醋酸铅对豚鼠耳蜗橄榄束传出神经毒性的研究

目的探讨醋酸铅对豚鼠内侧橄榄耳蜗传出神经的损害。方法 70只成年健康豚鼠随机分为对照组和实验组。对照组(10只)豚鼠腹腔注射生理盐水1ml,共7次。实验组又分为高铅组和低铅组(各30只),分别每天1次腹腔注射0.25%醋酸铅溶液40mg/kg和10mg/kg,连续一周,分别于停药后14、28天(各15只))进行血铅含量和畸变产物耳声发射(DPOAE)检测,检测完成后断头处死,行基底膜铺片染色。结果实验组醋酸铅染毒后,血清中铅含量迅速升高。对照组和低铅组耳蜗传出神经分布均匀,神经纤维连续,DPOAE出现了不同程度的对侧声抑制效应,低铅组14天和28天抑制幅度分别为3.06±1.19dB和2.86±1.33dB;高铅组14天后耳蜗传出神经纤维连续性中断,乙酰胆碱酯酶终末反应物减少,DPOAE对侧声抑制幅度下降为0.74±0.61dB;高铅组28天后传出神经损害最为显著,DPOAE未引出。结论铅可对豚鼠内侧橄榄耳蜗传出神经产生不可逆性的损害。     

Phase IIb study of pembrolizumab combined with S‐1 + oxaliplatin or S‐1 + cisplatin as first‐line chemotherapy for gastric cancer

The KEYNOTE‐659 study evaluated the efficacy and safety of first‐line pembrolizumab plus S‐1 and oxaliplatin (SOX) (cohort 1) or S‐1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open‐label phase IIb study enrolled patients with advanced programmed death‐ligand 1 (PD‐L1)‐positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)‐negative G/GEJ adenocarcinoma. The primary end‐point was the objective response rate (ORR). Other end‐points were duration of response (DOR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow‐up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment‐related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD‐L1‐positive, HER2‐negative G/GEJ adenocarcinoma.     

Effectiveness of doxifluridine (5′-DFUR)/docetaxel against advanced/recurrent gastric cancer showing resistance to various anticancer drug regimens

A 58-year-old man was diagnosed as having type 3 gastric cancer (poorly differentiated adenocarcinoma). He underwent total gastrectomy with splenectomy, as well as D3 dissection, and received postoperative chemotherapy combining oral uracil and futrafur (UFT) with cisplatin (CDDP), but results showed recurrence of multiple abdominal lymph node metastases around the aorta. He therefore received various anticancer drug regimens (irinotecan [CPT-11]/CDDP; 1 M tegafur-0.4 M gimeracil-1 M oteracil potassium [TS-1], methotrexate (MTX)/5-fluorouracil); however, final results showed growth of lymph node metastasis and simultaneous worsening of his general condition. The patient then received combined administration of doxifluridine (5′-DFUR)/docetaxel (5′-DFUR, 1000 mg/body [666.7 mg/m ² ], given by consecutive daily administration, orally, for days 1–14; and docetaxel, 80 mg/body [60 mg/m ² ], on day 8, by venous drip, every 3 weeks). Three courses of this regimen resulted in approximately 90% reduction of the abdominal lymph node size, disappearance of the right cervical lymph node metastasis, reductions of the levels of two tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]19-9), and improvement of his general condition. In total, seven courses of the regimen were carried out. The patient died on day 298 after starting this combined regimen and showed a response period of 126 days. The primary toxicity identified was neutropenia (grade 4), as well as other low-grade (grade 1, 2) hematological and nonhematological toxicities. In the field of gastric cancer treatment, especially for patients showing multiple resistance to anticancer drugs, an effective therapy is critically needed. Received: January 15, 2002 / Accepted: July 8, 2002 Offprint requests to: A. Sato     

Fetal intraventricular bleeding possibly due to maternal vitamin K deficiency

We report a rare case of fetal intraventricular bleeding possibly due to maternal vitamin K deficiency. A 20-year-old woman was admitted to our hospital due to impending premature delivery and loss of dietary intake at 28 weeks of gestation. Her blood examination showed metabolic alkalosis, prolonged prothrombin time, and extremely high level of plasma des-gamma-carboxyprothrombin (protein induced by vitamin K absence, PIVKA-II). Intraventricular hemorrhage was demonstrated by ultrasonography 6 days after admission. She delivered a 2,288-gram girl infant at 40 weeks of gestation. Cranial computerized tomography and magnetic resonance images obtained postnatally demonstrated a reduced cerebral parenchyma adjacent to the interior side of the right lateral ventricle and the deficit of left cerebellum. The infant's head control was insufficient and central impaired hearing was noted at 6 months of life.     

Anonymity and openness and the recruitment of gamete donors. Part I: semen donors

Since 1 April 2005, gamete donors in the United Kingdom (UK) have to be willing, in the future, to be identified to offspring should the offspring want this. This change in law has lead to considerable anxiety about the future availability of donors. This paper presents an overview of the research evidence concerning semen donors' views on anonymity and openness, as it appears in referred journals since 1995. Research evidence that is available, but not yet been published in referred journals, is also reviewed. The nature of this evidence is analysed and criticized. Research on the views of potential semen donors is also reviewed, as is the evidence that is available from jurisdictions that have changed the law and required donor openness. The evidence shows that it is possible to recruit semen donors who are required to be identifiable in the future. The evidence, while not conclusive, points to an open system attracting different kinds of men than an anonymous system, and this has clear implications for future recruitment policies. The evidence-based approach to recruitment of gamete donors challenges some of the beliefs, attitudes and fears that have been associated with this law change in the UK, and in other countries where similar changes have taken place.     

Microtubular inclusions in normal skin of systemic lupus erythematosus patients

Biopsy specimens of clinically normal skin of 9 consecutive patients with SLE were examined ultrastructurally to determine the presence and frequency of microtubular inclusions. Ten blood vessels were examined in each specimen; every specimen contained at least two positive blood vessels, and some contained 80 to 100% positive vessels. No correlation was found between the frequency of the inclusions and either the disease duration or antinuclear factor titer. The inclusions tended to be more frequent in patients with more acute disease. The absence of inclusions in normal skin may mitigate a diagnosis of SLE.     

Thermally stable mesoporous tetragonal zirconia through surfactant-controlled synthesis and Si-stabilization

Thermally stable, highly mesoporous Si-stabilized ZrO₂ was prepared by sol–gel-synthesis. By utilizing the surfactant dodecylamine (DDA), large mesopores with a pore width of ∼9.4 nm are formed. Combined with an NH₃-treatment on the hydrogel, a high specific surface area of up to 225 m² g⁻¹ and pore volume up to 0.46 cm³ g⁻¹ are obtained after calcination at 973 K. The individual contributions of Si-addition, DDA surfactant and the NH₃-treatment on the resulting pore system were studied by inductively coupled plasma with optical emission spectrometry (ICP-OES), X-ray diffraction (XRD), N₂ sorption, and transmission electron microscopy (TEM). Electron tomography was applied to visualize and investigate the mesopore network in 3D space. While Si prevents the growth of ZrO₂ crystallites and stabilizes the t-ZrO₂ phase, DDA generates a homogeneous mesopore network within the zirconia. The NH₃-treatment unblocks inaccessible pores, thereby increasing specific surface area and pore volume while retaining the pore width distribution.

Schematic representation of ZrO₂ crystallites; (a) monoclinic ZrO₂, (b) tetragonal ZrO₂ following Si-stabilization, (c) mesoporous t-ZrO₂ following Si-stabilization and use of surfactant dodecylamine.