Reduction of claudin-5 and aquaporin-4 in the rat hippocampal CA-1 and CA-3 regions of a learned helplessness model of depression.

BACKGROUND: Although findings from both animal and clinical research indicate that the blood-brain barrier (BBB) contributes to the pathogenesis of various psychiatric disorders (including depression), the underlying mechanisms are unknown. We investigated the levels of the tight-junction proteins claudin-5 and aquaporin-4 (AQP-4) in astrocytes of learned helplessness (LH) rats (an animal model of depression) and non-LH rats (a model of resilience). METHODS: We administered inescapable mild electric shock to rats and then identified the LH and non-LH rats by a post-shock test. The expressions of claudin-5 and AQP-4 in several brain regions of the LH and non-LH rats were then evaluated by a western blot analysis. RESULTS: The levels of both claudin-5 and AQP-4 in the CA-1 and CA-3 hippocampal areas of the LH group were significantly lower than those of the control group, whereas those of the non-LH rats were not significantly different from those of the control and LH rats. CONCLUSIONS: These results suggest that LH rats but not non-LH rats experienced down-regulations of claudin-5 and AQP-4 in the CA-1 and CA-3. It is possible that a region-specific modulation of claudin-5 and AQP-4 is involved in the mechanisms of vulnerability but not resilience in depression.

[A case of advanced hepatocellular carcinoma wherein readministration was made possible due to successful transcatheter arterial embolization for intratumoral hemorrhage during Lenvatinib administration].

The subject was a man in his late 70s who was seeing a family physician for diabetes and dyslipidemia on an outpatient basis. A routine medical checkup revealed liver dysfunction, prompting an abdominal ultrasound. As a result, a large hepatic tumor was discovered, prompting a thorough examination. The patient was diagnosed with hepatocellular carcinoma and multiple liver metastases, as well as tumor shadows that could indicate pulmonary metastases, after a thorough examination at our hospital. Due to the patient not having viral hepatitis or any drinking history and had formerly been confirmed as having fatty liver, a diagnosis of cirrhosis and hepatocellular carcinoma caused by NASH (nonalcoholic steatohepatitis) was given. A Child-Pugh score of 5 (A) and modified albumin-bilirubin (mALBI) grade 2 were used to maintain liver function. As a result, a 12-mg/day Lenvatinib treatment regimen was initiated. From the 6th day of the start of oral administration, the patient developed right hypochondralgia and loss of appetite. Blood samples showed increased levels of liver enzymes and inflammatory reaction, requiring hospitalization for closer examination. Intratumoral hemorrhage from hepatocellular carcinoma was discovered by dynamic CT scans. The patient's general condition was stable, and an angiogram was performed on the 3rd day of admission. As a result, persistent extravasation was discovered, necessitating transcatheter arterial embolization (TAE) treatment of the lesion for tumor vessel embolization. Thereafter, transient deterioration of the liver function occurred but an immediate improvement was seen. The patient was discharged without a recurrence of hemorrhage. An outpatient follow-up was performed, with blood test results indicating that liver function was maintained with a Child-Pugh score of 6 (A), and a dynamic CT showing that intratumoral hemorrhage was under control, allowing for readministration. Readministration of Lenvatinib was started at 4mg/day, one level lower, because the patient's body weight had dropped below 60kg. There are few reports on Lenvatinib-induced intratumoral hemorrhage, and this is a unique case worthy of reporting, with previous literary references, in which the entire process from intratumoral hemorrhage to readministration of Lenvatinib after embolization treatment has been documented.

Outcomes of esophagectomy for patients with esophageal squamous cell carcinoma accompanied by recurrent laryngeal nerve palsy at diagnosis.

BACKGROUND: Hoarseness is one of the classical symptoms in patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC), and it results from recurrent laryngeal nerve palsy, which is caused by nodal metastasis along the recurrent laryngeal nerve or by main tumors. We reviewed the short-term and long-term results of esophagectomy for patients with locally advanced ESCC and hoarseness at diagnosis. PATIENTS: Patients who initially presented with hoarseness from recurrent laryngeal nerve palsy between 2009 and 2018 and underwent esophagectomy for thoracic ESCC were eligible for this study. Pharyngolaryngectomy or cervical ESCC were exclusionary. RESULTS: A total of 15 patients were eligible, and 14 underwent resection of the recurrent laryngeal nerves. The remaining patient had nerve-sparing surgery. Nine patients (60%) had post-operative complications ≥ Clavien-Dindo class II and, pulmonary complications were most common. Two patients (13%) died in the hospital. The 5-year overall survival rate for all patients was 16%. Age (≤ 65 years), cT1/T2 tumor, and remarkably good response to neoadjuvant treatment were likely related to longer survival; however, these relationships were not statistically significant. CONCLUSIONS: Esophagectomy for ESCC patients who are diagnosed with recurrent laryngeal nerve paralysis at initial presentation could be a treatment option if the patient is relatively young, has a cT1/T2 tumor, or shows a remarkably good response to neoadjuvant treatment. However, clinicians should be aware of the possibility of postoperative pulmonary complications, which were frequently observed with the procedure.

Upregulation of heat-shock protein HSP-70 and glutamate transporter-1/glutamine synthetase in the striatum and hippocampus in haloperidol-induced dopamine-supersensitivity-state rats.

BACKGROUND: The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS. METHODS: Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions. RESULTS: The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats. CONCLUSIONS: These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted.

Effects of repeated electroconvulsive shocks on dopamine supersensitivity psychosis model rats.

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.

Astroglial glutamate transporter 1 and glutamine synthetase of the nucleus accumbens are involved in the antidepressant-like effects of allopregnanolone in learned helplessness rats.

Clinical studies have demonstrated that allopregnanolone (3α5α-tetrahydroprogesterone, ALLO) has antidepressant-like effects on patients with depression. Previous studies have shown alteration of the astroglial glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) in depression, and ALLO is known to modulate glutamate release. The present study aimed to investigate whether astroglial GLT-1 and GS are indeed involved in the antidepressant-like effects of ALLO in learned helplessness (LH) rats, a validated animal model of depression. The results of this study showed that bilateral microinjection of ALLO into the lateral ventricles could normalize the levels of GLT-1 and GS in the nucleus accumbens (NAc) and of GS in the hippocampal CA1 region of LH rats. These results suggest a certain connection between the antidepressant-like effects of ALLO and the astroglial GLT-1/GS system of the NAc in LH rats.

The alterations of glutamate transporter 1 and glutamine synthetase in the rat brain of a learned helplessness model of depression.

BACKGROUND: Although glutamate transmission via astrocytes has been proposed to contribute to the pathophysiology of depression, the precise mechanisms are unknown. Herein, we investigated the levels of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) of astrocytes in learned helplessness (LH) rats (an animal model of depression) and non-LH rats (an animal model of resilience). METHODS: We administered inescapable mild electric shock to rats and then discriminated the LH and non-LH rats by a post-shock test. Almost 55% of the rats acquired LH. We then measured the expressions of GLT-1 and GS in several brain regions of LH and non-LH rats by Western blot analysis. RESULTS: The levels of GLT-1 and GS in the CA-1, CA-3, dentate gyrus (DG), medial prefrontal cortex (mPF), and nucleus accumbens (NAc) of the LH group were significantly higher than those of the control group. The GS levels in the amygdala of the LH rats were significantly decreased compared to the controls. There were significant differences in GLT-1 and GS levels between the non-LH and LH rats in the CA-1 and CA-3. CONCLUSIONS: These results suggest that the LH rats experienced up-regulations of GLT-1 and GS in the CA-1, CA-3, DG, mPF, and NAc and a down-regulation of GS in the amygdala. It is possible that the effects of the GLT-1 and GS levels on astrocytes in the CA-1 and CA-3 are critical for the differentiation of resilience from vulnerability.

rCBF and cognitive impairment changes assessed by SPECT and ADAS-cog in late-onset Alzheimer's disease after 18 months of treatment with the cholinesterase inhibitors donepezil or galantamine.

Late-onset Alzheimer's disease (AD) differs substantially from early-onset AD. In this cross sectional study we investigated brain perfusion changes after 18 months of treatment with cholinesterase inhibitors (ChEIs) donepezil or galantamine. Twenty-five drug-naïve late-onset AD patients were recruited from outpatient clinics. We examined brain perfusion using single photon emission computed tomography (SPECT) and used three-dimensional stereotactic surface projection (3D-SSP) and the stereotactic extraction estimation method (SEE) level 3 to analyze classified gyrus level segments. We assessed cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) grouped into three subgroup domains, language, memory, and praxis. In the follow-up data, some regions were further hypoperfused, reflecting worsening of the disease, while other regions showed alleviated hypoperfusion, potentially related to the ChEIs treatment. Regional cerebral blood flow (rCBF) decreased in the parietal cortex and increased in the frontal and the limbic cortices. Increased hypoperfusion significantly correlated with ADAS-cog scores changes were seen in the superior parietal lobule, inferior parietal lobule, angular gyrus, and supramarginal gyrus of the parietal cortex. Alleviated hypoperfusion significantly related to recovery of ADAS-cog scores were seen in the rectal and paracentral lobule of the frontal cortex, and the anterior cingulate of the limbic cortex. These regions showed significant relationships with total ADAS-cog and language, memory and praxis subscales scores. The current longitudinal study indicates prominent rCBF changes and their relationships with changes in ADAS-cog scores in late-onset AD patients.

Wnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells in mice.

UNLABELLED: The molecular mechanisms regulating differentiation of fetal hepatic stem/progenitor cells, called hepatoblasts, which play pivotal roles in liver development, remain obscure. Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. Although a ß-catenin-independent noncanonical Wnt pathway is essential for cell adhesion and polarity, the physiological functions of noncanonical Wnt pathways in liver development are unknown. Here we describe a functional role for Wnt5a, a noncanonical Wnt ligand, in the differentiation of mouse hepatoblasts. Wnt5a was expressed in mesenchymal cells and other cells of wild-type (WT) midgestational fetal liver. We analyzed fetal liver phenotypes in Wnt5a-deficient mice using a combination of histological and molecular techniques. Expression levels of Sox9 and the number of hepatocyte nuclear factor (HNF)1ß(+) HNF4α(-) biliary precursor cells were significantly higher in Wnt5a-deficient liver relative to WT liver. In Wnt5a-deficient fetal liver, in vivo formation of primitive bile ductal structures was significantly enhanced relative to WT littermates. We also investigated the function of Wnt5a protein and downstream signaling molecules using a three-dimensional culture system that included primary hepatoblasts or a hepatic progenitor cell line. In vitro differentiation assays showed that Wnt5a retarded the formation of bile duct-like structures in hepatoblasts, leading instead to hepatic maturation of such cells. Whereas Wnt5a signaling increased steady-state levels of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in fetal liver, inhibition of CaMKII activity resulted in the formation of significantly more and larger-sized bile duct-like structures in vitro compared with those in vehicle-supplemented controls. CONCLUSION: Wnt5a-mediated signaling in fetal hepatic stem/progenitor cells suppresses biliary differentiation. These findings also suggest that activation of CaMKII by Wnt5a signaling suppresses biliary differentiation. (HEPATOLOGY 2013;).

[A case of recurrent breast cancer responding to vinorelbine/trastuzumab combination therapy].

A 60-year-old woman with Stage II, ER-positive, PgR-positive, HER2 (2+) cancer in the right breast underwent right mastectomy with right axillary dissection after chemotherapy with EC followed by docetaxel (DOC) alone. Exemestane was used for postoperative adjuvant treatment. She underwent a right chest wall tumor resection for local recurrence. Hormone therapy was continued with toremifene in place of exemestane. In December 2007, two years after the second surgery, CEA was elevated and PET showed a local recurrence in the right chest wall and metastases to the right axillary nodes and liver. The tumor was ER-positive, PgR-negative and HER2 (3+) at recurrence, and vinorelbine/trastuzumab combination was initiated as first-line chemotherapy for the recurrent lesion and liver metastasis. All lesions in the right chest wall, right axillary nodes and liver disappeared from PET and CT images after five courses of the regimen, resulting in clinical CR. Vinorelbine combined with trastuzumab appears to be a useful therapy for HER2-positive recurrent breast cancer.