Protective effect of hepatocyte growth factor against degeneration of the retinal pigment epithelium and photoreceptor in sodium iodate-injected rats

PURPOSE: To investigate the possible protective effect of hepatocyte growth factor (HGF) against degeneration of photoreceptors and retinal pigment epithelium (RPE) in vivo. METHODS: Sprague-Dawley (SD) rats received an intravitreal injection of HGF in the right eye. The left eye was injected with vehicle as a control. Two days after the intravitreal injections, rats were administered 40 mg/kg of sodium iodate (NaIO3) intravenously. Scotopic ERGs were elicited by different stimulus intensities with a maximum luminance of 0.84 log cds/m2. To evaluate RPE function, the azide response was evoked by intravenous injection of 0.1 mg sodium azide. These electrophysiological measurements were conducted on days 4, 7, 14, and 28 after the NaIO3 injections. After recording ERGs or azide response, animals were sacrificed for quantification of the histological change and immunohistochemical analysis using antibodies against RPE 65. RESULTS: The threshold for the scotopic b-wave was significantly lower in HGF-treated eyes than in untreated control eyes (p < 0.005), and maximum b-wave amplitudes (Vbmax) were significantly larger in HGF-treated eyes (p < 0.05) across all experimental time points after NaIO3 injection. Azide response amplitudes were significantly larger in the HGF-treated eyes than in the untreated eyes (p < 0.05). The structure of the outer retina was preserved to a greater degree in the HGF-treated eyes than in the untreated eyes (p < 0.05). Immunohistochemical analysis demonstrated that irregular alignment of the outer nuclear layer was confined to the retinal area that was not stained with RPE 65. CONCLUSIONS: Our results indicated that an intravitreal injection of HGF provided significant protection against degeneration of the photoreceptor and RPE induced by systemic administration of NaIO3. This suggests that HGF could be used as a therapeutic agent for degeneration of photoreceptors as well as RPE.     

Improvement of the tumor-suppressive effect of boron neutron capture therapy for amelanotic melanoma by intratumoral injection of the tyrosinase gene

Boron neutron capture therapy (BNCT) is successful when there is a sufficient (10)B concentration in tumor cells. In melanoma, (10)B-para-boronophenylalanine (BPA) accumulation is proportional to melanin-producing activity. This study was done to confirm enhancement of the tumor-suppressive effect of BNCT on amelanotic melanoma by intratumoral injection of the tyrosinase gene. D178 or FF amelanotic melanomas were implanted s.c. in Syrian hamsters. One group of D178- or FF-bearing hamsters (TD178 or TFF group) received intratumoral injections of pcDNA-Tyrs constructed as a tyrosinase expression plasmid. The other hamsters (pD178 and pFF groups) were injected with pUC119, and control hamsters (D178 and FF groups) only with transfection reagents. All the groups underwent immunofluorescence analysis of tyrosinase expression and BPA biodistribution studies. BNCT experiments were done at the Kyoto University Research Reactor. Tyrosinase expression increased in the tumors of the TD178 and TFF groups but remained the same in the pD178 and pFF groups. Tumor boron concentrations in the TD178 and TFF groups increased significantly (TD178: 49.7 +/- 12.6 versus D178: 27.2 +/- 4.9 microg/g, P < 0.0001; TFF: 30.7 +/- 6.6 versus FF: 13.0 +/- 4.7 microg/g, P < 0.0001). The BNCT tumor-suppressive effect was marked in the TD178 and TFF groups. In vivo transfection with the tyrosinase gene increased BPA accumulation in the tumors, the BNCT tumor-suppressive effect on amelanotic melanoma being significantly enhanced. These findings suggest a potential new clinical strategy for the treatment of amelanotic melanoma with BNCT.     

Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells

Despite recent improvements in multimodal therapies for osteosarcoma (OS) and Ewing's family of tumors (EFTs), the prognosis of relapsed cases remains very poor because of the resistance to chemotherapy. Histone deacetylase inhibitors (HDACIs), including members of the cyclic tetrapeptide family such as FK228 and apicidin, are novel antitumor agents that can induce cell cycle arrest and apoptosis in various cancer cells. HDACIs also exhibit potent antitumor effects on OS and EFTs. However, to date there have been no studies to our knowledge reporting the effects of HDACIs on drug-resistant OS and EFTs. Here, we demonstrated that FK228 and apicidin exhibited strong resistance in doxorubicin-resistant clones of OS and EFTs expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) and that P-gp and MRP1 might play a crucial role in the resistance mechanism to FK228 and apicidin. A P-gp inhibitor (verapamil) and an MRP1 inhibitor (MK571) could independently reverse the resistance to FK228 and apicidin in the drug-resistant clones. Moreover, the combination of verapamil and MK571 could enhance HDACI-induced cell number reduction in drug-resistant clones to a similar extent as that in their parental clones. Although these findings suggest the difficulty in treating drug-resistant tumors expressing P-gp and/or MRP1 with these HDACIs, the combination of P-gp and MRP1 inhibitors might reverse the resistance to the HDACIs in the treatment of those tumors. Because HDACIs are potent and promising antitumor drugs and seem to be close to clinical use, it is necessary to pay attention to the resistance mechanisms against HDACIs.     

Effect of Prostaglandin E1 on Ischemia–Reperfusion Injury During Abdominal Aortic Aneurysm Surgery

Objective Abdominal aortic aneurysm (AAA) surgery subjects the lower extremities to ischemia and reperfusion. Although it is not extensive or prolonged, ischemia of the lower extremities during aortic cross-clamping is gradually and steadily induced. We studied the effects of prostaglandin E₁ (PGE₁) on ischemia–reperfusion injury of the lower extremities during AAA repair. Methods During AAA surgery, two near-infrared spectroscopy probes were positioned on each calf muscle to monitor oxygen metabolism in the lower extremities. We also measured lactate concentration in both iliac veins. Results Near-infrared spectroscopy signals responded sensitively to aortic cross-clamping and declamping. Lactate increased time-dependently during aortic cross-clamping. The continuous venous administration of PGE₁ (20 ng/kg per minute) inhibited the accumulation of lactate during aortic cross-clamping. Declamping of the first iliac artery resulted in a further but transient increase in ipsilateral venous lactate, which may be one component in the mechanism of declamping shock. Prostaglandin E₁ eliminated the transient increase in ipsilateral lactate. The administration of PGE₁ inhibited the contralateral accumulation of lactate after first declamping, and the lactate level decreased gradually before the second declamping. Conclusions Prostaglandin E₁ seems to have a protective effect against ischemia–reperfusion injury of the lower extremities during AAA surgery.     

Neurological diseases that cause detrusor hyperactivity with impaired contractile function

AIMS: Detrusor hyperactivity with impaired contractile function (DHIC) was originally described in elderly women. It has not previously been well known whether neurological diseases cause DHIC. We investigated which neurological diseases commonly cause DHIC in our laboratory. MATERIALS AND METHODS: We searched for DHIC in our laboratory's computerized database of 1,514 case records, which included a lower urinary tract (LUT) symptom questionnaire and urodynamic study results. DHIC was defined as the presence of both (1) detrusor overactivity during the storage phase, and (2) underactive detrusor contraction during the evacuation phase. RESULTS: Two hundred and seventeen patients met the criteria for DHIC: 122 men and 95 women; mean age, 63 years. The neurological diseases that caused DHIC included Parkinsonian syndrome (18%), multiple system atrophy (18%), progressive supranuclear palsy/corticobasal degeneration (14%), multiple cerebral infarction (MCI) (12%), multiple sclerosis/acute disseminated encephalomyelitis (18%), spinal cord lesions (15%), and cervical spondylotic myelopathy (CS) (10%). CONCLUSIONS: The present study revealed that a wide spectrum of neurological disorders could cause DHIC.     

Spontaneous resolution of diabetes insipidus after pituitary stalk sectioning during surgery for large craniopharyngioma. Endocrinological evaluation and clinical implications for surgical strategy

The mechanism of spontaneous resolution of diabetes insipidus (DI) was investigated after surgery for large craniopharyngioma. Twenty-two adult patients (mean age 48.9 years old), who underwent surgery via the anterior interhemispheric trans-lamina terminalis approach, were divided into three groups: Group I, the entire pituitary stalk was preserved (n = 2); Group II, the stalk was dissected distally from the tumor but ultimately sacrificed (n = 9); Group III, the stalk was not identified and was sacrificed (n = 11). All patients were discharged without neurological deficits 1 month after surgery. Four patients underwent gamma-knife treatment for residual tumor or recurrence. Postoperative endocrinological functions were normal in Group I, and no replacement therapy was required. Hormonal replacement for pan-hypopituitarism and DI was necessary in Groups II and III (mean follow-up period 5.9 years). DI resolved at 2.7 +/- 1.3 years after surgery in four patients in Group II, and a hypertonic saline infusion test revealed production of small amounts of intrinsic antidiuretic hormone (ADH). Urine osmolarity was high in the morning, and a significant increase in urinary osmolarity was noted after Pitressin injection. These results indicate induction of hypersensitivity of the distal renal tubules to small amounts of intrinsic ADH, resulting in decreased urinary output. Recovery from DI can be expected, despite permanent impairment of anterior pituitary function, if the pituitary stalk is dissected as distally as possible.     

Bladder sensation in peripheral nerve lesions

OBJECTIVE: To present bladder sensory data of three common peripheral nerve lesions (e.g., distal, intermediate/focal, and proximal). METHODS: We measured first sensation (FS) and bladder capacity (BC) (not exceeding 600 ml) in 71 patients with peripheral nerve lesions: 35 diabetic neuropathy (D group), 6 post-pelvic surgery (S), and 27 cauda equina syndrome due to lumbar spondylosis (L). We excluded those with detrusor overactivity or low compliance that might affect bladder sensation. RESULTS: The mean FS was 301.7 ml (D), 271.3 ml (S), and 189.4 ml (L), with the largest being in the D group (P < 0.05); the mean BC was 495.2, 475.4, and 391.4 ml, with the largest being in the D group (P < 0.05); who commonly had less frequent toileting. The mean post-void residual volume was 106.5, 29.0, and 42.0 ml; the values tended to increase along with BC. In the D group, the mean FS in patients with skin hypoalgesia as detected by pin prick and in those without it was 407.8 and 210.0 ml. The percentage of patients with FS < 100 ml was 5.7%, 0%, and 7.4%, respectively, who commonly had urinary urgency and frequency. CONCLUSIONS: Bladder sensation is affected in diabetic neuropathy more severely than in intermediate/proximal lesions, together with somatic sensory disturbance. Bladder sensory disturbance leads to less frequent toileting, resulting in bladder over-distension and large post-void residuals. A small proportion of patients with peripheral nerve lesions develop urinary urgency, presumably reflecting irritation of the afferent nerve fibers or the urothelium.     

Differences between latent and clinical prostate carcinomas: lower cell proliferation activity in latent cases

BACKGROUND: Biological significance of prostate latent cancers as early phase of clinical cancers has been controversial. The characterization of the latent cancer may be important to investigate differences between latent and clinical prostate cancers. METHODS: Latent cancers of the prostate, discovered at autopsy in men with no prior treatment for prostate disease and clinical prostate cancers, were compared for cell proliferation activities with parameters such as markers Ag-nucleolar organizer regions (AgNOR), topoisomerase II-alpha, and Ki-67. We also immunohistochemically studied alpha-methylacyl-CoA racemase (AMACR) expression that was recently identified as a possible positive marker of the prostate cancers. We analyzed 50 latent cancers and 50 clinical cancers, and samples were analyzed with Gleason grades or tumor volume. RESULTS: In the latent cancers, Gleason grades 1-4 were observed, but in the clinical cancers Gleason grades 2-5 were recognized. Cell proliferation activities were significantly lower in the latent cancers in Gleason grade 3, and similar results were obtained but without statistical significance in Gleason grades 2 and 4. When analysis was performed according to the tumor size, it was shown that the growth activities of the tumor of the clinical cancer were higher than the latent cancer. CONCLUSIONS: These results indicate that proliferation activities of the latent cancers were lower than the clinical cancers at the same Gleason grades. The data also suggest that latent cancers are just of preclinical stage and there is a possibility to progress to clinical ones by changing life style and longer life expectancy.     

Staging and indications for hepatectomy in hepatic metastases of colorectal cancer

Factors adversely affecting prognosis after hepatectomy for hepatic metastases include residual tumor, hepatic lymph node metastases, satellite metastases, extrahepatic metastases, four or more hepatic metastases, resection margins of less than 10 mm, and carcinoembryonic antigen and carbohydrate antigen 19-9 values higher than normal preoperatively and 1 month postoperatively. As no significant differences were observed in terms of the H-number stipulated by the Japanese Classification of Colorectal Carcinoma, a new staging system based on the number of lymph node metastases from the primary lesion, the number of liver metastases number, and the size of metastatic tumors was developed. The proposed staging system appears to be useful in predicting the prognosis of patients with metastatic liver tumors from colorectal cancer. Favorable patient selection criteria for liver resection are: 1) medical fitness for hepatectomy; 2) radical resection of the primary colorectal lesion; 3) metastatic tumors anatomically confined within the liver allowing adequate preservation of the liver parenchyma; 4) no signs of disseminated disease; 5) no signs of hepatic lymph node metastases; 6) four or fewer metastatic tumors; and 7) resection margins of 10 mm or greater. Unilobar or bilobar disease with multiple lesions is not a significant prognostic factor.