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The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum-based risk model that could identify patients with low-risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma-glutamyl transferase&nbsp

The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with sofosbuvir (SOF) and velpatasvir (VEL) were assessed in hepatitis C virus (HCV) genotype 1- and 2-infected patients with decompensated cirrhosis. A total of 65 patients with HCV-related decompensated cirrhosis (Child-Pugh score of 7 points or more) who were treated with the SOF/VEL regimen were enrolled. The sustained virological response (SVR) rate and safety profile were analyzed. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment (SVR12). The percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 81.2% (95% confidence interval [CI], 69.5-89.9) (52/64), 98.4% (95% CI, 91.2-100.0) (60/61), and 98.5% (95% CI, 91.7-100.0) (64/65), respectively. The overall SVR rate was 92.3% (95% CI, 83.0-97.5) (60/65). Albumin-bilirubin (ALBI) scores decreased during and after treatment (p

Background It is unclear whether the fibrosis 4 index (FIB-4), a marker of liver fibrosis, at baseline and change in FIB-4 after sustained virological response (SVR) is associated with incident hepatocellular carcinoma (HCC) risk. In this study, we examined the association of incident HCC risk with baseline FIB-4 and sustained high FIB-4 (>3.25) at any time point after SVR. Methods A total of 3823 patients who received direct-acting antiviral treatment and achieved SVR were enrolled. The FIB-4 was measured 24 weeks after the end of direct-acting antiviral treatment and achievement of SVR (SVR24), and 1, 2, and 3 years after SVR24, after which subsequent HCC development was investigated. Results In patients with an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years after SVR24, subsequent HCC development was significantly higher than in those with an FIB-4 ≤3.25 at each point. The rates of HCC development 1, 2, 3, and 4 years after SVR24 were significantly higher in patients with sustained FIB-4 >3.25 than in those whose FIB-4 decreased to ≤3.25 (5.4%, 9.2%, 11.7%, and 16.0%, respectively, vs 2.2%, 3.1%, 3.7%, and 4.4%; P 3.25 at SVR24 and 1, 2, and 3 years later were 3.38 (2.4–4.8), 2.95 (1.9–4.7), 2.62 (1.3–5.1), and 3.37 (1.4–9.8), respectively. Conclusions The FIB-4 could be used to assess HCC development risk at any time after SVR, and changes in FIB-4 were associated with changes in the HCC development risk. Repeated assessments of FIB-4 could serve as a prognostic indicator of a high-risk HCC cohort that may require more intensive HCC surveillance strategy.

Nucleos(t)ide analogs (NA) suppress hepatitis B virus (HBV) replication and reduce the risk of hepatocellular carcinoma (HCC). However, NA cannot suppress carcinogenesis completely in patients with chronic hepatitis B. The aims of this study were to identify risk factors for HCC and develop a refined carcinogenesis prediction model. Patients receiving NA therapy (n = 1,183) were recruited retrospectively from the 16 hospitals. All patients had been receiving NA continuously for more than 1 year until the end of the follow-up. During a median follow-up of 4.9 (1.0–12.9) years, 52 (4.4%) patients developed HCC. A multivariate analysis revealed that male gender, older age, lower platelet counts at the baseline, and detectable HBV DNA during NA therapy were independent predictive factors of HCC development. The PAGE-B score was calculated by using these factors. 240 (20.3%), 661 (55.9%), and 282 (23.8%) patients were classified into low-, intermediate-, and high-risk groups, respectively. In the intermediate- and high-risk group, detectable HBV DNA was significantly associated with a higher risk of HCC development compared with continuously undetectable HBV DNA, respectively (HR 3.338; 95% CI 1.045–10.66/HR 3.191; 95% CI 1.543–6.597). PAGE-B–DNA, which is the combined PAGE-B and HBV DNA status, was valuable for a more refined stratification of PAGE-B.

Aim To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). Methods A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. Results The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. Conclusions For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.

AIM The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naive patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P

We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection. This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC). Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP-L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 ± 37.6 to 6.0 ± 10.6 ng/mL, p

Backgrounds & Aims We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection. Methods This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing. Results The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients. Conclusion Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.

To evaluate the role of contrast-enhanced ultrasonography (CEUS) in the diagnosis of ruptured hepatocellular carcinoma (HCC).CEUS and angiography were performed in ten cases of ruptured HCC. We evaluated whether this technique allowed us to determine the bleeding point by observing an extravasation of contrast media into the ascites.In four of the ten cases, CEUS demonstrated an extravasation of Levovist into ascites. Angiography showed an extravasation of contrast medium in three of these four cases. In three of the remaining six cases, in which CEUS did not show the presence of contrast medium in ascites, angiography demonstrated an extravasation. In eight cases, it yielded cessation of bleeding. In two cases, embolization was not successful. The bleeding point was not determined by CEUS or angiography in one case.CEUS allows us to differentiate active bleeding (presence of contrast medium in the ascites) from nonactive bleeding.

この章では，まず膵の解剖学的位置関係，特に周囲脈管系との関係を述べ，次いで，膵超音波検査で伝統的に用いられてきた走査法に，そして最後に我々が推奨する走査法の工夫について解説する．通常の走査法では，一断面で膵全体を観察するのは困難で，幾つかの走査面を組み合わせざるを得ない．大まかには，次の4走査法が中心となる．a）上腹部横走査：脾静脈を指標として膵頭体部を観察する．b）上腹部矢状走査：この断面では腹腔動脈と上腸間膜動脈に挟まれた膵が見える．これらは全て呼吸性に移動する．c）右上腹部斜走査：門脈本幹を指標にその腹側の頭部と背部の釣部を観察するのに適している．d）左上腹部斜走査：脾動静脈を指標にその腹側の膵尾部を観察するのに適している．我々は，走査法の工夫として，1）プローブを回転させる（回外運動），2）船頭の船こぎ様に手首を背屈させる（背屈運動），3）たすきがけの様に，膵尾部を見る時は頭部に，頭部を見る時は尾部に，プローブを移動させ，目的箇所を斜めに観察する．4）必要に応じ，プローブを円弧状に移動させるなど，1）‐3）を組み合わせたり変法を加える．なお，今まで引水法や体位の変換を推賞しているテキストもあったが，被検者にかかる負担が大きく，その割に効果がなかったのであまりお薦め出来ない．

Splenic inflammatory pseudotumor is a rare pathology, and the literature stresses the difficulty of preoperative diagnosis. There are no previous reports of contrast-enhanced ultrasound findings for this tumor in the literature. Our case appears to be the first to be examined using this technique. In our case, contrast-enhanced ultrasound showed the mass to be homogeneously and less enhanced than the surrounding parenchyma in all phases, and it included fine enhanced spots. We also briefly review the literature.

We present two cases of subcutaneous hematoma in which color Doppler US revealed colored areas under probe compression, and Doppler waveforms obtained from these areas changed rapidly (from a constant flow to a pulsatile flow, and from a high-velocity flow to a slow-velocity flow) according to the degree of probe compression. In our cases, a sufficient number of blood cells within the lesion moving under probe compression was thought to give rise to Doppler signals and changes in Doppler waveforms.

The laparoscopic appearance of the liver surface in patients with primary sclerosing cholangitis (PSC) has not been fully delineated. We examined 5 patients with PSC and reviewed 35 previously reported cases. Intense white markings in a mesh-like pattern were characteristic of PSC. The findings varied depending on the histologic stage and affected site. Red patches which have also been seen in primary biliary cirrhosis (PBC), green patches indicating cholestasis, and dilatation of the terminal bile ducts were also observed. The red patches were wider than those in PBC. The white markings were less well defined in the red patches than in other areas. The severity of the fibrosis and histologic damage was judged to be mild at the red sites. The green patches were caused by localized cholestasis. This indicated that PSC unevenly affects the liver. Severe obstruction may be present between the interlobular bile ducts and the septal bile ducts in anicteric stages. (Dig Endosc 1999; 10: 37–41)

There is a marked paucity of reports on contrast-enhanced ultrasonography (US) for focal splenic disease in the literature, and there are no previously reported contrast-enhanced US findings for splenic granuloma. We report the case of a 77-year-old cirrhotic woman with isolated splenic granulomas. We detail the diagnostic difficulty encountered in this case and briefly review the literature.

The efficacy of Interferon (IFN) therapy against hepatitis C is greatly affected by viral factors such as the level of viremia and the HCV genotype. The prognosis of those with high serum HCV-RNA levels in genotype 1b is poor. In the present report, we carried out a randomized controlled study of two IFN doses for patients with genotype 1b chronic hepatitis C whose serum HCV-RNA levels were at least 10 6 copies/ml as determined by multicyclic polymerase chain reaction (PCR) assay. These patients were randomly divided into two groups. Group A received 6 million units (MIU) of IFN 6 days per week for 8 weeks, followed by the same dose 3 days per week for 16 weeks (total IFN dose: 576 MIU). Group B received 6 MIU of IFN 6 days per week for 2 weeks, followed by the same dose 3 days per week for 22 weeks (total IFN dose: 480 MIU). The number of complete responders was four of 24 (16.6%) in group A and three of 20 (15.0%) in group B. There was no significant difference between the groups. On the basis of these findings, it appears that there is no advantage in lengthening the initial period of consecutive IFN administration to 8 weeks or in increasing the total dose by 100 MIU for those with genotype 1b hepatitis C and high virus levels.

Objective: We undertook this study to investigate the appearance of the diaphragmatic echo behind liver tumors and to analyze the possible mechanism of this artifact by using a microcomputer simulation model. Subjects and methods: (1) Sonograms of 76 liver tumors in the right intercostal scanning plane were analyzed. These 76 tumors consisted of 22 hepatocellular carcinomas (HCC), 23 liver metastasis and 31 hemangiomas. The appearances of the post-tumoral diaphragmatic echo were evaluated with respect to the remaining diaphragmatic echo. (2) We evaluated how the sound refraction through the liver tumor affects the displayed diaphragmatic echo, by using microcomputer simulation model. Results: (1) A clockwise rotation of the diaphragmatic echo was frequently seen in the metastasis group in comparison with the HCC or hemangioma groups (P

Gonadotropin-releasing hormone (GnRH) is a neuroendocrine peptide that plays a central role in the vertebrate hypothalamo-pituitary axis. The roles of GnRH in the control of vertebrate reproductive functions have been established, while its non-reproductive function has been suggested but less well understood. Here we show that the tunicate Ciona intestinalis has in its non-reproductive larval stage a prominent GnRH system spanning the entire length of the nervous system. Tunicate GnRH receptors are phylogenetically closest to vertebrate GnRH receptors, yet functional analysis of the receptors revealed that these simple chordates have evolved a unique GnRH system with multiple ligands and receptor heterodimerization enabling complex regulation. One of the gnrh genes is conspicuously expressed in the motor ganglion and nerve cord, which are homologous structures to the hindbrain and spinal cord of vertebrates. Correspondingly, GnRH receptor genes were found to be expressed in the tail muscle and notochord of embryos, both of which are phylotypic axial structures along the nerve cord. Our findings suggest a novel non-reproductive role of GnRH in tunicates. Furthermore, we present evidence that GnRH-producing cells are present in the hindbrain and spinal cord of the medaka, Oryzias latipes, thereby suggesting the deep evolutionary origin of a non-reproductive GnRH system in chordates.

Gastroepiploic artery aneurysm (GEAA) is very rare.1 Furthermore, most GEAA cases are diagnosed after their rupture. We report a case of asymptomatic GEAA. The patient was a 61-year-old man. Sonography (US) revealed a 2-cm anechoic mass in the epigastrium near the anterior abdominal wall. Color Doppler US and contrast-enhanced US showed arterial flow within the mass leading to the diagnosisof visceral artery aneurysm. CT and angiography confirmed the diagnosis of right GEAA, and the aneurysm was treated successfully with embolization. Follow-up US 6 months later confirmed the absence of blood flow within the lesion. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound, 2010

Hepatic hemangiomas are usually asymptomatic and very rarely produce abdominal symptoms. We report a painful 10 × 9 cm hemangioma situated at the hepatic surface of segment 6. The lesion showed a heterogeneous internal structure, composed irregularly of hyperechoic and hypoechoic areas, and it also showed weak posterior echo enhancement. Contrast-enhanced US showed the so-called fill-in pattern, leading to the diagnosis of hepatic hemangioma. The patient’s abdomen showed no other abnormal findings, which stressed the relationship between the hemangioma and the patient’s symptoms. When the diagnosis of hepatic hemangioma is conclusive, surgical therapy is indicated only in patients with severe symptoms. Our patient was considered to be a candidate for enucleation of the lesion. Histopathologically, the lesion included no areas of hemorrhage or necrosis, and the patient’s abdominal pain was likely due to distension of the liver capsule. After surgery, the patient was completely free of symptoms, and enucleation was considered to be appropriate.

Liver abscess is a rare complication of Crohn's disease and in most of the reported cases, the diagnosis of Crohn's disease preceded that of liver abscess. We report herein a case in which a liver abscess was the initial clinical manifestation of Crohn's disease in a 36 year old man who presented with high fever and weakness. The diagnosis of liver abscess was established by abdominal ultrasonography, computed tomography and an arterial blood culture. The abscess was resolved with antibiotic therapy alone and during the drug therapy, a barium enema examination was performed which revealed a stricture at the transverse colon. Resection of the transverse colon was performed and macroscopic and microscopic examination of the resected specimen established the diagnosis of Crohn's disease. The liver abscess was thus speculated to be secondary to the inflamed bowel. Although rare, Crohn's disease should be included in the differential diagnosis of diseases causing liver abscess.

Portal gas is relatively rare, and its relationship to ischemic bowel diseases has been emphasized. We report the case of a 70-year-old woman with acute obstructive cholangitis in whom portal gas was detected by ultrasonography (US) but not by computed tomography (CT). The former showed multiple echo spots moving in the portal vein. Doppler signals confirmed them to be bidirectional and spiky, which immediately led to the diagnosis of portal gas. Immediate appropriate antibiotic treatment and biliary drainage yielded the disappearance of the portal gas. We stress the usefulness of US and Doppler US for detecting and diagnosing portal gas. Our observation suggests that when portal gas is detected by US, the possibility of cholangitis should be included in the differential diagnosis.

Despite the semi-routine use of color Doppler sonography for evaluating portal circulation abnormalities, there is a relative paucity of information on portal-systemic (P-S) shunt through the right renal vein (P-SR shunt). We report such a case. The patient was a 60-year-old woman with hepatocellular carcinoma on liver cirrhosis. Serial sonography showed an aggravation in findings; an increase in the size of the tumor was followed by formation of a portal tumor thrombus, and then occurrence of a P-SR shunt. We present this case, with a comparison between the patient's clinical course and the color Doppler results. To our knowledge, this is the first report to make such a comparison in a P-SR shunt case. We also briefly review the literature.

We present a rare case of isolated liver metastasis from renal cell carcinoma 12 years after complete resection of the primary site. Such abnormal behavior of renal cell carcinoma has been reported elsewhere in the literature; thus, careful long-term surveillance should be performed in patients with a past history of renal cell carcinoma, even after radical resection of the primary site. We present also contrast-enhanced sonographic findings for this case.

Sixty-one chronic hepatitis C patients were randomly assigned to receive either 6x106 or 9x106 U of recombinant interferon-alpha-2a (IFNα-2a) six days a week for the first two weeks of treatment, followed in both cases by 6x106 U three days a week for the next 22 weeks. In the low dose group, 11 patients showed a complete response maintained for at least six months, 12 responded but then relapsed and nine did not respond; the corresponding figures in the high dose group were 10, 15 and five patients, respectively. The differences between groups are not statistically significant. Thus, this study provides no evidence of therapeutic benefit from increasing the initial dose of IFNα-2a. In both treatment groups, complete responders had significantly lower pretreatment viral titres than nonresponders and were significantly more likely to be infected by type 2a versus type 1b virus.

PC12 cells died by apoptosis at relatively low concentrations of H2O2, of which cytotoxicity was effectively suppressed by nerve growth factor (NGF), forskolin, and dbt-cAMP. Treatment with NGF or forskolin for 24 h increased the level of cellular antioxidant glutathione (GSH) by 1.6-2.0-fold. However, both NGF and forskolin protected cells against H2O2-stress even when cellular GSH was depleted by treatment with L-buthionine-(S,R)-sulfoximine (BSO). The GSH-independent protection effects of NGF and forskolin did not require new protein or RNA synthesis. Exogenous expression of an oncogenic ras suppressed apoptosis caused by H2O2 indicating that Ras protein also plays a role in suppressing apoptosis caused by oxidative radical stress.

The distribution of IgA1- and IgA2-containing cells was studied in 27 normal specimens taken from 3 parts of the intestine: the upper jejunum (8), the terminal ileum (5), and the large bowel (14). IgA1- and IgA2-containing cells were identified by an immunoperoxidase staining using mouse anti-IgA1 or IgA2 monoclonal antibody. The sum of IgA1-containing cells (IgA1+) and IgA2-containing cells (IgA2+) was greatest in the large bowel and least in the terminal ileum. IgA1+ were most frequent in the jejunum and least in the terminal ileum while IgA2+ were most frequent in the large bowel and least in the jejunum (p less than 0.005). The ratio of IgA1+/IgA2+ was 1.63 +/- 0.41 in the jejunum which was significantly higher than 0.65 +/- 0.46 in the terminal ileum (p less than 0.05) and 0.63 +/- 0.2 in the large bowel (p less than 0.001). These results lead to the new recognition that there is a shift in preponderance of IgA subclasses in the intestine, namely IgA1+ cells predominate in the jejunum and IgA2+ cells predominate in the intestine distal to the terminal ileum.

原発性硬化性胆管炎の経過中に潰瘍性大腸炎が明らかになった症例を報告した.症例は35歳,女性,28歳時肝機能異常を指摘されたが診断がつかず経過観察していたところ,33歳時掻痒感,黄疸が出現した.トランスアミナーゼの軽度上昇と,胆道系酵素の高度上昇があり,ERCPで三管合流部より上流の硬化像,肝内胆管の狭窄,拡張等の所見が見られ,肝生検ではperiductal fibrosisが見られた.胆石はなく,手術歴もないことから原発性硬化性胆管炎と診断した.さらに35歳時1日4～5回の下痢,粘血便,食欲不振が出現した.注腸検査でハウストラの消失があり,全体的に淡いバリウム斑がみられ,下掘れ型の潰瘍もみられた.Colonfibers-copeでは直腸よりびまん性にびらんがみられ,所々に不整形の潰瘍がみられた.以上から潰瘍性大腸炎を伴う原発性硬化性胆管炎と診断した.自験例を含め,本邦報告例9例について若干文献的に考察した.

The effects of muscarinic stimulation on cyclic AMP accumulation and on basal and thyrotropin-releasing hormone (TRH)-induced phosphoinositide turnover have been studied in rat pituitary GH 3 tumour cells. Carbachol produced a dose-dependent atropine-sensitive inhibition of basal cyclic AMP accumulation. It had no effect on basal or TRH-stimulated production of inositol phosphates. The majority of the muscarinic receptors had a low affinity ( K i , 0.22 μ M) for pirenzepine and can be classified as M 2 type, inhibiting adenylate cyclase but having no links with phosphoinositide metabolism.

The polyphosphoinositides (PtdIns4P and PtdIns(4, 5)P 2) have a considerable affinity for divalent cations and many years ago a physiological role in connection with calcium ions was suggested (Hawthorne and Kemp, 1964). In nervous tissue at least, the monoesterase and diesterase enzymes hydrolysing these lipids are much more active than the kinases responsible for their synthesis. The original description of PtdIns4P kinase by Kai et al. (1968) contains the following comment: “It (PtdIns(4, 5)P 2) resembles a transmitter substance in that the capacity for its destruction is very great”.