Decreased Levels of 2-Amino-3-methylimidazo[4,5-f]quinoline-DNA Adducts in Rats Treated with β-Carotene, α-Tocopherol and Freeze-dried Aloe

To assess mechanisms of chemoprevention of hepatocarcinogenesis by trans -β-carotene (β-C), DL-α-tocopherol (α-T), and freeze-dried whole leaves of Kidachi aloe (Aloe), formation of 2-amino-3-methylimidazo[4,5- f ]quinoline (IQ)-DNA adducts was measured by ³²P-post-labeling analysis, and CYP1A1 and CYP1A2 protein levels were analyzed by ELISA. Group 1 rats were fed diet containing 0.02%β-C, 1.5%α-T or 30% Aloe over an 8-day period, while group 2 was given basal diet alone. On day 7, all animals were subjected to two-thirds partial hepatectomy (PH). Twelve hours after PH, they received a single dose of the carcinogenic food pyrolysate IQ (100 mg/kg) intragastrically, to initiate hepatocarcinogenesis. Rats were killed 6, 12, 24 and 48 h after IQ administration. The levels of adducts, expressed as relative adduct labeling values in rats treated with β-C, α-T and Aloe, were decreased as compared with the control group at hour 24 (36 h after PH), with a significant difference in the case of the β-C group (46.4% of the control value). Similarly, all showed a tendency for decrease at hour 48. Furthermore, the levels of CYP1A2, known to be responsible for activation of IQ, showed a significant reduction at hour 24. It is concluded that β-C, and possibly also α-T and Aloe, have the potential to reduce IQ-DNA adduct formation, presumably as a result of decreased formation of active metabolites. The results may explain, at least in part, the previously observed inhibitory effects of these compounds on induction of preneoplastic hepatocellular lesions.     

Immunological Detection and Quantitation of DNA Adducts Formed by 4-Aminoazobenzene Species in vivo

Antibodies to 3-methoxy-4-aminoazobenzene (3-MeO-AAB) and 2-methoxy-4-aminoazobenzene (2-MeO-AAB) DNA adducts were raised in rabbits against in vitro-adducted DNA samples. The enzyme-linked immunosorbent assay (ELISA) was used to determine the sensitivity and specificity of these antibodies. They proved highly specific for the modified DNA used as the immunogen, but cross-reacted with each other. Moreover, they showed cross reactivity with DNA modified by 4-( o -tolylazo)- o -toluidine, but not by other carcinogens, such as 4-aminobiphenyl or 4-nitroquinoline 1-oxide. The 50% inhibition level of antibody binding in the competitive ELISA was at 10–20 fmol of modified base per assay (equivalent to 1–2 adducts per 10⁶ bases). Immunohistochemical staining indicated that these antibodies bind specifically to nuclear components of the liver in rats given either 3-MeO-AAB or 2-MeO-AAB at the dose of 50 mg/kg body weight.     

LIPOSARCOMA

Analysis of 365 cases of malignant soft tissue tumors revealed 83 cases of liposarcoma. The ages of the patients were distributed between 18 and 86 years with a mean average of 54.3 years. Approximately 50% of the cases were located in the lower extremity. Histologically, they consisted of 5 types; well differentiated (17 cases), myxoid (49 cases), round cell (3 cases), pleomorphic (11 cases), and mixed (3 cases). The appearance of lipoblasts of either the signet-ring type or mulberry (multivacuolated) type with displaced nuclei was the common characteristic feature for all types. Electron microscopically, lipid droplets were found inside of endoplasmic reticulum in Hpoblasts, and abundant glycogen granules were seen in the cells containing only few lipid droplets. The lipoblasts were usually located close to the vascular wall fn the interetitium, and findings suggesting an intimate relation between pericytes and lipoblasts were encountered. Although the differential diagnosis of malignant fibrous hietiocytoma and liposarcoma was made possible by the appearance of lipoblasts in the latter, storiform pattern and histiocyte-like cells sometimes appeared in poorly differentiated liposarcoma. This tendency was also found in angiosarcoma. A close follow-up of recurrent cases revealed that there are actually cases of liposarcoma with malignant fibrous histiocytoma-like pattern and angiosarcoma with malignant fibrous histlocytoma-like pattern. It was considered that malignant fibrous histiocytoma-like figures can appear in various poorly differentiated sarcomas.     

A possible mechanism for 2,2',4,4',5,5'-hexachlorobiphenyl-mediated decrease in serum thyroxine level in mice

Serum total thyroxine (T₄) level was markedly decreased, without significant increases in the levels of hepatic T₄-UDP-glucuronosyltransferase (T₄-UGT) and serum thyroid-stimulating hormone, 3 days after treatment with 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB153) (100 mg/kg, ip) in both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 and TCDD-resistant DBA/2 mice. Likewise, in either strain of mice, no CB153-mediated changes in the binding levels of [¹²⁵I]T₄ to serum proteins, such as transthyretin, albumin, and thyroxine binding globulin, were observed, while in CB153-pretreated C57BL/6 mice, but not in CB153-pretreated DBA/2 mice, the levels of biliary [¹²⁵I]T₄ and [¹²⁵I]T₄-glucuronide at 90-120 min after injection of [¹²⁵I]T₄ slightly increased, as compared with those in the corresponding control mice. Concerning tissue distribution of [¹²⁵I]T₄, liver-selective increases in the [¹²⁵I]T₄ accumulation by CB153-pretreatment were observed in both C57BL/6 and DBA/2 mice, and the hepatic levels of [¹²⁵I]T₄ in the C57BL/6 and DBA/2 mice became more than 44% and 34% of the [¹²⁵I]T₄ dosed, respectively. The present findings indicated that the CB153-mediated decreases in the level of serum total T₄ in C57BL/6 and DBA/2 mice occur mainly through an increase in the accumulation of T₄ in the liver.     

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Objective

To review the evidence that agents which preferentially affect serotonin (5-HT) attenuate the ability of N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (NMDA-RA), e.g., phencyclidine (PCP), dizocilpine (MK-801), and ketamine, to stimulate locomotor activity (LA), and to impair novel object recognition (NOR).

Rationale

NMDA-RA-induced increased LA and impairment of NOR are widely used models of the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs (APDs), and the identification of novel treatments. Serotonin (5-HT) plays an important role in attenuating these effects of NMDA-RA.

Results

Selective 5-HT_2A inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT_2A than D₂ antagonists, e.g., clozapine and lurasidone, are more effective than selective D₂ receptor antagonists to attenuate NMDA-RA-induced increased LA. 5-HT_2A inverse agonists alone are not effective to improve NMDA-RA-impaired NOR, but augment the effects of atypical, but not typical APDs, to improve NOR. The 5-HT_1A receptor partial agonist tandospirone alone and the 5-HT_1A agonist effects of atypical APDs may substitute for, or contribute to, the effects of D₂ and 5-HT_2A receptor antagonism to reverse the NMDA-RA impairment in NOR. 5-HT₆ and 5-HT₇ receptor antagonists may also attenuate these NMDA-RA-induced behaviors. 5-HT_2C receptor inverse agonist, but not neutral antagonists, block NOR in na?ve rats and the effects of atypical APDs to restore NOR in PCP-treated rats, suggesting the importance of the constitutive activity of 5-HT_2C receptors in NOR.

Conclusions

Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.     

The changing role of axillary lymph node dissection for breast cancer

Currently, it is standard practice that patients with negative sentinel lymph nodes (SLNs) do not undergo axillary lymph node dissection (ALND), whereas ALND is mandated in those with positive SLNs. However, the Z0011 trial showed that ALND could be safely omitted in selected patients with positive SLNs. This article presents a review and discussion of the current role and practice of ALND in the surgical management of breast cancer. A review of the English-language medical literature was performed using the MEDLINE database and cross-referencing major articles on the subject. It may be concluded that ALND can be avoided not only in patients with negative SLNs but also in those with positive SLNs who undergo breast-conserving therapy with whole-breast irradiation and appropriate systemic therapy. However, the omission of ALND would be indicated only in patients with a low axillary tumor burden. On the other hand, ALND remains a standard method of treating regional disease not only in patients with clinically positive nodes but also in other SLN-positive patients who do not meet the above criteria. Although the role of ALND has been limited to the prevention of axillary recurrence, SLN biopsy with whole-breast irradiation and systemic therapy can replace ALND in patients with a low axillary tumor burden.     

Impact of <Emphasis Type="Italic">ao-dake-humi</Emphasis>, Japanese traditional bamboo foot stimulator,on lower urinary tract symptoms,constipation and hypersensitivity to cold: a single-arm prospective pilot study

Background

Ao-dake-humi is a traditional Japanese bamboo foot stimulator consisting of a half-pipe-shaped step made of bamboo used to stimulate the foot by stepping on it, and is commonly used to promote general health among the elderly in Japan. However, its efficacy has not been reported in the scientific literature. This study was performed to investigate the role of ao-dake-humi focusing on lower urinary tract symptoms (LUTS), constipation, and hypersensitivity to cold (HC).

Methods

Participants with LUTS, constipation, or HC were enrolled in this study. Ao-dake-humi was used twice a day for 28 days. Before and 28 days after starting ao-dake-humi use, international prostate symptom score (IPSS), quality-of-life (QoL) score, and overactive bladder symptom score (OABSS) were measured to evaluate the efficacy of ao-dake-humi on LUTS. To evaluate the objective efficacy of ao-dake-humi on LUTS, a frequency-volume chart (FVC) was plotted in LUTS patients for 3 days. A visual analogue scale (VAS) was used to evaluate the efficacy of ao-dake-humi on constipation (VAS-constipation) and HC (VAS-HC) in the participants with constipation or HC.

Results

A total of 24 participants were enrolled in this study. Twenty-one participants had LUTS, 11 had constipation, and 17 participants had HC. IPSS, especially storage-subscore, QoL score and OABSS, decreased significantly after use of ao-dake-humi. The use of ao-dake-humi increased maximal bladder capacity, resulting in a significant decrease in urinary frequency as determined from the FVC. In accordance with the results of VAS-constipation and VAS-HC, both constipation and HC were significantly relieved after ao-dake-humi use.

Conclusion

The results of this prospective pilot study indicated that ao-dake-humi is safe and has therapeutic efficacy in cases of LUTS, constipation and HC. The possibility of using ao-dake-humi as physical neuromodulation therapy was shown in the management of LUTS, constipation and HC.

Trial registration

UMIN000019333 (UMIN-CTR, Registered October-15-2015) retrospectively registered.