Novel therapy for hearing loss: delivery of insulin-like growth factor 1 to the cochlea using gelatin hydrogel.

HYPOTHESIS: Local application of recombinant human insulin-like growth factor 1 (rhIGF-1) via a biodegradable hydrogel after onset of noise-induced hearing loss (NIHL) can attenuate functional and histologic damage. BACKGROUND: The biodegradable gelatin hydrogel makes a complex with drugs by static electric charges and releases drugs by degradation of gelatin polymers. We previously demonstrated the efficacy of local rhIGF-1 application via hydrogels before noise exposure for prevention of NIHL. METHODS: First, we used an enzyme-linked immunosorbent assay to measure human IGF-1 concentrations in the cochlear fluid after placing a hydrogel containing rhIGF-1 onto the round window membrane of guinea pigs. Second, the functionality and the histology of guinea pig cochleae treated with local rhIGF-1 application at different concentrations after noise exposure were examined. Control animals were treated with a hydrogel immersed in physiologic saline alone. RESULTS: The results revealed sustained delivery of rhIGF-1 into the cochlear fluid via the hydrogel. The measurement of auditory brainstem responses demonstrated that local rhIGF-1 treatment significantly reduced the threshold elevation from noise. Histologic analysis exhibited increased survival of outer hair cells by local rhIGF-1 application through the hydrogel. CONCLUSION: These findings indicate that local rhIGF-1 treatment via gelatin hydrogels is effective for treatment of NIHL.     

急性淋巴细胞白血病最新治疗策略(上)

利用目前的治疗手段,80%的急性淋巴细胞白血病(acute lymphoblastic leukem ia,ALL)患儿均能得到治愈,尚有部分患者需接受强化治疗,但治疗的副作用也带来了急性或远期的严重并发症。此外,成人ALL病人的生存率依然低于40%。因此,本病需要既可以提高治愈率又能改善生活质量的新治疗方案。本文讨论了新出现的可能会改善ALL病人预后的治疗方法,包括现有常规化疗药物的新剂型、新的抗代谢药和核苷衍生物、白血病相关抗原的单克隆抗体,针对白血病细胞的基因异常及相关信号通路的分子治疗。1常规化疗药物的新剂型化疗药物的脂质体剂型是将药物…     

TIMP-4 is regulated by vascular injury in rats

The role of basement membrane-degrading matrix metalloproteinases (MMPs) in enabling vascular smooth muscle cell migration after vascular injury has been established in several animal models. In contrast, the role of their native inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), has remained unproven despite frequent coregulation of MMPs and TIMPs in other disease states. We have investigated the time course of expression and localization of TIMP-4 in rat carotid arteries 6 hours, 24 hours, 3 days, 7 days, and 14 days after balloon injury by in situ hybridization, immunohistochemistry, and Western blot analysis. TIMP-4 protein was present in the adventitia of injured carotid arteries from 24 hours after injury. At 7 and 14 days after injury, widespread immunostaining for TIMP-4 was observed throughout the neointima, media, and adventitia of injured arteries. Western blot analysis confirmed the quantitative increase in TIMP-4 protein at 7 and 14 days. In situ hybridization detected increased expression of TIMP-4 as early as 24 hours after injury and a marked induction in neointimal cells 7 days after injury. We then studied the effect of TIMP-4 protein on the migration of smooth muscle cells through a matrix-coated membrane in vitro and demonstrated a 53% reduction in invasion of rat vascular smooth muscle cells. These data and the temporal relationship between the upregulation of TIMP-4, its accumulation, and the onset of collagen deposition suggest an important role for TIMP-4 in the proteolytic balance of the vasculature controlling both smooth muscle migration and collagen accumulation in the injured arterial wall.     

Tumor proliferative index is higher in mice undergoing laparotomyvs. CO2 pneumoperitoneum

PURPOSE: Our laboratory has previously shown that tumors are more easily established and grow larger after laparotomyvs. laparoscopy. The purpose of this study was to better characterize these differences in tumor growth by assessing tumor cell proliferationvia the proliferating cell nuclear antigen assay, which has been shown to be a reliable marker of cellular proliferation. METHODS: Female C3H/He mice (N=40) were inoculated intradermally in the dorsal skin with 10⁶ cultured mouse mammary carcinoma cells <1 hour before interventions. Anesthesia control mice underwent no procedure. Laparotomy group mice had a midline incision from xiphoid to pubis that was closed after 20 minutes. Insufflation group mice underwent CO₂ pneumoperitoneum (4–6 mmHg) for 20 minutes. On postoperative Day 6, tumors were excised from one-third of the mice in each group, and from the remaining mice on postoperative Day 12. Sections were made and stained immunohistochemically for proliferating cell nuclear antigen, and the proliferative index of each tumor was determined by taking the average of proliferating cell nuclear antigen-positive cells in five high-power fields (×450), counted in a blinded fashion with the aid of an optical grid. RESULTS: On postoperative Day 6, the mean proliferative index for the laparotomy group was significantly higher than those for both the insufflation (P<0.04) and the control (P<0.001) groups. Of note, the proliferative index of the insufflation group was significantly higher than that of the control (P<0.01) group. Similarly, on postoperative Day 12, the mean proliferative index for the laparotomy group was significantly higher than for both the insufflation (P<0.05) and the control (P<0.005)groups. The proliferative index in the insufflation group was also significantly higher than that of the control (P<0.04) group. CONCLUSIONS: We have demonstrated that there is a significantly higher rate of tumor cell proliferation with the mouse mammary carcinoma cell tumor line after laparotomy than after pneumoperitoneum or anesthesia alone at two postoperative times. Additionally, insufflation alone increases postoperative tumor cell proliferation but to a lesser extent than laparotomy. The mechanism underlying these findings is unclear.Poster presentation at the meeting of The American Society of Colon & Rectal Surgeons, Philadelphia, Pennsylvania, June 9 to 14, 1997. Winner, The American Society of Colon and Rectal Surgeons/New Jersey Society of Colon and Rectal Surgeons' Award for Best Poster Presentation.     

DIABETES MELLITUS AND ADDISON'S DISEASE IN AN ADOLESCENT FEMALE

Abstract. Matsaniotis, N., Tzortzatou-Stathopoulou, F., Thomaidis, Th., Karakatsani-Kerasioti, Z., Theodoridis, Ch. and Dacou-Voutetakis, C. (First Department of Paediatrics of Athens University, "Aghia Sophia" Children's Hospital, Athens, Greece). Diabetes mellitus and Addison's disease in an adolescent female. Acta Paediatr Scand, 70: 949, 1981.-This short report describes a 16-year-old female who presented with Addison's disease 6 years after diabetes mellitus had been diagnosed. The possibility of both conditions being present should be borne in mind whenever an unexplained reduction of insulin requirements is noted, especially if this is accompanied by cutaneous pigmentation. The metabolic interrelationships of the two conditions are briefly discussed.     

Cytotoxic triterpenes fromCrataegus pinnatifida

Bioassay-guided fractionation of Crataegus pinnatifida (Rosaceae) gave two cytotoxic ursane-type triterpenes which were identified as uvaol (1) and ursolic acid (2) by physicochemical and spectroscopic methods. 3-Oxo-ursolic acid (3) was synthesized from ursolic acid (2) by Jones method. The cytotoxic activities of these compounds were tested against murine L1210 and human cancer cell lines (A549, SK-OV-3, SK-MEL-2, XF498, and HCT15) in vitro. Compounds 1 and 2 showed moderate cytotoxicities against L1210, whereas they showed weak activities against human cancer cell lines. However, compound 3 exhibited potent cytotoxic activities both in murine and in human cancer cell lines.     

Metabolic tumor volume by positron emission tomography/computed tomography as a clinical parameter to determine therapeutic modality for early stage Hodgkin's lymphoma

Recent studies have shown that metabolic tumor volume (MTV) by positron emission tomography/computed tomography (PET/CT) is an important prognostic parameter in patients with non‐Hodgkin's lymphoma. However, it is unknown whether doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) alone in early stage Hodgkin's lymphoma would lead to similar disease control as combined modality therapy (CMT) using MTV by PET/CT. One hundred and twenty‐seven patients with early stage Hodgkin's lymphoma who underwent PET/CT at diagnosis were enrolled. The MTV was delineated on PET/CT by the area ≥SUV_max, 2.5 (standardized uptake value [SUV]). Sixty‐six patients received six cycles of ABVD only. The other 61 patients received CMT (involved‐field radiotherapy after 4–6 cycles of ABVD). The calculated MTV cut‐off value was 198 cm³. Clinical outcomes were compared according to several prognostic factors (i.e. age ≥50 years, male, performance status ≥2, stage II, B symptoms, ≥4 involved sites, extranodal site, large mediastinal mass, CMT, elevated erythrocyte sedimentation rate and high MTV). Older age (progression‐free survival [PFS], P = 0.003; overall survival [OS], P = 0.007), B symptoms (PFS, P = 0.006; OS, P = 0.036) and high MTV (PFS, P = 0.008; OS, P = 0.007) were significant independent prognostic factors. Survival of two high MTV groups treated with ABVD only and CMT were lower than the low MTV groups (PFS, P < 0.012; OS, P < 0.045). ABVD alone was sufficient to control disease in those with low MTV status. However, survival was poor, even if the CMT was assigned a high MTV status. The MTV would be helpful for deciding the therapeutic modality in patients with early stage Hodgkin's lymphoma.     

Combined tadalafil and α-blocker therapy for benign prostatic hyperplasia in patients with erectile dysfunction: a multicenter, prospective study

This prospective study evaluated the safety of tadalafil 5 mg taken once a day in terms of hypotensive side effects and whether it improves lower urinary tract symptoms (LUTS) and restores sexual function in patients with erectile dysfunction who are receiving concomitant α-blocker (AB) therapy for benign prostatic hyperplasia (BPH). A total of 158 LUTS/BPH patients receiving AB therapy for ≥3 months were given tadalafil 5 mg once a day. Before treatment with tadalafil (V1), and 4 weeks (V2) and 12 weeks (V3) after starting tadalafil, blood pressure, heart rate, International Prostate Symptom Score (IPSS), maximal urine flow rate (Qmax), postvoiding residual urine volume, and International Index of Erectile Function (IIEF-5) score were measured. Of the 158 LUTS/BPH patients, a total of 119 completed the trial. Blood pressure (systolic and diastolic) and heart rate did not change. IPSS and IIEF-5 scores improved significantly, but Qmax and postvoiding residual urine volume did not; however, in the 39 men with a low baseline Qmax (≤10 mL/s), Qmax rose significantly from 7.97 ± 1.44 mL/s (baseline) to 8.91 ± 1.60 mL/s (V3; P = .012). The remaining patients (baseline Qmax >10 mL/s) did not change. At V2 and V3, adverse side effects were observed in 10 men (7.30%) and 6 men (5.04%), respectively. Facial flushing was the most common adverse side effect (6 men at V2 and 4 men at V3), followed by headache (2 men each at V2 and V3) and dizziness (2 men at V2). Two patients dropped out of the study because of adverse side effects. In conclusion, tadalafil 5 mg once a day in combination with AB appeared to have few adverse effects on hypotensive events and can improve LUTS and restore sexual function.