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Adverse effects of morphine on locomotor function after moderate to severe spinal cord injury (SCI) have been reported; however, the effects after mild SCI without damage of lumbar α-motoneurons have not been investigated. We investigated the effects of lumbar intrathecal morphine on locomotor function after mild thoracic SCI and the involvement of classic opioid receptor activation. A mild thoracic contusive SCI was induced in adult rats at the T9-T10 spine level under sevoflurane anesthesia. We evaluated the effects of single doses of intrathecal morphine and selective μ-, δ-, and κ-opioid receptor agonists, continuous infusion of intrathecal morphine for 72 hours, and administration of physiological saline on locomotor function and muscle tone in the hindlimbs. The numbers of damaged and total α-motoneurons in the lumbar spinal cord were also investigated. Single doses of morphine aggravated residual locomotor function after SCI but did not affect functional recovery. Single doses of morphine and μ- and δ-opioid receptor agonists significantly aggravated residual locomotor function with increases in muscle tone after SCI, and the effects of the drugs were reversed by naloxone. In contrast, continuous infusion of morphine led to persistent decline in locomotor function with increased muscle tone, which was not reversed by naloxone, but did not increase the number of damaged lumbar α-motoneurons. These results indicate that a single dose of morphine at an analgesic dose transiently increases muscle tone of the hindlimbs via activation of spinal μ- and δ- opioid receptors, resulting in further deterioration of locomotor function in the acute phase of mild SCI. Our results also suggest that an increased dose of morphine with prolonged administration leads to persistent decline in locomotor function with increased muscle tone via mechanisms other than direct activation of classical opioid receptors. Morphine should be used cautiously even after mild SCI.

The purpose of our study was to test the efficacy and toxicity of palbociclib therapy for breast cancer treatment. Ten patients diagnosed with breast carcinoma were selected for this retrospective study between 2017 and 2018. After the patients had previously been administered palbociclib, they received either capecitabine or eribulin. As a result, the median PFS of capecitabine and eribulin were 6.4 months(3-10)and 5.8 months(4-7), respectively. Therefore, the treatment administered after palbociclib therapy may be useful for breast cancer patients.

Breast cancer patient(invasive ductal carcinoma, ER[+], PgR[+], HER2[3+], Ki-67: 30%)had neoadjuvant chemotherapy( FEC followed by docetaxel plus trastuzumab). After surgical operation(mastectomy and Ax)was performed and she received trastuzumab plus hormone therapy. After 2 years later, she had liver metastasis that showed IDC, ER(+), PgR (+), HER2(-). In addition, BRCA positive was shown. Therefore, the patient received olaparib tablets(300 mg twice daily). After 2 months later, liver metastasis reduced dramatically.

Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1α in vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Prostaglandin E2(PGE2) is well known as a mediator of inflammatory symptoms such as fever, arthritis, and inflammatory pain. In the present study, we evaluated the analgesic effect of our selective PGE2synthesis inhibitor, compound I, 2-methyl-2-[cis-4-([1-(6-methyl-3-phenylquinolin-2-yl)piperidin-4-yl]carbonyl amino)cyclohexyl] propanoic acid, in rat yeast-induced acute and adjuvant-induced chronic inflammatory pain models. Although this compound suppressed the synthesis of PGE2selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI2) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI2signaling in rat inflammatory pain models using prostacyclin receptor (IP) antagonist, RO3244019. RO3244019 showed no analgesic effect in inflammatory pain models, but concomitant administration of compound I and RO3244019 showed analgesic effects comparable to celecoxib, a specific cyclooxygenase- (COX-) 2 inhibitor. Furthermore, coadministration of PGE2receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2signaling, especially through the EP4 receptor, and PGI2signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.

Preparations and in vitro antifungal activities of triazolopyridines, imidazopyridines, and a pyrazolopyridine were reported. Among those scaffolds, triazolopyridine was found to be the specific inhibitor of the synthesis of beta-1,6-glucan, an essential component of the fungal cell wall, and to show potent antifungal activities against several Candida species.

Metastatic tumors of the stomach are rare, with an incidence of 0.2%-0.7%, and they have been reported to result mainly from primary breast cancers, lung cancers, and melanoma. Further, among such metastatic tumors, the metastasis of renal cell carcinoma (RCC) to the stomach is an extremely rare disease, and it is usually reported in autopsy series. We report a rare case of metastatic gastric tumor derived from right renal carcinoma. Gastric endoscopy confirmed a large, polypoid, friable mass (type 1 tumor, about 7 cm in diameter) in the middle part of the stomach body. The mass was surgically excised and pathological examination showed that the gastric tumor was derived from a metastasis from the right kidney, because it was composed of malignant cells that were identical to those from the removed RCC. In addition, the tumor cells were immunoreactive for CD10, CD15, Ecadherin, early membrane antigen (EMA), and vimentin, but no reactivity was observed for cytokeratins 7 and 20 or c-KIT. Although gastric metastatic tumor derived from renal carcinoma is rare, the precise pre- and postoperative diagnosis may be important; thus, investigation for such metastatic tumors should be performed routinely in the follow up of patients who have been treated for RCC.

The purpose of our study was to test the efficacy and toxicity of hyperthermia for treating breast cancer. Ten patients received treatment (AC, paclitaxel, S-1, and aromatase inhibitor) in combination with hyperthermia. The hyperthermia device was a microwave heating device with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. Two patients had a partial response to treatment with only mild toxicity (grade 1 acute skin toxicity). Therefore, hyperthermia combined with chemotherapy for treating breast cancer seems to be effective and generally tolerable. A larger patient cohort is needed to confirm these results in the future.

The purpose of our study was to test the efficacy and toxicity of hyperthermia in conjunction with chemotherapy for breast cancer. Between 2009 and 2014, 6 patients diagnosed with breast carcinoma were selected for this retrospective study. Patients received standard chemotherapy (AC followed by paclitaxel ) in combination with hyperthermia. The hyperthermia device employed microwave heating with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. Following hyperthermia therapy, 4 patients had a partial response to treatment and the toxicity was mild, consisting of Grade 1 acute skin toxicity. Therefore, hyperthermia combined with chemotherapy for breast cancer seems to be effective and generally tolerable. A larger patient cohort is needed to confirm these results.

We present a patient with metastastic renal cell carcinoma to the ethmoid sinus. A 68-year-old male consulted with complaints of left epistaxis and nasal cavity tumor. His status was post left total nephrectomy for renal cell carcinoma. The histological diagnosis was renal cell carcinoma (clear cell type). We performed skull base surgery for total ethmoid sinus resection. We report on this case and discuss metastasis of renal cell carcinoma to the head and neck region.

In order to investigate structure-activity relationships between antimycobacterial activities and basic substituents at the C-10 position of levofloxacin (LVFX), we synthesized a series of pyridobenzoxazine derivatives by replacement of the N -methylpiperazinyl group of LVFX with various basic substituents. A compound with a 3-aminopyrrolidinyl group had one-half the activity of LVFX against Mycobacterium avium , M. intracellulare , and M. tuberculosis . Mono- and dimethylation of the 3-amino moiety of the pyrrolidinyl group increased the activities against M. avium and M. intracellulare but not those against M. tuberculosis . On the other hand, dialkylation at the C-4 position of the 3-aminopyrrolidinyl group enhanced the activities against M. avium , M. intracellulare , and M. tuberculosis . Thus, introduction of an N -alkyl or a C -alkyl group(s) into the 3-aminopyrrolidinyl group may contribute to an increase in potency against M. avium , M. intracellulare , and/or M. tuberculosis , probably through elevation of the lipophilicity. However, among the compounds synthesized, compound VII, which was a 2,8-diazabicyclo[4.3.0]nonanyl derivative with relatively low lipophilicity, showed the most potent activity against mycobacterial species: the activity was 4- to 32-fold more potent than that of LVFX and two to four times as potent as that of gatifloxacin. These results suggested that an increase in the lipophilicity of LVFX analogues in part contributed to enhancement of antimycobacterial activities but that lipophilicity of the compound was not a critical factor affecting the potency.

For a considerable tissue defect of the orbitofacial region after skull base or head and neck tumor en bloc extirpation, we have developed the "flying buttress" technique using the vascularized hard tissue rather than the multi-stage operative method using bone graft or alloplastic materials. The procedure reconstructs the inferior orbital rim and the zygomatic prominence--flying buttresses bridging transversely in a missing face--with free flap coverage, simultaneously in the primary surgery so that the bony structure is maintained for years and ptosis of a large flap is minimized. We prefer to use the rectus abdominis myocutaneous flap for tissue restoration and two types of vascularized hard tissue: the costal cartilages combined with the flap and the temporalis muscle-pedicled calvarial bone. Representative cases are illustrated and the technique is detailed.

A series of novel LVFX (7) analogues bearing 4, 4-dialkyl-3-aminopyrrolidines at the C-10 position of pyridobenzoxazine was synthesized and their antibacterial activities, pharmacokinetics and acute toxicities in animals were evaluated. Non-alkylated pyrrolidine derivative 26a showed greater activity than LVFX (7) against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa, but 26a possessed high acute toxicity in mice and unfavorable pharmacokinetics in rats. When compared with 26a, 4, 4-dialkylated derivatives 26c, e, g showed more potent activity against gram-positive bacteria along with an improvement of pharmacokinetics and reduction of acute toxicity. Increases in lipophilicity by alkylation on the pyrrolidine ring resulted in a good influence on the above profiles.

A 70-year-old man was found to have an immature teratoma in his paranasal sinuses. A biopsy showed components of all three germ-cell layers: neural, epithelial, and glandular elements. MRI revealed a large irregular tumor invading the anterior cranial base. Intra and extracranial approaches were used for total resection. The bony defect of the anterior cranial base was reconstructed with a pericranial flap and temporal muscle flap. The patient was treated with chemotherapy and radiation following surgery. However several pulmonary metastases and effusion appeared, and he died 8 months after the operation.

Background Gastrointestinal stromal tumors (GISTs) and adenocarcinoma are distinct neoplasms originating from different cell layers. Approximately 20% of patients with GIST develop other cancers. Case presentation We report a case of the coexistence of adenocarcinoma and gastrointestinal stromal tumor (GIST). Gastric endoscopy showed the ulcerated tumor with bleeding along the lesser curvature of the proximal stomach and a submucosal nodule that measured about 3 cm in diameter in the lower part of the stomach body. Their pathological examination showed gastric cancer (poorly differentiated diffuse adenocarcinoma) and GIST (low-risk category). Further, immunohistochemical staining for C-kit and CD34 was positive, while that for SMA and S-100 was negative. Conclusion Although it is not easy to speculate on the coexistence of adenocarcinoma and GIST, pre-and post-operative diagnoses may be essential, and such cancer development is not considered to be unusual.

A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.

Neuronal ceroid lipofuscinoses (NCL) are in a group of autosomal recessive inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material in many cell types. Clinical manifestations of NCL are progressive mental and motor deterioration, seizures, and visual loss. We report anesthetic management for two siblings with NCL. Placement of percutaneous endoscopic gastrostomy tubes were scheduled for both 31-year-old woman and her 29-year-old sister with NCL. Although they were treated with several anticonvulsants, the grand mal and myoclonic seizures persisted. Anesthesia was maintained with propofol, nondepolarizing muscle relaxant, and narcotics. They showed no complications except for mild hypothermia during anesthesia. However, BIS index fluctuated widely during anesthesia in both cases. Their postoperative course was uneventful.

Following a known lead and using various synthetic approaches a series of 1,3-benzoxazole-4-carbonitriles is synthesized and evaluated for antifungal potency.

A series of 1,3-benzoxazole-4-carbonitriles was synthesized and evaluated for its antifungal activity, solubility, and metabolic stability. Among those compounds, 4-cyano-N,N,5-trimethyl-7-[(3S)-3-methyl-3-(methylamino)pyrrolidin-1-yl]-6-phenyl-1,3-benzoxazole-2-carboxamide (16b) exhibited potent in vitro activity against Candida species, higher water solubility, and improved metabolic stability compared to lead compound 1. Compound 16b showed potent in vivo efficacy against mice Candida infection models and good bioavailability in rats.

Combined cranial and facial procedures for resection of malignancies of the paranasal sinuses and nasal cavity have been increasing in recent years.For patients undergoing combined craniofacial procedures for these tumors are reported. In three of these cases, the defect caused by a resection of the skull base was reconstructed with a free rectus abdominis flap.The patients in this series showed no major complications and all have remained free of disease during the short follow-up period.

Several title compounds of type (VI), (VIII), or (IX) are evaluated for their antifungal activities.

Synthesis and in vitro antifungal evaluations of 1,3-benzoxazole-7-carbonitrile 3, 1,3-benzoxazole-4-carbonitrile 4, benzofuran 5, benzoxazine 7, and benzimidazole 8 were reported. Among them, 1,3-benzoxazole-4-carbonitrile was found to be a superior scaffold structure with moderate growth inhibition against Candida species. 1,3-Benzoxazole-4-carbonitrile 6 showed potent activity against Candida species compared to 5-desmethyl compound 4 and triazolopyridine 2. Compound 6 was efficiently prepared from versatile intermediate 24, which possessed six different substituents on the benzene ring. Conversion of benzene 24 into various 1,3-benzoxazole derivatives such as 2-aliphatic 34, 2-amino 35, and lactone 38 was demonstrated.

Based on the HTS hit compound 1a, an inhibitor of beta-1,6-glucan synthesis, we synthesized novel pyridobenzimidazole derivatives and evaluated their antifungal activity. Among the compounds synthesized, we identified the potent compound 15e, which exhibits excellent activity superior to fluconazole against both Candida glabrata and Candida krusei. From the SAR study, we revealed essential moieties for antifungal activity.

A 20-year-old man presented with severe exophthalmos on the left as a result of a traffic accident. X-ray films revealed that foreign bodies, suspected of being parts of the windshield, had extended into the orbital apex. An intracranial lesion, however, could not be excluded. Craniotomy (fronto-zygomatic approach) was performed to remove the orbital foreign bodies, while preserving the optic nerve, and to identify intracranial foreign bodies in a wide surgical field. No dural lacerations or intracranial foreign bodies were observed during surgery. Total removal of the orbital foreign bodies was accomplished via the left fronto-zygomatic approach. Postoperatively, there was marked improvement in the severe exophthalmos, and visual acuity was restored. This type of surgical procedure is a good approach for removing deep orbital foreign bodies and checking for the presence of possible intracranial foreign bodies.

β-1,6-Glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of β-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against Candida glabrata . Interestingly, although it only weakly reduced the growth of Candida albicans in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited β-1,6-glucan synthesis of C. albicans , leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of C. albicans cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of C. albicans without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against C. albicans by inhibiting its invasion process.

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.

An operative technique called the extensive transbasal approach is reported with the operative results of 11 cases. This is an operative mode in which en bloc osteotomy of the orbital roofs and frontal sinus is performed after ordinary bifrontal craniotomy. Through this approach, a far wider operative space than that afforded by conventional operative techniques is possible, and reconstruction of the frontal base can be made securely. We consider this approach of major clinical value.

Th Erythropoietin (EPO), the kidney hormone regulating erythrocyte production, activates the erythropoietin receptor (EPOR), resulting in antiapoptosis. To investigate the clinical significance of EPOR expressed in neuronal cells of the brain, EPO was administered to patients within 8 hours of the onset of stroke symptoms, which ultimately resulted in the reduction of cerebral infarct size and improvement of functional neurologic performance. Rodents treated with EPO in an animal model of myocardial ischemia and infarction recently demonstrated superior myocardial function. The expression of the EPOR was shown for a variety of rodent and rabbit primary and permanent cardiomyocyte cell lines. But, as noted by several investigators, proof of the presence of the EPOR in the adult human heart is missing. To overcome this deficit, we investigated adult human ventricular and atrial tissue for the expression of the EPOR.

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.

Recent clinical studies have demonstrated that As2O3 is an effective drug in the treatment of acute promyelocytic leukemia (APL) by inducing apoptosis and inhibiting the proliferation of leukemia cells both in vitro and in vivo. As a novel anticancer agent for the treatment of solid cancer, As2O3 is promising, but no experimental investigations of its efficacy on glioblastoma have been conducted at concentrations that may be achieved clinically. In addition, the cell proliferation and cell cycle regulating mechanism of As2O3 has not yet to be clarified, especially in solid cancers. We investigated the effect of As2O3 on proliferation and cell cycle regulation with change in cyclins in two human glioblastoma cell lines differing in p53 status (U87MG-wt; T98G-mutated). Sensitivity to As2O3 varied depending on the dose with the IC50 of the U87MG and T98G cells being 1.78 and 3.55 microM, respectively. Analysis by laser scanning cytometry (LSC) indicated that As2O3 inhibited the proliferation of the two cell lines via cell cycle arrest both at the G1 and G2 phases. To address the mechanism of the antiproliferative effect of As2O3, we examined its effect on cell cycle-related proteins by means of LSC, confocal microscopy and Western blot analysis. As2O3 induced an increase in p53 level and a decrease in level of cyclin B1 combined with cell arrest at G2/M in both cell lines. Cell arrest in G1, however, was associated with a decline in cyclin D1 expression only in the wt U87MG cells. As2O3 also induced apoptosis of U87MG cells as evidenced by the presence of cells with fractional DNA content ( cell populations). The present evidence that As2O3 at relatively low concentration effectively inhibited proliferation of U87MG and T98G cells in vitro, suggests that the drug may be considered for in vivo testing on animal models and possibly clinical trials on glioma patients.

A series of 8-methoxyquinolones bearing 3-amino-4-methylpyrrolidines or 3-amino-4-fluoromethylpyrrolidines at the C-7 position was synthesized and their physicochemical and biological properties were evaluated. All of the compounds synthesized showed more potent activity than LVFX (3) against both gram-positive and - negative bacteria. Increases in lipophilicity of these compounds had desirable effects on their potency of single intravenous toxicity and pharmacokinetic profiles in animals. Among the compounds synthesized, 1-fluorocyclopropyl derivatives 17 and 20, and 7-(cis-3-amino-4-fluoromethylpyrrolidinyl) derivative 19 (DC-756h) showed negative responses in the micronucleus test in mice while 1-cyclopropyl-7-(3-aminopyrrolidinyl) derivative 16 showed a positive response. These results suggested that the introduction of a fluorine atom into the 3-aminopyrrolidinyl substituent resulted in favorable influence on genetic toxicity as well as into the N-1 cyclopropyl substituent.

A new approach to malignant tumor in the anterior skull base using a hemifacial dismasking flap is described. A bicoronal incision is extended unilaterally down to the neck, degloving the craniofacial tissue to widely expose the skeleton underneath, allowing easy resection of an extensive tumor without postoperative scarring of the face. This method has been used successfully on five patients.

✓ Lesions in the base of the frontal fossa have conventionally been approached extra- and intradurally through a bilateral frontal craniotomy. However, when the lesion is large or deeply situated, wider bilateral retraction of the frontal lobes is required to obtain a sufficiently large operative field. The authors describe a new operative approach for huge tumors at the frontal skull base, employing an en bloc bilateral osteotomy of the orbital roofs and frontal sinus. This procedure, which is a modification of the transbasal approach described by Derome and Guiot, is termed the “extensive transbasal approach.” The advantages of this technique over conventional operative approaches are described.

A practical route was developed for synthesizing the C-7 substituent of DQ-113 (6, 5-amino-7-[(3S,4R)-4-(1-aminocycloprop-1-yl)-3-fluoropyrrolidin-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methyl-4-oxoquinolin-3-carboxylic acid), a new quinolone antibacterial agent for serious infections caused by Gram-positive pathogens. The key step was the intramolecular Homer-Wadsworth-Emmons reaction. In addition, the yield of the final aromatic nucleophilic substitution reaction was improved.

Six cases of normal perssure hydrocephalus (NPH) were found among 160 surgical cases of intracranial hematoma due to severe head injury, in the past 10 years. Out of the 160 cases, 80 were followed up. The incidence of post-traumatic NPH was 3.7%, or 7.5% in the followed-up cases. After a little improvement following the removal of intracranial hematoma, these cases showed prolonged disturbance of consciousness or a delayed recovery rate and a progressive enlargement of the ventricle without cerebral atrophy on CT scan. Diagnosis of post-traumatic NPH was made by the plateau level of clinical improvement accompanied by absence of intracranial hypertension and a progressive ventricular dilatation shown by an increased bicaudate cerebroventricular index on CT scan. Radioisotope serum albumin cisternography revealed disturbance of cerebrospinal fluid (CSF) circulation in all these cases and was a reliable tool for determining the indication for a shunting operation, which brought a marked improvement in five patients. The authors believe that the shunting operation should be tried on post-traumatic NPH patients who do not show cerebral atrophy. Presence of a subarachnoidal and a contusional hemorrhage on brain surfaces, noted in the operation, suggests the need to pay attention not only to the disturbance of the conventional extracerebral CSF pathway, but to that of the intracerebral pathway as regards the pathogenesis of post-traumatic NPH.

The effect of multidisciplinary therapy is discussed, focusing on the results of the combined use and single use of intracarotid injection of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), fractionated irradiation by 60Co, and subcutaneous injection of OK-432 on brain tumor-bearing rats as well as on 31 human glioma cases. The experiments using brain tumor-bearing rats demonstrated the dose dependency of ACNU, and ACNU combined with 60Co irradiation resulted in an additive promoting effect, compared with the results of single use of each therapy. As for the mechanism of this effect, in addition to cell synchronization, the cell-killing effect of ACNU enforced by the circulatory disturbance due to irradiation was shown by the histological study. Multidisciplinary therapy for clinical cases, on the other hand, demonstrated good results among 60% of glioblastoma patients and 73% of benign astrocytoma patients, resulting in an improved survival rate. In in vivo study, OK-432 showed no cytocidal effect; however, OK-432 was an important agent for clinical use as it was effective in maintaining the general condition, or in reducing side effects induced by the combined use of ACNU and 60Co irradiation.

A synthetic method of 6-hydroxy-1,2-dihydrocyclobuta[a]naphthalene-2-carboxylic acid as well as a new methodology for the synthesis of A,B-ring aromatized steroids from its 6-deoxy derivative are elaborated.

A novel method is described for the introducing the 2, 2-dichloroethyl group at the 2-quinolone ring. The method from 4-substituted 2-quinolone consists of 1) photoaddition of the quinolone to 1, 1-dichloroethylene, 2) base treatment of the cross adduct giving a bicyclobutane, and 3) conversion of the latter to the final product with hydrogen chloride. By applying this reaction to 4-methoxy-2-quinolone, a short-step synthesis of dictamnine is accomplished.

A novel method is described for the introducing the 2, 2-dichloroethyl group at the 2-quinolone ring. The method from 4-substituted 2-quinolone consists of 1) photoaddition of the quinolone to 1, 1-dichloroethylene, 2) base treatment of the cross adduct giving a bicyclobutane, and 3) conversion of the latter to the final product with hydrogen chloride. By applying this reaction to 4-methoxy-2-quinolone, a short-step synthesis of dictamnine is accomplished.

Lesions in the frontal base have been conventionally approached extra- and intradurally through a bilateral frontal craniotomy. However, when the lesion is large or deeply situated, wider retraction of the bilateral frontal lobes is required to obtain a sufficient operative field. The authors describe a new operative approach to dumbbell-shaped tumors in the frontal base, consisting of en bloc osteotomy of the bilateral orbital roofs and frontal sinus. This procedure, which is a modification of the transbasal approach described by Derome, is termed the "extensive transbasal approach." Successful applications of this procedure in three patients with frontal base tumors, two with frontal base fractures, one with a frontal arteriovenous malformation, and one with a frontal sinus mucocele are described. Also, the advantages of this approach over other, conventional operative approaches are discussed.