Prediction of major complications after hepatectomy using liver stiffness values determined by magnetic resonance elastography.

BACKGROUND: Liver fibrosis is a risk factor for hepatectomy but cannot be determined accurately before hepatectomy because diagnostic procedures are too invasive. Magnetic resonance elastography (MRE) can determine liver stiffness (LS), a surrogate marker for assessing liver fibrosis, non-invasively. The aim of this study was to investigate whether the LS value determined by MRE is predictive of major complications after hepatectomy. METHODS: This prospective study enrolled consecutive patients who underwent hepatic resection between April 2013 and August 2016. LS values were measured by imaging shear waves by MRE in the liver before hepatectomy. The primary endpoint was major complications, defined as Clavien-Dindo grade IIIa or above. Logistic regression analysis identified independent predictive factors, from which a logistic model to estimate the probability of major complications was constructed. RESULTS: A total of 96 patients were included in the study. Major complications were observed in 15 patients (16 per cent). Multivariable logistic analysis confirmed that higher LS value (P = 0·021) and serum albumin level (P = 0·009) were independent predictive factors for major complications after hepatectomy. Receiver operating characteristic (ROC) analysis showed that the best LS cut-off value was 4·3 kPa for detecting major complications, comparable to liver fibrosis grade F4, with a sensitivity of 80 per cent and specificity of 82 per cent. A logistic model using the LS value and serum albumin level to estimate the probability of major complications was constructed; the area under the ROC curve for predicting major complications was 0·84. CONCLUSION: The LS value determined by MRE in patients undergoing hepatectomy was an independent predictive factor for major complications.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Investigation of the extraordinary null reconstruction phenomenon in polarization volume hologram.

Polarization holography is the superposition of differently polarized beams. Due to its ability to record the polarization states, some extraordinary optical phenomena were found in the polarization holography. For example, the recently reported null-reconstruction phenomenon in polarization volume hologram is odd for the conventional holography which only records the amplitude and phase. In this paper, we perform a thorough investigation of the null reconstruction of polarization hologram recorded by orthogonal circularly polarized waves. To explore the mechanism behind this phenomenon, an interferometry was built to measure the phase difference between the same polarized components within the reconstructed wave. The phase difference of π was secured in our experiment, indicating a destructive interfering effect, which nicely explains the extraordinary null reconstruction observed in the polarization hologram.

Tropomyosin-related receptor kinase B at the invasive front and tumour cell dedifferentiation in gastric cancer.

BACKGROUND: Tropomyosin-related receptor kinase B (TrkB) promotes proliferation and invasion, relating to poor prognosis of various malignancies. We examined the role of TrkB at the invasive front of gastric cancer (GC) and its association with tumour cell dedifferentiation and tumour budding. METHODS: Immunoreactive TrkB was evaluated at the tumour centre and margin using whole-tissue sections of 320 GC patients. Tumour cell dedifferentiation was defined as higher histologic grade at the tumour margin than the surface or tumour centre. Tumour budding was also scored on cytokeratin-stained sections. RESULTS: Sixty-five patients (20%) showed higher TrkB expression at the invasive front (TrkB expression was higher at the tumour margin than tumour centre). It was significantly associated with several aggressive phenotypes in the full cohort (n=320). It showed a prognostic significance in test subgroup (n=98) and was identified as an independent prognostic factor (HR=2.09; 95% CI: 1.26-3.53) by multivariate analysis in validation subgroup (n=222). Twenty-one patients showed tumour cell dedifferentiation. In predominantly differentiated tumour, higher TrkB at the invasive front was significantly associated with tumour budding rather than tumour cell dedifferentiation. CONCLUSIONS: Assessment of immunoreactive TrkB at the invasive front by whole-tissue sections provides prognostic information for GC patients.

Preoperative drainage using a transanal tube enables elective laparoscopic colectomy for obstructive distal colorectal cancer.

BACKGROUND AND STUDY AIMS: Acute colorectal obstruction (ACO) often accompanies colorectal cancer (CRC) and requires urgent treatment, but achieving elective laparoscopy-assisted colectomy (LAC) is difficult in this setting. The aim of the current study was to assess the clinical outcomes of a transanal tube (Dennis colorectal tube [DCT]) for CRC with ACO, focusing in particular on the impact of the DCT on subsequent elective LAC. PATIENTS AND METHODS: Among 1142 patients who underwent surgery for CRC between January 2007 and December 2011, 92 patients with ACO were identified retrospectively. Of these 92 patients, the DCT procedure was performed in 66 patients who fulfilled the indications for DCT, and these patients were included in the study. RESULTS: All 66 patients presented with complete obstruction. Technical and clinical success rates for DCT were 93.9 % and 86.4 %, respectively. Perforation after DCT occurred in 4.5 % and the mortality rate was 1.5 %. The rate of LAC was 48.5 %, and the rate of primary stoma was 13.6 %. For curative stage II/III CRC with ACO, DCT resulted in a primary stoma rate of 13.6 %, a one-stage surgery rate of 90.9 %, a LAC rate of 50.0 %, and a 3-year survival rate of 73.1 %. For stage II/III CRC cases with clinical success by DCT, the one-stage surgery rate was 97.4 % and the LAC rate was 56.4 %. CONCLUSIONS: DCT achieved a high rate of clinical success and enabled safe one-stage surgery and LAC for CRC with ACO. DCT followed by LAC is proposed as a promising non-invasive strategy for CRC with ACO.

Experimental demonstration of multiuser communication in deep water using time reversal.

Multiuser communication is demonstrated using experimental data (450-550 Hz) collected in deep water, south of Japan. The multiple users are spatially distributed either in depth or range while a 114-m long, 20-element vertical array (i.e., base station) is deployed to around the sound channel axis (~1000 m). First, signals received separately from ranges of 150 km and 180 km at various depths are combined asynchronously to generate multiuser communication sequences for subsequent processing, achieving an aggregate data rate of 300 bits/s for up to three users. Adaptive time reversal is employed to separate collided packets at the base station, followed by a single channel decision feedback equalizer. Then it is demonstrated that two users separated by 3 km in range at ~1000 m depth can transmit information simultaneously to the base station at ~500 km range with an aggregate data rate of 200 bits/s.

Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16.

BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.

Long-range time reversal communication in deep water: experimental results.

In December 2011 a long-range acoustic communication experiment was conducted in deep water, west of Izu-Ogasawara Islands, Japan. The experiment involved a stationary source (450-550 Hz) and an 18-element vertical array (102-m aperture), both deployed at around the sound channel axis. Initial analysis of data demonstrates that a data rate of 400 bits/s can be achieved over ~600-km range in deep water using 16 quadrature amplitude modulation and passive time reversal equalization.

ACTIVATION OF HUMAN FIBROBLASTS BY CHRONIC RADIATION RATHER THAN ACUTE RADIATION.

Cancer-associated fibroblast (CAF), an activated type of fibroblast, is a major stromal cell that contributes to tumor initiation and development in the tumor microenvironment (TME). We previously reported that fractionated radiation rather than acute radiation causes progressive damage to mitochondria and increases the generation of reactive oxygen species, playing an important role in the fibroblast activation in normal tissue injury. Activated fibroblasts then become CAF by interacting with tumor cells, promoting tumor growth in vivo. We here examined the chronic radiation effect on fibroblast activation. Acute radiation (<2.5 Gy) did not increase alpha-Smooth muscle actin, a CAF marker expression in healthy human cells, whereas chronic radiation (2.5 Gy) did. It can be concluded that the induction of fibroblast activation changes across acute radiation, fractionated radiation, and chronic radiation depending on the irradiation technique. This study highlights that radiation activates fibroblasts, playing a role in radiation-related tumor development via TME formation.

Characteristic endoscopic findings of gastrointestinal malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma.

Background and study aims: The gastrointestinal (GI) tract is the most common site of extra-nodal involvement for non-Hodgkin's lymphoma (NHL). The features of GI NHLs remain unclear. The aim of this study was to clarify endoscopic characteristics of GI NHLs. Patients and methods: We retrospectively analyzed the morphological characteristics of 63 GI malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma. Lesions were diagnosed between 2005 and 2020. Macroscopic findings were classified into five subtypes: superficial (S); protruding without ulcer (P); protruding with ulcer (PU); fungating (F); and multiple nodules (MN). Results: Thirty-one lesions in the stomach were classified as S type in 3 cases (9.6%), P type in 6 (19%), PU type in 13 (42%), and F type in 9 (29%). In the stomach, the ulcerated phenotype was more frequent for diffuse large B-cell lymphoma (DLBCL) (89.5%) than for other histological types (41.7%; P = 0.01). In the intestine, 23 tumors were classified as S type in 4 cases (17%), P type in 1 (4%), PU type in 6 (26%), F type in 1 (4%), and MN in 11 (48%). Eleven of the 14 cases (78.6%) of intestinal follicular lymphoma lesions showed MN type. In the colon, eight tumors were classified as S type in 2 cases (25%), P type in 2 (25%), PU type in 1 (13%), and F type in 3 (38%). Conclusion: We have clarified the endoscopic features of GI NHL using macroscopic classifications. The ulcerated phenotype was the most frequent endoscopic finding for DLBCL.

E/N-cadherin switch mediates cancer progression via TGF-ß-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a fundamental process governing not only morphogenesis in multicellular organisms, but also cancer progression. During EMT, epithelial cadherin (E-cadherin) is downregulated while neural cadherin (N-cadherin) is upregulated, referred to as 'cadherin switch'. This study aimed to investigate whether cadherin switch promotes cancer progression in cholangiocarcinoma (CC). METHODS: CC cell lines were examined for migration, invasion, and morphological changes with typical EMT-induced model using recombinant TGF-ß1. The changes in E-cadherin and N-cadherin expression were investigated during EMT. We also examined E-cadherin and N-cadherin expression in resected specimens from extrahepatic CC patients (n=38), and the associations with clinicopathological factors and survival rates. RESULTS: TGF-ß1 treatment activated cell migration, invasion, and fibroblastic morphological changes, especially in extrahepatic CC HuCCT-1 cells. These changes occurred with E-cadherin downregulation and N-cadherin upregulation, that is, cadherin switch. Patients with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression (P=0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression (P=0.017). CONCLUSION: Cadherin switch promotes cancer progression via TGF-ß-induced EMT in extrahepatic CC, suggesting a target for elucidating the mechanisms of invasion and metastasis in extrahepatic CC.

Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFIRI) for colorectal cancer.

BACKGROUND: Chemotherapy-induced interstitial lung disease (ILD) in colorectal cancer (CRC) patients is rarely reported, but its clinical features remain to be clarified. PATIENTS AND METHODS: Using a computerized database, we retrospectively identified patients who developed ILD from 734 patients with CRC treated with infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) or infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) from April 2005 to December 2008 at the National Cancer Center Hospital East. RESULTS: Of 734 patients, 11 patients developed ILD (1.5%) and 4 of those patients died (0.54%). Of the 11 patients, 10 showed pulmonary shadows other than lung metastases before chemotherapy. ILD developed during FOLFOX in six patients, at 137 days after completion of FOLFOX in one patient, during oxaliplatin interruption of FOLFOX in one patient and during FOLFIRI in the remaining three patients. FOLFOX had been administered at some point for all ILD patients, with a median of 10 cycles (range 2-17 cycles) and a median dose of administered oxaliplatin of 850 mg/m(2) (range 170-1445 mg/m(2)). CONCLUSIONS: ILD following FOLFOX or FOLFIRI is an uncommon but life-threatening complication. Care must be taken regarding the onset of ILD, not only during but also after chemotherapy for CRC.

Multiplexing capability in polychromatic reconstruction with selective detection method.

Holographic reconstruction with polychromatic light was investigated in terms of the multiplexing capability in a volume holographic memory. The broadband spectrum of the probe beam considerably degrades the angular selectivity and causes a serious deterioration of the multiplexing capability, but this can be overcome if an additional suitable optical component is used in the imaging system. We could selectively detect the signal image alone even though the angular separation between holograms was insufficient to suppress the diffraction from other holograms. We theoretically derived the minimum angular separation for multiplexing and experimentally demonstrated the effectiveness of this selective detection method.

The effectiveness of packed therapy with three drugs in Helicobacter pylori eradication in Japan.

Primary Helicobacter pylori eradication rate using triple therapy (a proton pump inhibitor [PPI] + amoxicillin [AMPC] + clarithromycin [CAM], over 7 days) is showing a declining trend. In this study we report recent eradication rates and have evaluated the usefulness of a pack preparation of three drugs. H. pylori eradication rate was 85.1% (57/67) in 2004 but then fell to 75.2% (79/105) in 2005, 70.1% (68/97) in 2006 and 69.9% (58/83) in 2007. With the introduction of packs (lansoprazole [LPZ] 60 mg, AMPC 1500 mg, CAM 400 mg) the eradication rate recovered to 78.0% (110/141) in 2008. A comparative study in 2008 delineated that the eradication rate in the pack group (88.4%, 38/43) was significantly higher than that of the conventional group (73.5%, 72/98). These results suggest that packs of eradication medicine are useful in increasing eradication success.

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers.

BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT-PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.

p21 provides stage specific DNA damage control to preimplantation embryos.

The early stage embryogenesis of higher eukaryotes lacks some of the damage response pathways such as G1/S checkpoint, G2/M checkpoint and apoptosis. We examined here the damage response of preimplantation stage embryos after fertilization with 6 Gy irradiated sperm. Sperm-irradiated embryos developed normally for the first 2.5 days, but started to exhibit a developmental delay at day 3.5. p21 was activated in the delayed embryos, which carried numerous micronuclei owing to delayed chromosome instability. Apoptosis was observed predominantly in the inner cell mass of the day 4.0 embryos. Sperm-irradiated p21-/- embryos lacked the delay, but chromosome instability and apoptosis were more pronounced than the corresponding p21 wild-type embryos. We conclude from the result that damage responses come in a stage-specific manner during preimplantation stage development; p53-dependent S checkpoint at the zygote stage, p21-mediated cell cycle arrest at the morula/blastocyst stages and apoptosis after the blastocyst stage in the inner cell mass.

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint.

The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53-/- MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis revealed that 1 Gy irradiation suppressed replication fork progression in p53 WT MEFs, but not in p53-/- MEFs. Proliferating cell nuclear antigen (PCNA), clamp loader of DNA polymerase, was phosphorylated in WT MEFs after 1 Gy irradiation and redistributed to form foci in the nuclei. In contrast, PCNA was not phosphorylated and dissociated from chromatin in 1 Gy-irradiated p53-/- MEFs. These results demonstrate that the novel low-dose-specific p53-dependent S-phase DNA damage checkpoint is likely to regulate the replication fork movement through phosphorylation of PCNA.

The basolateral nucleus of the amygdala mediates caloric sugar preference over a non-caloric sweetener in mice.

Neurobiological and genetic mechanisms underlying increased intake of and preference for nutritive sugars over non-nutritive sweeteners are not fully understood. We examined the roles of subnuclei of the amygdala in the shift in preference for a nutritive sugar. Food-deprived mice alternately received caloric sucrose (1.0 M) on odd-numbered training days and a non-caloric artificial sweetener (2.5 mM saccharin) on even-numbered training days. During training, mice with sham lesions of the basolateral (BLA) or central (CeA) nucleus of the amygdala increased their intake of 1.0 M sucrose, but not saccharin. Trained mice with sham lesions showed a significant shift in preference toward less concentrated sucrose (0.075 M) over the saccharin in a two-bottle choice test, although the mice showed an equivalent preference for these sweeteners before training. No increased intake of or preference for sucrose before and after the alternating training was observed in non-food-deprived mice. Excitotoxic lesions centered in the BLA impaired the increase in 1.0M sucrose intake and shift in preference toward 0.075 M sucrose over saccharin. Microlesions with iontophoretic excitotoxin injections into the CeA did not block the training-dependent changes. These results suggest that food-deprived animals selectively shift their preference for a caloric sugar over a non-caloric sweetener through the alternate consumption of caloric and non-caloric sweet substances. The present data also suggest that the BLA, but not CeA, plays a role in the selective shift in sweetener preference.

Contribution of functional groups of 19-nor-progestogens to binding to progesterone and estradiol-17beta receptors in rabbit uterus.

The structural elements of 19-norprogestogens which may be essential for binding to progesterone and estradiol-17beta(E2) receptors were investigated in the rabbit uterine cytosol. The kinetic study showed that 19-nor-progestogens are competitive inhibitors of progesterone-receptor (8S) binding and E2-receptor binding. The affinities of steroids for the progesterone receptor were as follows: norethindrone (Ki of 2.3 X 10(-9)M) greater than 5alpha-dihydronorethindrone greater than norethindrone acetate greater than lynestrenol greater than 17alpha-ethynyl-estra-4-ene-3beta, 17beta-diol greater than ethynodiol diacetate (Ki of 1.3 X 10(-7) M). The affinities of steroids for the E2 receptor were as follows: ethynodiol diacetate (Ki of 1.3 X 10(-7)M) greater than 17alpha-ethynyl-estra-4-ene-3beta, 17beta-diol greater than norethindrone acetate greater than norethindrone greater than 5alpha-dihydronorethindrone greater than lynestrenol (Ki of 8.4 X 10(-7)M). The results indicate that 3-ketone and 17beta-hydroxyl groups, and the plane of ring A/B of 19-norprogestogen are important for binding to the progesterone receptor. The affinities of 19-nor-progestogens for the E2 receptor were very weak. Their affinities for the E2 receptor increased with addition of acetate or hydroxyl groups at the 3beta and 17beta positions, and were decreased by the elimination of a 3 oxygen function or the reduction of ring A.

Salient responsiveness of parabrachial neurons to the conditioned stimulus after the acquisition of taste aversion learning in rats.

The pontine parabrachial nucleus is considered to be one of the most critical regions for the acquisition of conditioned taste aversion which is an associative learning of taste and illness. To further clarify the possible involvement of the parabrachial nucleus in conditioned taste aversion, we recorded neuronal responses to taste stimuli from the parabrachial nucleus of rats under deep urethane anaesthesia. Animals were separated into two groups: the conditioned taste aversion group that had acquired a taste aversion to 0.1 M NaCl (conditioned stimulus) after paired presentations of the taste stimulus with intraperitoneal injection of LiCl (unconditioned stimulus), and the control group that had received only the unconditioned stimulus before experiments. Taste-responsive neurons in the conditioned taste aversion group showed larger responses to NaCl at below 0.1 M, but similar responses to 0.3 M and 0.5 M NaCl when compared with those in the control group. Furthermore, hierarchical cluster analyses revealed a strong similarity among responses to sodium salts in neurons of the conditioned taste aversion group compared with the control group. These results suggest that the aversive conditioning to NaCl modified parabrachial units so that the sodium taste was more salient than other tastes. This modification may reflect a long-term plastic change persisting without support of forebrain structures, and would facilitate the gustatory discrimination of the conditioned stimulus, which is required by conditioned animals.