Ionotropic and metabotropic GABA and glutamate receptors in primate basal ganglia

The functions of glutamate and GABA in the CNS are mediated by ionotropic and metabotropic, G protein-coupled, receptors. Both receptor families are widely expressed in basal ganglia structures in primates and nonprimates. The recent development of highly specific antibodies and/or cDNA probes allowed the better characterization of the cellular localization of various GABA and glutamate receptor subtypes in the primate basal ganglia. Furthermore, the use of high resolution immunogold techniques at the electron microscopic level led to major breakthroughs in our understanding of the subsynaptic and subcellular localization of these receptors in primates. In this review, we will provide a detailed account of the current knowledge of the localization of these receptors in the basal ganglia of humans and monkeys.     

Antihypertensive therapy in patients with stroke

Most patients with acute ischemic stroke do not need antihypertensive therapy, because the rapid lowering of blood pressure (BP) may reduce cerebral blood flow due to impaired cerebral autoregulation. In patients with severe hypertension, or associated with other complications (hemorrhagic transformation, myocardial infarction, renal failure or dissection of the aorta), antihypertensive therapy should be done cautiously. In chronic phase, the optimal BP level for the prevention of stroke recurrence remains unclear. The presence of the J-curve phenomenon is still controversial. The several large scale trials are now in progress to determine the optimal BP level for the secondary prevention in stroke patients.     

A case of adenoid cystic carcinoma (acc) of the Breast and review of the utility of preoperative imaging diagnose

A case of adenoid cystic carcinoma (ACC) of the breast in a 66-year-old woman is reported herein. ACC accounts for about 0.1% of all breast cancers. Our patient presented with a small, elastic and hard mass, measuring 2.0x2.0 cm, between both outer quadrants of the right breast. Although physical examination, ultrasonography and magnetic resonance (MR) mammography suggested a benign tumor, aspiration biopsy cytology (ABC) was performed twice, and the second ABC specimen was evaluated as suspicious for breast carcinoma. Breast conserving surgery with a level II lymph node dissection was subsequently performed. There was no lymph node metastases and estrogen receptor (ER) status was negative. Light microscopy revealed various growth patterns, with the cells showing biphasic cellularity. According to immunohistochemical analyses, CEA, actin and vimentin were positive, S-100 protein was negative, and the cytokeratin reaction was partially positive. Therefore, ACC of the breast was diagnosed. Although ACC of the breast is a rare neoplasm, it should be considered in the differential diagnosis even if various diagnostic imaging studies suggest a benign tumor of the breast. Awareness of this tumor will help prevent misdiagnosis.     

REVIEW ARTICLE: Mechanism of Prolonged Sperm Storage and Sperm Survivability in Hen Oviduct: A Review

A unique property of the avian oviduct is to store sperm for a prolonged period. The sperm storage tubules (SST) are located in the utero‐vaginal junction of the oviduct, where sperm can be stored and survived for a few weeks after insemination or natural mating. The immune system in the oviduct is essential to prevent tissue infection by various microorganisms, and it may also affect the fate and survivability of sperm in the oviduct. Anti‐sperm immunoresponses including infiltration of leukocytes may be induced in the vagina of the oviduct. Sperm that will participate in fertilization may be selected by these immunoresponses. However, sperm stored in the SST may be protected from the immunoresponse by SST structures and transforming growth factor β, whose expression is increased during sperm storage in the SST. In this review, the mechanism of sperm survivability with reference to the regulation of anti‐sperm immunoresponses in hen oviduct is emphasized.     

Factors related to impairment of activities of daily living.

OBJECTIVE: We examined the factors related to the impairment of activities of daily living (ADL). METHODS: ADL was evaluated by using ADL-20, which consists of 20 items from 4 major categories of activities; mobility, self-care, instrumental, and communication. The patients' gender, birth date, clinical diagnosis, past history, life styles, physical findings, laboratory data, and details of therapy were also recorded. Patients A total of 1,163 outpatients aged 50 years or older were included. Data from 1,093 patients were analyzed. RESULTS: We divided the subjects into two groups; Group I having full marks of ADL-20 (n=582) and group II exhibiting an impairment of ADL (n=511). Multiple logistic analysis revealed that in both sexes age and stroke were common independent factors related to the impairment of ADL. Other factors associated with impairment of ADL were smoking in men and presence of proteinuria in women. The presence of hyperlipidemia was associated with preservation of the ADL in women. CONCLUSION: The results demonstrated significant associations of smoking in men and the presence of proteinuria in women with the impairment of ADL in elderly Japanese outpatients. There appears to be a sex difference in the risk factors of impairment of ADL.     

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.     

Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.

The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2) receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V(1a)/V(2) receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12-4mUkg(-1)min(-1)) dose-dependently produced decreases in the cardiac contractility indicator LV dP/dt(max) and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of conivaptan (0.1mgkg(-1)) rapidly attenuated the AVP (4mUkg(-1)min(-1))-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of conivaptan in treating congestive heart failure.     

Adrenal gland lymphoma accompanied by renal cell carcinoma]

A 76-year-old man was admitted with right hypochondralgia. Computed tomography revealed tumors measuring 90 mm and 20 mm in the right adrenal gland and kidney, respectively. Under a diagnosis of renal and adrenal cancer, the patient underwent nephro-adrenectomy, which revealed renal cell carcinoma in the kidney and non-Hodgkin's B-cell lymphoma of the diffuse large cell type in the adrenal grand. The patient has been disease-free for ten months after the operation. To our knowledge, this is the first report of coexisting renal cell carcinoma and adrenal lymphoma. The relationship between these two disorders in our patient is discussed.     

Allodynia and hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficacy of analgesics

The complete Freund's adjuvant (CFA)-induced arthritic rat model has extensively served as a laboratory model in the study of arthritic pain. However, the time courses of allodynia and hyperalgesia and the efficacies of different analgesics have not fully been analyzed in this model. Mechanical allodynia, thermal and joint hyperalgesia, and other disease development parameters (body weight, mobility, paw volume, and joint stiffness) were measured on postinoculation days (PIDs) 0 to 28 in rats. Acute analgesic efficacies of drugs were evaluated on PID 9 when degrees of allodynia, hyperalgesia, and joint stiffness in the ipsilateral paw reached almost the maximum, although those in the contralateral paw changed only slightly. In the ipsilateral paw, thermal hyperalgesia reached the maximum on PID 1, whereas mechanical allodynia and joint hyperalgesia progressively developed during the first 7 or 8 days, being tuned in to arthritis development. In the contralateral paw, thermal hyperalgesia never occurred, whereas mechanical allodynia and joint hyperalgesia developed after PID 11. Morphine and tramadol had full efficacies for all the pain parameters tested at sedation-inducing doses. Indomethacin and diclofenac significantly but partially improved thermal and joint hyperalgesia. Amitriptyline significantly reduced thermal and joint hyperalgesia only at sedation-inducing dose. Acetaminophen, carbamazepine, and gabapentin had, at the most, very small efficacies. In conclusion, the present study provided integrated information about the time course of pain and other disease development parameters in the CFA-induced arthritic rats, and clarified acute efficacies of different categories of analgesics for the allodynia and hyperalgesia.