Radioimmunoscintigraphy and radioimmunotherapy of renal cell carcinoma xenografts

From a panel of monoclonal antibodies (MAb) reactive with human renal cell carcinoma generated by this laboratory, three (designated A6H, C5H, and D5D) were selected for in vivo studies with a nude mouse xenograft model. These studies included 131I- and 111In-labeled MAb radioimmunoscintigraphy and 131I-labeled MAb radioimmunotherapy. In the imaging studies, these radiolabeled MAb allowed visualization of subcutaneous xenografts larger than 40 mg and subrenal capsule xenografts smaller than 20 mg. Comparisons of tumor to non-tumor tissue radiolabel distribution yielded unusually high ratios and depended on the MAb-xenograft combination. The 111In-radiolabeled A6H showed increased accumulation in the liver compared with 131I-A6H, but this still did not necessitate background subtraction for good visualization of small, subrenal capsule renal cell carcinoma xenografts. Radioimmunotherapy studies with 131I-A6H in BALB/c nu/nu mice bearing established renal cell carcinoma xenografts showed a prolonged (greater than 90 days) regression in tumor burden and possible "cures," whereas three sets of control mice showed progressive and rapid increases in tumor size. These studies indicated that MAb, which show good tissue biodistribution and high imaging sensitivity, could also be capable of delivering effective radiotherapy to the tumor when "human equivalent" radiolabeled-MAb doses are used.     

Isolation and partial characterization of neurofibrillary tangles and amyloid plaque core in Alzheimer's disease: immunohistological studies

Fractions enriched in neurofibrillary tangles (NFT) and amyloid fibrils were isolated from the cerebral cortex of three cases of senile dementia of the Alzheimer type. Distilled water suspensions of these fractions were excluded from all pore size gels and resisted digestion with various proteolytic enzymes. Formic acid/chloroform treatment of each fraction resulted in the appearance of 4,000-6,000, 15,000-17,000 and 24,000 molecular weight proteins, with concomitant diminution in the amount of excluded material at the top of each gel. The 4,000-6,000 dalton band was best seen in fractions containing randomly arranged amyloid fibrils, and its amino acid composition resembled that of the recently reported "beta" protein. A polyclonal antiserum to purified NFT reacted with tangles in neurons and in dystrophic neurites around plaques by immunoperoxidase staining. No reaction was obtained with cerebrovascular or plaque core amyloid immunohistologically, or with the 4-6 kD protein on immunoblots. Cross-reactivity with the neurofibrillary lesions occurring in Pick's disease, progressive supranuclear palsy, postencephalitic Parkinsonism and dementia pugilistica was also seen. Specific binding of this antiserum to the double filamentous structure was confirmed by immunoelectron microscopy. Although the presence of "beta" protein in both NFT and amyloid-containing fractions suggests that it may be an important constituent of both, cross-contamination cannot be excluded.     

Complicaciones durante la intubación traqueal repetida en la unidad de cuidados intensivos. Estudio prospectivo,observacional comparando primera intubación y reintubación

Background of the studyThe goal of the study was to compare the incidence of complications, technical difficulty of intubation and physiologic pre-intubation status between the first intubation and reintubation performed on the same patient in an ICU.Materials and methodsThe study was approved by the ethics committee of Galicia (Santiago-Lugo, code No. 2015-012). Due to the observational, noninterventional, and noninvasive design of this study, the need for written consent was waived by the ethics committee of Galicia. Patients requiring tracheal intubation and reintubation in the ICU were included in this prospective observational study. Main endpoint was to compare the incidence of complications, physiologic pre-intubation status, and the rate of technical difficulty of intubation between the first intubation and reintubation performed on the same patient in an ICU.Results and discussion504 patients were intubated in our ICU during the study period, and 82 (16%) required reintubation. There was no difference between the first intubation and reintubation regarding number of total complication (35% vs 33%; P = .86), hypotension (24% vs 24%; P = 1), hypoxia (26% vs 26%; P = 1), esophageal intubation (1% vs 1%; P = 1), and bronchoaspiration (2% vs 1%; P = .86). Physiologic pre-intubation status and technical difficulty of intubation did not differ between the first intubation and reintubation.ConclusionsIn our ICU patients requiring tracheal reintubation, incidence of complications, physiologic pre-intubation status, and technical difficulty of intubation did not differ between the first intubation and reintubation.     

Granuloma formation and parasite disintegration in porcine cysticercosis: comparison with human neurocysticercosis

Taenia solium cysticerci infect human beings and pigs, causing cysticercosis. In this study the pig was used as a model to characterize the immune response against cysticerci, given the difficulties in analysing the developing immune response in infected human brains. Metacestodes in different stages of viability or degeneration were isolated from the brain, heart and skeletal muscle of naturally infected swine, and the adjacent tissue was examined histologically. The immune response elicited by the cysticerci was classified into four separate stages. In stage I the parasites were surrounded by a thin layer of collagen type I, and by stage II there was a sparse inflammatory infiltrate. In stage III, granuloma formation was evident, and by stage IV the parasite was surrounded by an eosinophil-rich infiltrate and its vesicular membrane had begun to degenerate. The final stage, IV, was detected mainly in the heart but not in the brain. The granulomatous reaction in swine resembled that described previously in human patients, but differed in the abundance of eosinophils, the relative paucity of plasma cells, and the discrete deposition of collagen. These differences were probably due to the fact that in pigs the immune response can be examined earlier than in human patients, in whom sampling is inevitably made at a more chronic stage.     

β-Cyclodextrin tetradecasulfate/tetrahydrocortisol±minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic lewis lung carcinoma

Tetrahydrocortisol, -cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 M, 24 h) and -cyclodextrin tetradecasulfate (100 M, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 M, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studies. Tetrahydrocortisol and -cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14×5mg/kg, days 4–18) and cyclophosphamide (3×150 mg/kg, days, 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.Abbreviations 14(SO₄)ßCD -cyclodextrin tetradecasulfate - THC tetrahydrocortisol - CDDP cis-diamminedichloroplatinum(II) - 4-HC 4-hydroperoxycyclophosphamide - BCNU N,N-bis(2-chloroethyl)-N-nitrosourea - CAM chick embryo chorioallantoic membrane; IC₅₀, concentration of a drug required to kill 50% of the cells This work was supported by NIH grant P01-CA38493 and a grant from Bristol-Myers-Squibb, Inc., Wallingford, Connecticut     

Binding of osteopontin to the osteoclast integrin αvβ3

Occupancy of the chicken osteoclast _v3 integrin stimulates immediate cell signals. Peptides from osteopontin containing Arg-Gly-Asp and peptides from the osteopontin and bone sialoprotein sequences containing Arg-Gly-Asp stimulated immediate reductions in osteoclast cytosolic Ca²⁺. The changes in cytosolic Ca²⁺ required the Arg-Gly-Asp sequence, and were blocked by LM609, a monoclonal antibody to the _v3 integrin. Osteoclast stimulation by the proteins through the integrin did not require immobilization since soluble peptides produced changes in cytosolic Ca²⁺ and inhibited osteoclast binding to bone particles and bone resorption. The decrease in cytosolic Ca²⁺ stimulated by osteopontin and related peptides was due to activation of a plasma membrane Ca²⁺-ATPase. Thus, the data suggest that ligand binding to the osteoclast _v3 integrin results in a reduction in cytosolic Ca²⁺ which participates in regulation of osteoclast function.     

The carbamate insecticide ZZ-Aphox® induced structural changes of gills,liver, gall-bladder,heart, and notochord of Rana perezi tadpoles

Embryos of Rana perezi were kept under laboratory conditions and treated with carbamate ZZ-Aphox^® at chronic doses of 0.02 and 0.14 for 9 weeks. Both the histological study and the analysis of mortality show a direct relationship between the dosage and the effects of the pesticide. The histological study of the survivors over 56 days show damages in gills, liver, gall-bladder, heart, and notochord. Damages on the epithelia of gills (on their distal portion) and gall-bladder recover over a few days, whereas those provoked on the compacting of the hepatic parenchyma and the hepatocytes, the auricle and the perinotochordal collagenic fibers alter their structure in a lasting way. Potentials of such alterations are discussed, with special reference to the possible interference of the pesticide on the successful synthesis of the supporting connective sheaths.     

Storage, surgery, outcome, complications, and new developments in corneal and conjunctival grafts

This review covers last year's literature on corneal, limbal, and conjunctival transplantation including tissue storage and eye banking. In this area, the main themes were related to a better evaluation of tissue viability and the exclusion of disease transmission. An analysis of the changing indications for penetrating keratoplasty shows the differences between American and European series. Most efforts in relation to surgical techniques are oriented toward obtaining better refractive results, whereas the study of large series sheds new light on the risk factors for graft failure and other complications. Limbal transplants have acquired the status of a new field in the surgical treatment of ocular surface disease, particularly in relation to corneal stem cell deficiencies.     

Diet and oral premalignancy in female south Indian tobacco and betel chewers: a case-control study

The diets of 158 tobacco/betel quid-chewing women diagnosed with oral premalignant lesions and 155 quid-chewing but lesion-free controls, frequency matched for age, tobacco/betel habits, and socioeconomic status, were assessed using a food frequency survey. Index scores generated from the food frequency survey indicated that the mean levels of consumption for foods of animal origin (p < 0.001), total vegetables and fruit (p = 0.001), vegetables alone (p = 0.006), fruits alone (p = 0.006), and green leafy vegetables (p = 0.015) were significantly lower in cases than in controls. The mean index score for cobalamin (vitamin B12) was lower in cases with a borderline significance (p = 0.05), whereas the indexes for folate and carotene were not significantly different. The analysis of index scores estimating the number of 100-g servings per week of foods of animal origin [meat, eggs, milk, curd (yogurt), fish] consumed revealed that women who ate fewer servings were more likely to have premalignant lesions than those who ate more animal foods [odds ratio (OR) 3.38, 95% confidence interval (CI) 2.07-5.54, p = 0.001]. The risk for low consumption of vegetables was not as significant as that for foods of animal origin. However, those eating low levels of vegetables and low levels of foods of animal origin were at the greatest risk for lesions (OR 5.38, 95% CI 1.72-22.17, p < 0.05). In South Indian female tobacco/betel chewers, a diet deficient in foods of animal origin appears to be a more significant risk factor for oral premalignancy than is a diet deficient in fruits and vegetables.     

Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin three different parenteral administrations compared in 30 arthroplasties

• (i) The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin.
• (ii) Six groups of five patients participated in the study. The first three groups (A–C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D–F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously.
• (iii) Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients.
• (iv) Large inter-individual variation in bone concentration was observed.
• (v) The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent.