancreaticogastrostomy did not reduce the incidence of clinical POPF compared with handsewn closure of the pancreatic stump after distal pancreatectomy. Registration number UMIN000007426 (http://www.umin.ac.jp).

Concurrent analysis of human equilibrative nucleoside transporter 1 and ribonucleotide reductase subunit 1 expression increases predictive value for prognosis in cholangiocarcinoma patients treated with adjuvant gemcitabine-based chemotherapy.

BACKGROUND: The aim of this study was to investigate the predictive and prognostic values of intratumoural human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase subunit 1 (RRM1) expression in advanced cholangiocarcinoma patients treated with adjuvant gemcitabine-based chemotherapy (AGC). METHODS: Intratumoural hENT1 and RRM1 expression levels were investigated immunohistochemically in 127 patients with advanced cholangiocarcinoma who underwent surgical resection (68 with AGC and 59 without AGC). The impacts of hENT1 and RRM1 expression on survival were evaluated. RESULTS: High intratumoural hENT1 and RRM1 expression levels were observed in 86 (68%) and 67 (53%) patients, respectively. In a multivariate analysis of 68 patients who received AGC, high hENT1 (P=0.044) and low RRM1 expression (P=0.009) were independently associated with prolonged disease-free survival (DFS), whereas low RRM1 expression (P=0.024) was independently associated with prolonged overall survival (OS). Moreover, concurrent high hENT1 and low RRM1 expression was a powerful independent predictor of prolonged DFS (P<0.001) and OS (P=0.001) when the combined classification of hENT1 and RRM1 was introduced. CONCLUSIONS: Concurrent analysis of hENT1 and RRM1 expression may increase the predictive value of these biomarkers for survival of advanced cholangiocarcinoma patients treated with AGC.

Physical impairment and walking function required for community ambulation in patients with cervical incomplete spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To identify the physical impairments and walking function required for community ambulation in patients with cervical incomplete spinal cord injury (ISCI). SETTING: Chubu Rosai Hospital, Nagoya, Japan. METHODS: Forty patients with cervical ISCI (mean age: 49.9 years, American Spinal Injury Association Impairment Scale D) were included. The primary outcome measure was community ambulation based on Spinal Cord Independence Measure outdoor scores for a distance of >480 m. We measured the upper- and lower-extremity motor scores (UEMS and LEMS), sensory and spasticity. The walking tests included 10 m of walking at a comfortable- and maximum-walking speed (CWS and MWS; m s(-1)), 6 min walking test (6 MWT; m) and the walking index for spinal cord injury II (WISCI II). Multivariate logistic regression models were used to assess the physical impairments associated with community ambulation. Receiver operating characteristic curves were analyzed to determine the cutoff points for physical impairment and walking function. RESULT: The LEMS (beta coefficient (ß)=0.71) and UEMS (ß=0.41) were independently associated with community ambulation in patients with cervical ISCI. The cutoff points of the LEMS, UEMS, CWS, MWS, 6MWT and WISCI II were 41.5, 36.5, 1.00 m s(-1), 1.32 m s(-1), 472.5 m and 17.5, respectively, which suggests moderate to high accuracy. CONCLUSION: The LEMS and UEMS were the most important factors affecting community ambulation in patients with cervical ISCI. The cutoff points of the walking function tests were highly accurate; therefore, these points can serve as targets for walking training in the future.

Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks.

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2 R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

Amyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptor.

Dysfunction in the synapse is recognized as an early and the primary pathological process in Alzheimer's disease (AD). N-cadherin, an essential adhesion molecule for excitatory synaptic contact, forms a complex with presenilin 1 (PS1) and beta-catenin in the synaptic membrane. N-cadherin is sequentially cleaved by ADAM10 and PS1/gamma-secretase, producing a cytoplasmic fragment, N-cadherin C-terminal fragment (Ncad/CTF2) after NMDA receptor stimulation [Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK (2003) A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635-645; Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. EMBO J 24:1762]. Ncad/CTF2 translocates to the nucleus together with beta-catenin to enhance beta-catenin nuclear signaling [Uemura K, Kihara T, Kuzuya A, Okawa K, Nishimoto T, Bito H, Ninomiya H, Sugimoto H, Kinoshita A, Shimohama S (2006a) Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin. Biochem Biophys Res Commun 345:951-958]. To examine whether an impairment of N-cadherin metabolism is involved in AD pathogenesis, we investigated the effect of amyloid beta peptide (Abeta) treatment on sequential N-cadherin cleavage. Here, we demonstrate that both synthetic and cell-derived Abeta species inhibit ectodomain shedding of mouse N-cadherin. Inhibition of N-cadherin cleavage by Abeta treatment was suggested to be mediated by the enhanced endocytosis of NMDA receptor, resulting in reduced turnover of N-cadherin. Since both N-cadherin and beta-catenin are essential for synaptic plasticity, impairment of N-cadherin cleavage caused by Abeta may underlie the synapse toxicity involved in AD pathogenesis.

Inclusion of an S-nitrosylating agent in the insufflating gas does not alter gastric activity in rats following pneumoperitoneum.

BACKGROUND: We have previously shown that mixing the S-nitrosylating agent ethyl nitrite with carbon dioxide can attenuate pneumoperitoneum-induced decreases in splanchnic blood flow, but it was unclear if this agent would alter gastric function. This question was answered using rats by assessing gastric emptying and gastrointestinal transit times following gavage with radioactive chromium. METHODS: There were five experimental groups: absolute control, anesthesia control, and carbon dioxide alone or with 100 or 300 parts per million ethyl nitrite. The period of insufflation was 1 h, and all animals were euthanized 6.5 h after chromium administration. RESULTS: The mean amount of radioactivity remaining in the stomach ranged between 16% and 27% of the total administered; these differences were not statistically significant (p > 0.05). Modest differences in chromium distribution were identified in the gastrointestinal tract, but for all treatments, the peak amount of radioactivity was located in the distal portion. Location of the peak, expressed as a percentage of total tract length, varied between 70% and 85% (p = 0.366). CONCLUSIONS: This study found no adverse effect of ethyl nitrite on postoperative gastric emptying or gastrointestinal transit time following pneumoperitoneum. The findings support continued assessment of the clinical utility of ethyl nitrite in the setting of laparoscopic surgery.

In vitro determination of basement membrane invasion predicts liver metastases in human gastrointestinal carcinoma.

We described previously (H. Imamura, et al., Cancer Res., 54: 3620-3624, 1994) a quantitative and reproducible 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for tumor cell invasiveness that uses a water-repellent, paraffin-treated Chemotaxicell chamber to produce a uniform Matrigel layer. In the present experiments, we studied 71 human gastrointestinal carcinomas, including 53 maintained as xenografts in nude mice and 18 fresh surgical specimens. We found a correlation between metastatic behavior and the percent invasion (PI) calculated from the MTT assay. Tumors producing liver metastases had a significantly higher PI than did tumors without liver metastases (P < 0.01), and seven of nine fresh tumors with a PI greater than 1.0 showed liver metastases within 2 years. No significant correlations were noted between the PI and clinicopathological factors. In the tumor xenografts, type IV collagenase activity was significantly higher in tumors with clinically evident liver metastases than in those without liver metastases (P < 0.05). Colorectal carcinomas with liver metastases and a high PI showed higher expression of matrix metalloproteinase 9 than matrix metalloproteinase 2 as assessed by gelatin zymography. Thus, the invasion-MTT assay is clinically useful for predicting liver metastases. Type IV collagenase plays an important role in the development of liver metastases from human gastrointestinal carcinoma.

Characterization of glycolipids from the gastric cancer of a patient of p,O,Le(a-,b+) blood type: presence of incompatible blood group antigens in tumor tissues.

The antigens present in a gastric tumor obtained from a patient of blood group p,O,Le(a-,b+) were studied. The neutral glycolipids were isolated from the cancer tissues and characterized chemically and immunologically. The glycolipid pattern of the tumor was similar to that of the surrounding uninvolved mucosae. The major neutral glycolipids were found to be glucosylceramide, galactosylceramide, lactosylceramide, and the lacto series glycolipids, including the H, Lea, and Leb active fucolipids. The cancer tissues and the uninvolved mucosae did not contain galabiosylceramide, globotriaosylceramide, or globotetraosylceramide after separations by both thin layer chromatography and gas-liquid chromatography. Thin layer chromatography immunostaining was performed to detect incompatible blood group antigens. Immunostaining revealed the presence of globotriaosylceramide, globotetraosylceramide, Forssman glycolipid, and A active glycolipids in the cancer tissues. These incompatible blood group active glycolipids were absent from the uninvolved mucosae. The results indicate that the cancer tissues possess the ability to produce the globo series of glycolipids and the A active antigens but that the surrounding uninvolved mucosae could not synthesize these glycolipids.

The presence of blood group A-active glycolipids in cancer tissues from blood group O patients.

Glycolipids were isolated from human gastric cancer tissues and normal mucosae. Sulfogalactosylceramide, ganglioside and neutral glycolipid fractions were separated by DEAE-Sephadex and silica gel column chromatography. Sulfogalactosylceramide contents were higher in the cancer tissues than in the normal mucosae. Ganglioside contents showed considerable variations but in the cancer tissues in mole percentage of ganglioside GM3 was higher than in the normal mucosae. The cancer tissues contained more neutral glycolipids than normal tissues. Glycolipids of lacto-series, including fucolipids, were markedly increased in the cancer tissues. Blood group A-active glycolipids were found in the cancer tissues from two patients with blood group O but not found in the uninvolved tissue associated with the cancer tissue.

Glycolipid of human pancreatic cancer; the appearance of neolacto-series (type 2 chain) glycolipid and the presence of incompatible blood group antigen in tumor tissues.

Glycolipid isolated from normal and cancerous human pancreatic tissues were characterized chemically and immunologically. The major neutral glycolipids in both normal and cancerous tissues were composed of globo-series glycolipids and lacto-series glycolipids. The mole percentage of fucolipids in the total neutral glycolipids of normal tissues was 20-40%, and in general the fucolipids corresponded to blood group glycolipids related to the patient's blood group, however, in cancerous tissues the amount of these fucolipids was decreased. Immunostaining revealed that normal tissues contained only lacto-series (type 1 chain) glycolipids. In contrast, cancerous tissues contained the neolacto-series (type 2 chain) glycolipids as well as the lacto-series glycolipids. Incompatible blood group antigens, A active glycolipids in a blood type O patient and B active glycolipids in a blood type A patient, were also detectable in the neutral glycolipid fractions of the pancreatic cancer tissues.

Identification of immuno-reactive lipocortin 1-like molecules in serum and plasma by an enzyme immunoassay for lipocortin 1.

A two-site enzyme immunoassay for lipocortin 1 (LC1) has been developed. The detection limit of LC1 was 0.2 ng/tube and the optimal assay range was 1 to 100 ng/tube. The assay system enabled us to identify immunoreactive lipocortin 1-like molecules (IR-LC1) in human serum and plasma. Normal human serum and plasma IR-LC1 concentrations were 44.6 ng/ml for males and 43.1 ng/ml for females with no significant difference between both sexes. The age-related analysis among nine age groups from newborn to 69 years old revealed that the serum or plasma level was high in infants (77.5 ng/ml for newborn and 75.6 ng/ml for 1 month-1 year group), and the 40-year-old (52.2 ng/ml) and 50-year-old (51.3 ng/ml) groups. The major population of plasma IR-LC1 was of 70 kDa in size corresponding to that of the LC1 homodimer. The present enzyme immunoassay system is sufficiently sensitive for the clinical study of LC1 in human body fluids, tissues and organs.

Glycosphingolipid carriers of carbohydrate antigens of human myeloid cells recognized by monoclonal antibodies.

Six monoclonal antibodies with known specificities for the carbohydrate antigens i, X or Y, and seven anti-myeloid antibodies (determinants unknown) selected for their differing reaction patterns with human leucocytes were tested in chromatogram binding assays for reactions with myeloid cell glycolipids derived from normal human granulocytes and chronic myelogenous leukemia cells. Antigenicities were found exclusively on minor glycolipids which were barely or not at all detectable with orcinol-sulphuric acid stain. Among these, a neutral glycosphingolipid bound the anti-i antibody Den and chromatographed as the ceramide octasaccharide, Gal beta 1----4GlcNac beta 1----3Gal beta 1----4GlcNac beta 1----3Gal beta 1----4GlcNAc beta 1----3Gal beta 1----4Glc-Cer. Several species of neutral glycosphingolipids with six to more than ten monosaccharides were detected which carry the X antigen and others the Y antigen: Gal beta 1----4(Fuc alpha 1----3)GlcNAc and Fuc alpha 1----2Gal beta 1----4(Fuc alpha 1----3)GlcNAc, respectively. In addition, three new types of carbohydrate specificities were detected among the myeloid cell glycolipids. Two were associated with neutral glycolipids: the first, recognised by anti-myeloid antibodies VIM-1 and VIM-10, was expressed on a distinct set of glycolipids with six or more monosaccharides, and the second, recognized by VIM-8, was expressed on glycolipids with more than ten monosaccharides. The third specificity, recognised by the anti-myeloid antibody VIM-2, was expressed on slow migrating sialoglycolipids with backbone structures of the poly-N-acetyllactosamine type that are susceptible to degradation with endo-beta-galactosidase. Thus, we conclude that the i and Y antigens occur among the glycolipids of normal myeloid and chronic myelogenous leukemia cells and that a high proportion of hybridoma antibodies raised against differentiation antigens of myeloid cells are directed at carbohydrate structures.

A marker of human foetal endoderm defined by a monoclonal antibody involves Type 1 blood group chains.

This report demonstrates that a marker of human embryonic endoderm and embryonal carcinoma cells recognized by a hybridoma antibody FC 10.2, involves Type 1 blood group chains with the sequence Gal beta 1 leads to 3G1cNAc beta 1 leads to 3Gal beta 1 leads to 4G1c. This conclusion has been reached from antigenic analyses of meconium, ovarian cyst glycoproteins, oligosaccharides and glycolipids having Type 1 or Type 2 blood group chains. From knowledge of saccharide sequences and blood group related antigens in gastrointestinal tissues of man, we deduce that the 'disappearance' of FC 10.2 antigen from the normal, differentiated cells of the adult may result from masking by additional glycosylations or other substitutions.

Involvement of the hippocampus in central nervous system-mediated glucoregulation in rats.

To find out whether the hippocampus is involved in central nervous system-mediated glucoregulation, we injected saline, neostigmine, dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, and prostaglandin F2 alpha into the dorsal hippocampus in anesthetized fed rats. After injection of dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, or prostaglandin F2 alpha, the level of hepatic venous plasma glucose did not differ from that in saline-treated control rats. However, neostigmine, an inhibitor of acetylcholine esterase, caused a dose-dependent increase in the hepatic venous plasma glucose concentration. This neostigmine-induced hyperglycemia was dose-dependently suppressed by coadministration of atropine, but not by hexamethonium. Injection of neostigmine (5 X 10(-8) mol) resulted in an increase not only in glucose but also in glucagon, epinephrine, and norepinephrine in hepatic venous plasma. In bilateral adrenalectomized rats, neostigmine-induced hyperglycemia was suppressed, but the hepatic venous plasma glucose concentration still increased significantly. These results indicate that the hippocampus is involved in central nervous system-mediated glucoregulation through cholinergic muscarinic activation, partly via epinephrine secretion.

The relative importance of nervous system and hormones to the 2-deoxy-D-glucose-induced hyperglycemia in fed rats.

We examined the relative contributions of hormones and nervous system to the total 2-deoxy-D-glucose (2-DG)-induced central nervous system-mediated hyperglycemia. 2-DG was injected into the third cerebral ventricle in the following four groups of rats, and hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were measured: 1) intact rats; 2) intact rats receiving somatostatin with insulin infusion through the femoral vein to inhibit glucagon secretion and maintain the basal insulin level; 3) bilateral adrenalectomized (ADX) rats to prevent epinephrine secretion; and 4) ADX rats receiving somatostatin with insulin infusion. Comparing areas under glucose curves among the intact rats, those receiving somatostatin with insulin infusion, ADX rats, and ADX rats receiving somatostatin with insulin infusion, the area under the glucose curve was intact rats greater than intact rats receiving somatostatin with insulin infusion greater than ADX rats receiving somatostatin with insulin infusion greater than ADX rats. These results suggest that there are three distinct sympathetic nervous system responses to 2-DG-induced central nervous system-mediated hyperglycemia. 2-DG-induced hyperglycemia is not dependent on only one of those three systems, it is dependent on all of them. The relative potency of the factors to 2-DG-induced hyperglycemia increases in the following order: direct neural innervation of liver (including suppressive epinephrine action on insulin secretion), glucagon, and direct epinephrine action on liver.

Central nervous system-mediated glucagon secretion is enhanced by alpha 2-adrenoreceptor activation.

We assessed the response of the adrenergic receptor in pancreatic glucagon secretion to central nervous system stimulation. Injection of neostigmine (5 x 10(-8) mol) into the third cerebral ventricle in intact rats resulted in increased epinephrine and norepinephrine secretion associated with glucagon secretion. This glucagon secretion was still observed in bilateral adrenalectomized (ADX) rats, although its concentration was significantly lower than that in the intact rats. This glucagon rise was significantly inhibited by ip treatment of ganglionic blocker with hexamethonium. Intraperitoneal injection of alpha-adrenergic receptor antagonist phentolamine (5 x 10(-7) mol), but not of beta-adrenergic receptor antagonist propranolol (1 x 10(-6) mol), reduced the hyperglucagonemic effect of a subsequent neostigmine injection in intact and ADX rats, although these antagonists did not influence epinephrine or norepinephrine secretion in intact rats. In addition, ip injection of the selective alpha 2-receptor antagonist yohimbine (5 x 10(-7) mol), but not of the selective alpha 1-receptor antagonist prazosin (1 x 10(-6) mol), inhibited the neostigmine-induced glucagon secretion in intact and ADX rats. From this evidence it is suggested that central nervous system-mediated glucagon release is enhanced by alpha 2-adrenoreceptor stimulation by either catecholamines or the autonomic nervous system.

Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: studies of seventy autopsied cases.

Postmortem histological examination of the thyroid gland and measurement of serum antithyroid antibodies were performed in 70 patients without overt thyroid disease. Lymphocytic infiltration, antithyroglobulin hemagglutination antibody (TGHA), and antithyroid microsomal hemagglutination antibody (MCHA) were found in 12, 2, and 9 cases, respectively. The incidence of lymphocytic infiltration in females was three times that in males. Ten of the 12 cases with lymphocytic infiltration had positive antibodies (either TGHA or MCHA), while 10 of 11 patients with positive antibodies showed lymphocytic infiltration. Thus, the correlation between morphological and serological findings was highly significant at P less than 0.001. The incidence of a small thyroid gland of less than 15 g in weight was higher in patients with lymphocytic infiltration and/or positive antibodies than in patients with a normal thyroid gland. These data suggest that positive serum antithyroid antibodies in subjects without overt thyroid disease may indicate the existence of lymphocytic infiltration in the thyroid gland, that is presumably subclinical autoimmune thyroiditis.

A new approach of weighted integration technique based on accumulated images using dynamic PET and H2(15)O.

We developed a new technique of weighted integration for the measurement of local cerebral blood flow (LCBF) and the blood-tissue partition coefficient (p) using dynamic positron emission tomography (PET) and H2(15)O. The weighted integration in the new technique is carried out on the equation of the first time integration of the Kety-Schmidt differential equation. Practically, serially accumulated images with sequentially prolonged accumulation times are weighted by two arbitrary functions. The weighting functions do not have to be differentiated because of the exclusion of the differential term in the starting equation. Consequently, the method does not require data at the end of the scan. The technique was applied to H2(15)O dynamic PET performed on four normal subjects, and was verified to provide a better signal-to-noise ratio than the previously developed integrated projection (IP) technique. Computer simulations were carried out to investigate the effects of statistical noise, tissue heterogeneity, and time delay and dispersion in arterial input function. The simulation showed that the new technique provided about a 1.4 times lower statistical error in both LCBF and p at 50 ml 100 g-1 min-1 compared to the IP technique, and it should be noted that the new technique was less sensitive to the shape of the weighting functions. The new technique provides a new strategy with respect to the statistical error for estimation of LCBF and p.