Cytokines as an adjuvant to tumor vaccines: Efficacy of local methods of delivery

Background: We examined alternative methods of delivering cytokines as an adjunct for priming lymph node (LN) cells draining sites of vaccine inoculation for the purpose of generating immune cells for adoptive immunotherapy. Methods: Using syngeneic murine tumors we examined the ability of IL-2, IL-4, or GM-CSF delivered locally to a site of tumor inoculum to induce antitumor reactive draining LN cells. Mice were inoculated subcutaneously with tumor cells transduced to secrete cytokine; tumor cells admixed with fibroblasts transduced to secrete cytokine; or intralesional inoculation of cytokine in established tumor to induce sensitized LN cells capable of mediating tumor regression in adoptive transfer. Results: Both IL-4 and GM-CSF cytokines were effective in enhancing the antitumor reactivity of vaccine-primed LN cells compared to IL-2, which was ineffective. The local delivery of GM-CSF by autocrine or paracrine secretion of genetically engineered cells, as well as direct intratumoral delivery was capable of upregulating LN sensitization compared to systemic administration, which did not. Conclusions: The local delivery of GM-CSF as an adjuvant for tumor vaccination can be accomplished by various methods, including direct injection, which avoids the need for gene transfer.     

Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. V. Effect of water extract from Arctostaphylos uva-ursi (L.) Spreng. (bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethasone ointment]

Effects of water extract (UW-ext) from the leaf of Arctostaphylos uva-ursi (L.) Spreng (Bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethasone ointment were investigated. One or 2% UW-ext ointment did not inhibit the ear swelling by picryl chloride-induced contact dermatitis (PC-CD) and carrageenin-induced paw edema. UW-ext augmented the inhibitory effect of dexamethasone ointment (0.005 or 0.025%) on these allergic and inflammatory models, but not the side effect of it. These results suggest that Bearberry leaf increases the inhibitory effect of dexamethasone on the allergic and inflammatory models.     

Protective effects of benidipine on arachidonic acid-induced acute cerebral ischemia in rats.

Acute cerebral ischemia was produced in rats by injection of arachidonic acid (AA) into the internal carotid artery. Evans blue (EB) was intravenously injected and its extravasation into the brain was determined as an indicator of disturbances in the blood-brain barrier and endothelial cells. Control animals showed severe cerebral edema and marked blue staining of the brain. Benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content and the extravasation of EB. Similarly nicardipine (100 micrograms/kg, i.p.) suppressed the elevation of water content and the extravasation of EB. Furthermore, both benidipine (30 micrograms/kg, i.p.) and nicardipine (100 micrograms/kg, i.p.) improved the neuronal injuries following AA-injection. An antiplatelet agent, ticlopidine (100 mg/kg, i.p.), and a thromboxane A2 synthetase inhibitor, OKY-1581 (3 mg/kg, i.p.), also suppressed the elevation of cerebral water content. A lipoxygenase inhibitor, AA-561 (200 mg/kg, p.o.), and a cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.p.), did not prevent the increase in cerebral water content. Neither benidipine (3-30 micrograms/kg, i.v.) nor nicardipine (100 micrograms/kg, i.v.) inhibited the AgNO3-induced thrombus formation of the abdominal aorta, whereas ticlopidine (100 mg/kg, p.o.) and OKY-1581 (3 mg/kg, i.v.) prevented the thrombus formation. From the present results, it is suggested that benidipine, as well as nicardipine, may protect against AA-induced acute cerebral infarction via a mechanism independent of antithrombotic action.     

Neuropathology of schizophrenia: A mini review

The neuropathology of schizophrenia remains obscure despite the fact that many neuropathologists have investigated this area for over 100 years. While remarkable progress has been made in the neuropathological study of neurodegenerative diseases including Alzheimer's disease, progress in studying the neuropathological entity of schizophrenia has not kept pace; the phrase “schizophrenia is the graveyard of neuropathologists” has been stated in the field. Since the 1980s, the morphological or functional abnormalities in the brains of schizophrenia patients have been reported by means of CT or MRI and with advanced functional brain image technology such as positron emission tomography or single photon emission computed tomography. Results from such imaging studies have led to neuropathological examination of the post mortem brains of schizophrenia patients being undertaken again. These neuroimaging studies have influenced the neuropathological investigation of the schizophrenic brain. Not only the classical microscopic observation of neuropathology, but also measurement and statistical analysis using computer imaging software or using immunohistological techniques has been performed. Based on the neuropathological studies of schizophrenia over the last 20 years, it is clear that schizophrenia is not a pure functional disease without organic factors. Reports of neuropathological abnormalities in the post mortem schizophrenic brain indicated they were found in almost all areas of the brain, but there are more reports describing the temporal lobe and frontal lobe compared to those describing other areas of the brain. These observed neuropathological abnormalities are explained rationally by the hypothesis of a neurodevelopmental disorder in this disease. In recent molecular biology studies, several putative candidate genes were reported, and some of these genes might have the function of neurodevelopment or making neuronal networks. It is important to consider together these findings with morphometric studies in neuropathological observation, neuroimaging studies and genome studies to pursue the etiology of schizophrenia from various perspectives.     

Poor oxygenation in the lungs of patients with hyperosmolar hyperglycemic non-ketotic diabetic coma after cardiac surgery

The ratio of PaO₂ to FiO₂ was often low (300 or less) in four patients with complications of hyperosmolar hyperglycemic non-ketotic diabetic coma (HHNKDC) following open heart surgery. Four of our patients had poor oxygenation and subsequent spontaneous recovery from in the immediate post-operative period, although HHNKDC occurred only in one during this period. In the 3 others, poor oxygenation without accompanying HHNKDC lasted for 1–6 days and HHNKDC developed about 2 weeks after open heart surgery at time when poor oxygenation reoccurred. If a working diagnosis of congestive heart failure was made only on the basis of the most common probability, and the fluid supply was restricted, HHNKDC would readily occur or be aggravated by the dehydration iatrogenically produced. It is thus concluded that HHNKDC should be included in diagnoses for pulmonary dysfunction.     

A case of primary ureteral carcinoma in the duplicated renal pelvis and ureter diagnosed by transurethral uretero-renoscopy

We present a case of primary ureteral carcinoma in the duplicated renal pelvis and ureter diagnosed by transurethral uretero-renoscopy. The case was of a 78-year-old man with the complaint of sudden asymptomatic macrohematuria. An excretory urogram strongly suggested the presence of duplication of the right collecting system, and cystoscopy revealed a gross hematuria from the right ureteral orifice. A retrograde ureteropyelogram revealed incomplete duplication of the right renal pelvis and ureter fused at about the ureter crossing over the iliac vessels, and a polyp-like filling defect in the lower segment of duplicated ureter at about 4 cm from the fusion of the ureters. Transurethral uretero-renoscopy was employed to investigate the filling defect, and a papillary tumor extended into the lower segment of duplicated ureter was revealed. Tumor was resected by a rigid operating instrument under transurethral uretero-renoscopy. The pathological diagnosis was grade I-transitional cell carcinoma of the ureter, so that right total nephroureterectomy with partial cystectomy was carried out subsequently. Surgical specimen after right total nephroureterectomy with partial cystectomy showed no other tumor in the pelvis or ureter macroscopically, and histopathological studies of surgical specimens were no evidence of malignancy. We believe that transurethral uretero-renoscopy significantly increases the diagnostic accuracy in determining the nature of upper urinary tract lesions, and this procedure is indispensable in the diagnosis of ureteral tumors. The present case was the 7th case of primary ureteral carcinoma in the duplicated renal pelvis and ureter in the Japanese literature.     

Pharmacokinetic analysis of antibody localization in human colon cancer: Comparison with immunoscintigraphy

The biodistribution and imaging characteristics of the 111In-labeled anti CEA monoclonal antibody ZCE-025 were studied in five patients with suspicion of colorectal carcinoma. Evaluation included antibody pharmacokinetics and assessment of antibody distribution in surgical specimen, making a comparison with whole-body imaging with a gamma camera. ZCE-025 localization in tumors was demonstrated by gamma-camera imaging in 4 of the 5 patients, corresponding to surgical findings. Persistent accumulation of 111In in the lymph nodes was observed in one patient, whereas surgical exploration of these lymph nodes showed no gross or microscopic evidence of metastases of colon carcinoma. Analysis of individual plasma by size exclusion HPLC showed two radioactivity peaks, labeled antibody and free DTPA. No transchelation of 111In to circulating transferrin was observed. The blood clearance was fitted to a two-compartment equation and its half-lives were found to be 10.8 +/- 8.7 h and 69.5 +/- 21.8 h for t1/2 alpha and t1/2 beta, respectively. Total urinary excretion averaged 0.3% of the injected dose/h with a small patient to patient variation. At 24 hrs postadministration the predominant radiolabeled species in urine was free DTPA. Thereafter, radioactivity in urine was partly present as a low molecular weight catabolic product. No apparent correlation between CEA content and uptake of 111In-ZCE-025 in tumors resected by surgery could be found. How 111In-labeled antibody is accumulated into tumors as well as into some nontumor tissues needs further study.     

Significance of the BTA Test in Bladder Cancer: A Multicenter Trial

Background :
The BTA test is a latex agglutination assay for the qualitative detection in the urine of analytes that are associated with bladder tumor. We compared the results of the BTA test with those of voided urine cytology (VUC) in patients with bladder cancer.
Methods :
A multicenter trial was performed at 6 institutions. A total of 132 patients with histologically diagnosed bladder cancer were enrolled. Urine samples were split for BTA and VUC testing.
Results :
The sensitivities of the BTA test and VUC were 57.6% and 37.9%, respectively; this difference was significant ( P < 0.001). The BTA test had much higher sensitivity for small, solitary, superficial tumors than did VUC.
Conclusion :
The BTA test is simple to perform, gives rapid results, and is far more sensitive than VUC for detection of bladder cancer. The BTA test has the potential to become an additional tool for detecting bladder cancer.     

Influence of acetylcholine on neuronal activity of monkey amygdala during bar press feeding behavior

Single neuron activity in the monkey amygdala was investigated during cue signalled conditioned bar press feeding behavior and the effects of electrophoretically applied acetylcholine (ACh) and atropine were analyzed. ACh increased the firing rate of one third of the neurons tested; these excitatory responses were inhibited by the muscarinic receptor antagonist atropine. No characteristic location of ACh-sensitive neurons was found, cells were diffusely distributed throughout the amygdala. Activity of ACh-sensitive neurons did not correlate with any particular event during the bar press feeding task. However, continuous application of ACh at low current intensity during the task significantly enhanced the task-related excitatory firing patterns, or markedly attenuated the inhibitory responses. Continuous application of atropine elicited or enhanced inhibitory response patterns. These results suggest that the cholinergic system of the monkey amygdala facilitates neuronal excitation but attenuates inhibition related to various phases of feeding behavior, such as to cue recognition, food aquisition and rewarding process.