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A replicated trial was conducted with suckled Angus and Polled Hereford cows (110 d postcalving) to determine metabolic and endocrine responses to an energy-restricted diet after cows had re-established postpartum estrous cyclicity. Cows were individually fed 26.5 Mcal ME (H) or 15.2 Mcal ME (L) for a 30-d preliminary period and fitted with an indwelling jugular cannula at synchronized estrus. Average daily weight change during the estrous cycle was .60 +/- .25 and -1.37 +/- .30 kg/d for H and L, respectively (P less than .05). Blood concentrations of cortisol, progesterone and LH during the estrous cycle were not affected by diet, nor did diet affect frequency or amplitude of LH pulses (P greater than .05). No dietary differences were observed for daily concentrations of total protein, glucose, nonesterified fatty acids or acetate. Mean blood concentrations of propionate and butyrate were not different between diets; however, L cows had lower concentrations of propionate and butyrate on d 11 of the cycle (P less than .05). Cows fed L had higher concentrations of blood urea nitrogen (P less than .05), but they had lower concentrations of cholesterol (P less than .05) on d 4, 11, 18 and subsequent estrus (E). Insulin was not different on d 4 and 11; however, cows fed L had lower insulin concentrations on d 18 and d E (P less than .05). Dietary energy restriction in these cyclic cows caused no change in endocrine responses. Of metabolic responses measured, only blood urea nitrogen, cholesterol and insulin showed consistent changes.

The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144 was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069; thus a therapeutic gain was achieved with RB-6145 in a murine tumor model.

Commercial soybean lecithin replaced hydrogenated fat in steer diets to determine if phospholipids enhance fatty acid digestion and microbial fermentation in ruminants. Four diets were fed in a 4 x 4 Latin square to four Angus steers with ruminal cannula. One diet contained no added fat (control) and three contained hydrogenated fat and lecithin in weight ratios of 100:0, 86:14, and 72:28. All diets with added fat had lower fatty acid digestibilities compared with the control diet with no difference due to level of lecithin. Ruminal acetate and acetate:propionate ratios were reduced by all fat supplements but reduced less for the supplements containing lecithin. Plasma triglyceride and cholesterol concentrations were increased from dietary fat but not increased as much if lecithin were present in the diet. Feeding lecithin to ruminants does not improve digestibility of hydrogenated fats that are highly saturated.

alpha-[(1-Aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, where Im = 2-nitroimidazole and R1, R2, R3, R4 = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo. Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-, where R1, R2, R3, R4 = H, Me, and X = F, Cl, Br, I. These 2-haloethylamines were evaluated as prodrugs of the parent aziridines. The rates of ring closure in aqueous solution at pH approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-[2-hyroxy-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone. The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. alpha-[[(2-Bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-[(1-aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions.

We have developed a technique of partially-restrained molecular mechanics enthalpy minimisation which enables the sequence-dependence of the DNA binding of a non-intercalating ligand to be studied for arbitrary sequences of considerable length (greater than = 60 base-pairs). The technique has been applied to analyse the binding of berenil to the minor groove of a 60 base-pair sequence derived from the tyrT promoter; the results are compared with those obtained by DNAse I and hydroxyl radical footprinting on the same sequence. The calculated and experimentally observed patterns of binding are in good agreement. Analysis of the modelling data highlights the importance of DNA flexibility in ligand binding. Further, the electrostatic component of the interaction tends to favour binding to AT-rich regions, whilst the van der Waals interaction energy term favours GC-rich ones. The results also suggest that an important contribution to the observed preference for binding in AT-rich regions arises from lower DNA perturbation energies and is not accompanied by reduced DNA structural perturbations in such sequences. It is therefore concluded that those modes of DNA distortion favourable to binding are probably more flexible in AT-rich regions. The structure of the modelled DNA sequence has also been analysed in terms of helical parameters. For the DNA energy-minimised in the absence of berenil, certain helical parameters show marked sequence-dependence. For example, purine-pyrimidine (R-Y) base pairs show a consistent positive buckle whereas this feature is consistently negative for Y-R pairs. Further, CG steps show lower than average values of slide while GC steps show lower than average values of rise. Similar analysis of the modelling data from the calculations including berenil highlights the importance of DNA flexibility in ligand binding. We observe that the binding of berenil induces characteristic responses in different helical parameters for the base-pairs around the binding site. For example, buckle and tilt tend to become more negative to the 5'-side of the binding site and more positive to the 3'-side, while the base steps at either side of the centre of the site show increased twist and decreased roll.

A series of 15 pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones has been synthesized and evaluated for in vitro DNA binding by thermal denaturation and fluorescence quenching studies with calf thymus (CT) DNA. The results indicate that two compounds of the series, 7 and 8, elevate the melting point of DNA by 2.9 +/- 0.6 and 3.3 +/- 0.8 K, respectively. Similarly, a significant quenching of the fluorescence of the dihydroxy analogue 8 was observed upon interaction with CT-DNA. As controls, the dihydroxy isomer 9 with the reverse stereochemistry at C2 and the non-substituted parent dilactam 12, failed to increase the DNA melting point or exhibit significant quenching upon interaction with DNA. In addition, preliminary experiments with GC- and AT-rich polymers suggest some sequence-dependent properties for dilactams 7 and 8. Overall, these results indicate a highly specific structural requirement for DNA binding. Molecular modelling with d(GTAGATC), d(GCAGATC) and d(GCGTAGC) duplex sequences has provided a model based on hydrogen bonding between the dihydroxy dilactam 8 and DNA, that rationalizes some of the results obtained. It is possible that the observed interactions represent the non-covalent (binding) component of the interaction of covalently-bonding anthramycin-type anti-tumour antibiotics with DNA.

Monocular and binocular transient visually evoked responses (VER) were recorded on 50 adult subjects using a pattern reversal stimulus (check size 5.5 min arc). The peak-to-trough amplitude of the VER wave was measured and compared with the subjective visual acuity (Landolt C). The binocular amplitude enhancement over the monocular amplitude was around 26% across the acuity range studied, whereas the mean binocular subjective visual acuity improvement was around 11.3%, but this varied from 1% at the high acuity end to 17% at the low acuity end of the range.

The three-dimensional structure of a complex between the dodecanucleotide d(CGCGAATTCGCG) and the anti-trypanocidal drug berenil, has been determined to a resolution of 2.5 A. The structure has been solved by molecular replacement and refined to an R factor of 0.177. A total of 49 water molecules have been located. The drug is bound at the 5'-AAT-3' region of the oligonucleotide. At one end of the drug the amidinium group is in hydrogen-bonded contact with N3 of the adenine base complementary to the thymine of the AAT. The other amidinium group does not make direct interactions with the DNA. Instead, a water molecule mediates between them. This is in hydrogen-bonded contact with an amidinium nitrogen atom, N3 of the 5' end adenine base and the ring oxygen atom of an adjacent deoxyribose. Molecular mechanics calculations have been performed on this complex, with the drug at various positions along the sequence. These show that the observed position is only 0.8 kcal/mol higher in energy than the best position. It is suggested that there is a broad energy well in the AATT region for this drug, and that water molecules as well as the neighbouring sequence, will determine precise positioning. More general aspects of minor groove binding are discussed.

Six Hampshire wethers with ruminal and duodenal cannulas were fed three diets in a replicated 3 X 3 latin square to compare phospholipids with triglycerides for their effects on ruminal digestion. The diets (56% concentrate, 44% bermuda-grass hay, air-dried basis) contained either no added fat (control), 5.2% soybean lecithin or 2.4% corn oil on a DM basis. All diets were isonitrogenous and both fat-supplemented diets had similar fatty acid and energy contents. Fat added to the diet, regardless of source, reduced digestibilities of DM, energy, ADF and fatty acids in the rumen but had no effect on total tract digestibility coefficients. Lecithin slightly increased (P = .06) fatty acid digestion in the hindgut compared to corn oil (91.0 and 87.0%, respectively). Both fat sources decreased (P less than .01) ruminal ammonia concentration and increased (P less than .10) N flow to the duodenum. Added fat also reduced ruminal (P less than .01) and total tract (P less than .05) N digestibilities. Microbial N flow to the hindgut was not affected by diet, but adding fat increased (P less than .06) true efficiency of microbial protein synthesis. Overall, phospholipids from soybean lecithin inhibited ruminal fermentation similarly to triglycerides from corn oil. Despite ruminal degradation of lecithin by microbial phospholipases as shown in other studies, feeding lecithin tended to increase fatty acid digestion in the hindgut.

Radiation-reduced 2-nitroimidazoles (misonidazole, RSU-1137, Ro.03-8799 and Ro.03-8800) incubated in air with plasmid DNA (pH 7.0, 310K) induce DNA strand breakage, as revealed following subsequent heat or alkali treatment. Only RSU-1137 resulted in the binding of a [2-14C] fragment and significant yields of heat-labile strand breaks (greater than 20% loss of type-I DNA after 48 hr incubation). RSU-1137 was shown to be greater than 6 times more effective than misonidazole at producing alkali-labile breaks. In fact, the efficiency of alkali-induced strand break production is in the order: misonidazole less than Ro.03-8799 approximately Ro.03-8800 less than RSU-1137. Reaction of these reduced 2-nitroimidazoles with 2'-deoxyguanosine (dG) also results in the formation of a common glyoxal-dG product, with its yield and rate of production being dependent upon the 2-nitroimidazole used. It has been demonstrated that these variations are influenced by the N-1 side-chain of the 2-nitroimidazole. Product yields are approximately 5-6 times greater with misonidazole than with RSU-1137. From the evidence presented, it is apparent that formation of glyoxal (or a glyoxal-like product) is not responsible for the DNA strand breakage seen. It is inferred that these breaks are induced by a nitro-reduction product(s) which remains unidentified.

Conventional methods of treatment were given to 50 young amblyopes, with the result that 26% showed no improvement and 50% improved by at least two Snellen lines. A 0.67 correlation coefficient was found between acuity before and after treatment. Whilst there was some differences in approach to convergent squint amblyopes and to non-squinting amblyopes, the degree of success in the two subdivisions was similar.

The mixed-function radiosensitizer RSU-1069 and its analogues possess both alkylating and electron-affinic properties, and have been shown to be more efficient radiosensitizers than misonidazole both in vivo and in vitro. The pharmacokinetics following intraperitoneal injection of three members of this series, RSU-1069, RSU-1164, and RSU-1172 have been studied in C57BL mice bearing B16 melanoma. Peak tumor levels of each compound, and tumor/plasma ratios (T/P) were found to be high: T/P RSU-1069 = 3.8, RSU-1164 = 3.7; RSU-1172 = 4.0. In contrast, other normal tissues including brain showed tissue/plasma ratios close to 1. The mechanisms responsible for differential tumor uptake are unknown, but may depend on the basicity of the compounds, leading to preferential uptake in areas of low pH, or alternatively they may be associated with the alkylating function. This group of compounds appear to demonstrate highly favorable tissue distributions.

A series of 1-alkyl-3-nitro-1,2,4-triazoles has been prepared and assessed in vitro as radiosensitizers of hypoxic cells and as bioreductive cytotoxins. The differential hypoxic:aerobic cytotoxicities of representative compounds have been determined and compared with analogous 2-nitroimidazoles. It is found that the 3-nitrotriazoles are considerably less effective than the corresponding 2-nitroimidazole derivatives. This result includes dual-function nitrotriazoles where potential alkylating moieties have been incorporated into the molecule. In contrast, the 3-nitrotriazoles show similar or slightly improved radiosensitizing efficiency, in accord with their redox behaviour, and significantly lower chronic aerobic toxicity compared with the corresponding 2-nitroimidazoles. On the basis of a derived in vitro therapeutic ratio, 1-(3-nitro-1,2,4-triazol-l-yl)-3-piperidino-2-propanol (8) has been identified as particularly active and warrants further evaluation as a hypoxic cell radiosensitizer in vivo.

A technique is described for predicting visual acuity in adult humans by using the visually evoked response (VER). This involves using a pattern-reversal checkerboard with a small check size (5.5. min arc) as the stimulus, and measuring the peak-to-trough amplitude of the VER wave arising from it. The technique is therefore both rapid and convenient. The pattern-reversal rate was varied in order to assess the influence of the temporal modulation on the VER waves. The results suggest that a rapid pattern reversal rate produces a VER which displays a reduced association with spatial processing.

Recent research has demonstrated the effectiveness of added fat in diets to maintain milk production and fat percent. Much of the earlier work which indicated that fat affects digestion negatively may not be applicable because of great differences in the nature of diets and fats fed and especially in total feed intake. Nevertheless, much remains to be learned about interactions of fat, fiber, calcium, and rumen microorganisms if feeding of fat is to be maximized. The uniquely high acidity in the duodenum combined with detergent action of bile acids, lysolecithin, and fatty acids causes saturated fatty acids to be more digestible in ruminants than in nonruminants. Large quantities of added dietary fat increase concentrations in plasma of very low density lipoprotein triglyceride which increases their uptake by the mammary gland with inhibition of short chain fatty acid synthesis and consequent changes in milk fatty acid composition. In some cases, secretion of milk fat is increased. Current research and practice demonstrate that 3 to 5% fat may be added to diets for lactation to increase energy intake of high-producing cows and/or to reduce starch feeding, thereby increasing the ratio of forage to concentrate to prevent depression of milk fat.

The amplitude repeatability of pattern reversal visual evoked response using a 5.5 and 40' arc check was investigated in twelve subjects with each subject recording ten 64 sweep runs. The variability by visual inspection or by analysis of variance suggests that a single run will provide a representative amplitude for a 40' arc check whereas the 5.5' check will require more runs merged together before the amplitude is stable. The larger spread of error encountered with the 40' arc check may point to a visual component contributing to more amplitude variability. The possibility of making some assessment of the level of noise present during recording is discussed.

C7H11N3O4, Mr = 201, monoclinic, P2(1)/c, a = 6.997 (1), b = 7.862 (1), c = 17.024 (3) A, beta = 97.06 (2) degrees, U = 929.4 (5) A3, Z = 4, D chi = 1.44 Mg m-3, lambda(Cu K alpha) = 1.5418 A, mu = 0.916 mm-1, F(000) = 424, ambient temperature, R = 0.049 for 1324 unique reflections. All bond lengths and angles have normal values and the planes of the nitro group and imidazole ring form a dihedral angle of 7.9 (1) degrees.

A series of novel 1-(hydroxyaminoalkyl)-substituted nitroimidazoles has been synthesized as potential radiosensitizers for hypoxic mammalian cells. These compounds were synthesized via N-(hydroxyalkyl)phthalimide nitroimidazole intermediates which, on reaction with hydrazine hydrate, yielded the corresponding amines. The intermediates were prepared by reacting the epoxide derived from nitroimidazole with phthalimide and/or the epoxide derived from phthalimide with the nitroimidazole. The method was used successfully for the preparation of 2-, 4- and 5-nitroimidazole derivatives. In a modification of this procedure, 1-(2-aminoethyl)-2-nitroimidazole has been prepared by a new route which avoids the use of aziridine. These agents were tested for cytotoxicity and radiosensitizing ability in vitro using Chinese hamster V79 cells. All of the 2-nitroimidazoles tested showed toxicity similar to that previously reported for misonidazole and Ro 03-8799 (1-(2-hydroxy-3-piperidinopropyl)-2-nitroimidazole), two compounds currently undergoing clinical evaluation. In addition, all the novel primary amines were shown to function as hypoxic cell radiosensitizers. The 2-nitroimidazole derivatives were the most efficient compounds to be examined and showed at least as much activity as misonidazole.

A pattern reversal stimulus (check size 5.5 min arc) was used to elicit visually evoked responses (VER's). The peak to trough amplitude of the VER wave was measured and compared to the subjective visual acuity (Landolt C) in 30 subjects. The recordings were made at 3, 6, and 12 pattern reversals per s. The correlation coefficients are reasonably high (r = 0.81) for both the 3 and 6 reversal rates with a considerably lower correlation coefficient (r = 0.54) for the 12 reversals per s stimulus. Repeatability measurements on a further 6 subjects taken over a 5-week period produced an amplitude coefficient of variation of 13% for the 6 subjects with the 3 reversals per s stimulus.

Factors which determine the ability of activated charcoal to increase systemic drug clearance include adsorption characteristics, the extent of back diffusion, and biliary excretion into the gut. Orally absorbed drugs diffuse back into the gut, but it is not known whether non-absorbed agents also diffuse back. Tobramycin was studied with a highly activated charcoal to determine whether this occurs. Five volunteers received a single IV dose of tobramycin on two occasions. Using a randomized, crossover design, subjects received 10 g of activated charcoal (as SuperCharR suspension) 2 hr prior, and at 0, 2, 6, and 8 hr after tobramycin administration during one of the study days. In vitro, tobramycin adsorbed to charcoal at pH 5.6, but not at pH 2.6. A 20:1 charcoal:tobramycin ratio resulted in 34.9% of tobramycin adsorbed to activated charcoal. Blood (0-12 hr) and urine (0-24 hr) were collected and tobramycin concentrations determined. Urinary tobramycin recovery, renal and total drug clearance, half-life, and volume of distribution were calculated. There were no differences in these parameters between the two groups. We conclude that activated charcoal has no effect on tobramycin distribution or elimination in normal volunteers, and that back diffusion does not occur with this drug.

Pattern reversal visually evoked responses (VER's) at a frequency of 7 Hz were recorded from 10 subjects. Peak-to-trough amplitudes were measured at centrally fixated field sizes from 1 to 8 degrees for check sizes from 2.5 to 30 min. Check size for maximum amplitude decreased as field size was reduced. The amplitude--check size relation was not necessarily linear across its full range. When using an extrapolation technique for estimating visual acuity, a curvilinear regression may be more appropriate than the assumption of a linear regression.

Fixation disparity has been shown to be produced by prism stress, and it has therefore been proposed that its presence constitutes a sign that binocular vision is under stress (decompensated heterophoria). Fixation disparity can be present in the absence of any other indication of stress, and therefore may have a physiological basis. This study investigates the effect on fixation disparity and visual discomfort of placing the visual system under a different type of stress, that of requiring the subject to read under conditions of inadequate illumination. In 50 young adults, it was found that fixation disparity increased under inadequate illumination and that this was accompanied by symptoms in the form of visual discomfort. After a period of rest from any near-vision task, the fixation disparity decreased and the symptoms were reduced.

Overnight exposure of Chinese hamster cells (V. 79-753B) in vitro to 1 micrograms/ml dexamethasone increases the radiation resistance of the cells by about 20% both in air and in hypoxia, while having no appreciable effect on the oxygen enhancement ratio (OER). This is accompanied by substantially higher levels of glutathione. When dexamethasone-treated hypoxic cells are irradiated in the presence of nitroxyl biradicals there is no effect on the slope ratio of of the exponential portion of the survival curves. In the case of uncharged biradicals, Ro.03-6061 and RSU-4072. which have been shown to modify the shoulder region of the hypoxic cell survival curve, there is an increase in extrapolation number in dexamethasone-treated cells. When hypoxic cells are exposed to the charged biradical RSU-4073, which does not exhibit shoulder modification, there is no change in extrapolation number. Experiments to examine the effect of concentration of these compounds on radiosensitization show that lower concentrations of both RSU-4072 and RSU-4073 are required to mediate changes in the slope of the hypoxic cell survival curve than to mediate shoulder modification, in the case of RSU-4072. Quantitative ESR data comparing the uptake of RSU-4072 and RSU-4073 with the monoradical TMPN into cells suggest that the cell membrane may act as a barrier to the incorporation of biradicals, and that this is greater for charged than for uncharged compounds. Treatment of cells with dexamethasone does not affect the uptake of the compounds. The data suggest, however, that the cell membrane may be an important site for localization of uncharged biradicals and that this may be important in determining shoulder modification.

[2-14C]-RSU-1069 [1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol], either as a parent (unreduced) or following radiation reduction, binds to calf thymus DNA in vitro. Radiation-reduced RSU-1069 binds to a greater extent and more rapidly than the parent compound. RSU-1137, a nonaziridino analogue of RSU-1069, binds following radiation reduction. Radiation-reduced misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol) exhibits binding ratios a thousand-fold less than those of reduced RSU-1069. There is no evidence for binding of parent misonidazole. Both parent and reduced RSU-1069 cause single strand breaks (ssbs) in pSV2 gpt plasmid DNA with the reduced compound causing a greater number of breaks. Parent and reduced RSU-1137 and misonidazole do not cause ssbs. It is inferred that the aziridine moiety present in both parent and reduced RSU-1069 is required for ssb production. RSU-1069 reacts with inorganic phosphate probably via nucleophilic ring-opening of the aziridine fragment. Incubation of plasmid DNA with reduced RSU-1069 in the presence of either phosphate or deoxyribose-5-phosphate at concentrations greater than 0.35 mol dm-3 prevents strand breakage, whereas 1.2 mol dm-3 deoxyribose does not protect against strand breakage formation. From these findings it is proposed that the observed binding to DNA occurs via the aziridine and the reduced nitro group of RSU-1069 and that these two have different target sites. Binding to DNA via the reduced nitro group may serve to increase aziridine attack due to localization at or near its target.

The use of changes in fixation disparity, the associated phoria, and the dissociated phoria in assessing the degree of visual stress requires that we know the effect of vision under close working conditions (40 cm) on these parameters. The authors have previously reported that reading under the stress of abnormally low illumination, or at too close a working distance (20 cm), increases fixation disparity and associated phoria and is associated with symptoms and visual discomfort. The current study shows that reading at photopic levels of illumination and at a working distance of 40 cm does not change the magnitudes of fixation disparity and associated phoria. Reading under these conditions is not accompanied by an onset of symptoms or visual discomfort. This result indicates that changes in fixation disparity and associated phoria are a product of visual stress and are not produced by reading itself.

Changes with age in heterophoria, associated heterophoria, fixation disparity and stereopsis for near vision were investigated in a sample of 187 subjects (age range from 10 to 65 years) divided into six age groups. With increasing age, heterophoria, associated heterophoria and fixation disparity increased in the exo-direction. No change in stereopsis was found. A comparison with visual symptoms for near vision indicated a relationship between symptoms and the magnitude of fixation disparity and associated heterophoria for all age groups, but no relationship was found between the presence of symptoms and heterophoria measurement. No relationship between the presence of symptoms and the central slope of the forced vergence fixation disparity curve was found. These findings suggested that neither the measurement of heterophoria nor the forced vergence disparity curve are appropriate tests in the assessment of binocular vision anomalies. However, fixation disparity and associated heterophoria are related to binocular problems for near vision in all age groups.

RB-6110: C6H9N5O4, Mr = 215.17, monoclinic, C2/c, a = 20.595 (3), b = 4.713 (1), c = 19.914 (4) A, beta = 110.69 (1) degree, V = 1808.3 A3, Z = 8, Dx = 1.588 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.838 mm-1, F(000) = 675, T = 298 K, final R = 0.042 for 1219 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6162: C8H11N5O3, Mr = 225.21, monoclinic, P2(1)/c, a = 7.515 (1), b = 14.758 (2), c = 9.813 (1) A, beta = 108.49 (1) degree, V = 1032.1 A3, Z = 4, Dx = 1.450 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.927 mm-1, F(000) = 472, T = 298 K, final R = 0.042 for 1113 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6110 and RB-6162 are 3-nitro-1,2,4-triazoles with potential application as anticancer agents. The nitro groups are in the plane of the aromatic triazole ring with dihedral angles of 1.2 (4) and 4.6 (4) degrees, respectively. The arizidine substituent of RB-6162 is almost perpendicular [dihedral angle 80.1 (4) degrees] to the triazole plane. Molecular-orbital calculations on RB-6162 have confirmed that this geometry is energetically favoured. The energy barrier to rotation about the triazole-aziridine bond has been determined as 51.5 (5) kJ mol-1 by the dynamic NMR method.

Chopped hay supplemented with a volatile fatty acid salt mixture at 20% of metabolizable energy (ME) was fed to 30 Suffolk X Corriedale lambs (mean wt 29.6 kg) to determine the effects of dietary propionate on weight gain, body composition and plasma metabolites. Propionate accounted for 0, 25, 50, 75 or 100% of the salt mixture energy, and acetate accounted for the remainder. Each diet was fed at two levels of daily intake (158.7 and 130.6 kcal ME/W.75). Lambs on the high level of intake lost more (P less than .05) energy in feces, lost less (P less than .05) energy in CH4 and had carcasses with more (P less than .10) water and fat than lambs on the low intake level. Percentage of propionate in the salt mixture had no effect on ME or body composition of lambs. Increasing the percentage of propionate in the salt mixture increased plasma propionate in blood samples taken at 1 and 2 h after feeding (linear, P less than .05). Empty body weight gain per megacalorie of ME above maintenance increased as the percentage of propionate in the salt mixture increased, but not until propionate reached 75% of the salt mixture (linear, P less than .05; cubic, P less than .05). These results show that propionate in the blood has a positive, but nonlinear, effect on weight gain, even when energy intake is held constant.

The crystal structure of the experimental antitumour compound N-(2-dimethylaminoethyl)-2-phenylquinoline-8-carboxamide has been determined. The geometry and conformation have been used as starting points for molecular modelling of the intercalative interactions with DNA shown by the parent compound and analogues with the phenyl ring located at alternative positions on the quinoline chromophore. A molecular mechanics force field program was used for energy minimization and calculation of intermolecular (enthalphic) binding energies. The parent quinoline-8-carboxamide and derivatives with a phenyl substituent at the 4- or 5-position were judged to be poor intercalators in both structural and energetic terms. By contrast, the 2-, 3-, and 6-phenyl derivatives all had high calculated binding energies with the phenyl groups involved in stacking with DNA base pairs. The order of energies calculated for this series of compounds has been found to correlate well with both the order of experimentally derived free energies and with the in vitro cytotoxic activity.

Some of the recently suggested methods for treating amblyopes are reviewed. A survey of the success rate in 50 young amblyopes, using conventional methods, is described. Whilst 26% did not improve at all in visual acuity, 50% improved by at least two Snellen lines. The suggestion is made that the success rate in the clinic described is similar to that found elsewhere.

A survey of 100 patients who received orthoptic treatment in the Bradford University Clinic is examined to see the level of success with the different binocular anomalies, indicating what factors were common in successful cases, and the type of treatment given. A successful outcome or worthwhile improvement was achieved in enough cases to conclude that orthoptics in teenage patients is often appropriate, even in strabismus, if the cases are selected carefully. There was no indication that the actual age made any difference once the patients was between 11 and 19 years, but the starting acuity was significant.

Convergence insufficiency represents a significant problem in optometric practice. The percentage of cases in a rural area was compared with that in a previous sample from an urban area, with respect to the general incidence, and the effects of age and taking of medicines as an indicator of health. The percentage of convergence insufficiency in the rural area was about half that in the urban area, and the percentage taking medicines was about two-thirds. The incidence of convergence insufficiency increased with age in both populations. When both samples were taken together, the incidence of convergence insufficiency was three times greater in those taking medicines.

Four in vitro trials were conducted to determine how ruminal fermentation is affected by source of fat, level of fat, and combinations of fatty acids. Trials I and II examined how volatile fatty acids (VFA) were changed by three sources of fat (blended animal-vegetable fat, corn oil and tallow fatty acids) each added to a hay substrate at six levels (0, 2, 4, 6, 8 and 10%). Increasing blended fat caused no changes in VFA levels except to decrease butyric acid from 12.1 to 9.9% of the total VFA (P less than .05). Corn oil and tallow fatty acids both increased propionic acid, causing the ratio of acetic to propionic acids (A/P) to decrease (P less than .01). Trial III tested different ratios of oleic/stearic and linoleic/stearic acids to determine if certain combinations were better for fermentation. There was no evidence of synergism among fatty acids since increasing the ratio of unsaturates steadily reduced A/P. Trial IV was designed to determine how changes in VFA levels reflect changes in fiber digestibility of substrates containing added fat. Volatile fatty acids having significant regressions with fiber digestibility were acetic acid (r = .648), propionic acid (r = -.670), total VFA concentration (r = .742) and A/P (r = .831). Results are interpreted to show that blended animal-vegetable fats are less toxic in the rumen than equal levels of other lipids, and the beneficial effects of blended fat cannot be attributed to a unique combination of fatty acids acting synergistically.

Phospholipid supplements were incubated in vitro or fed to sheep to determine how they affected ruminal fermentation, nutrient digestion and serum lipid concentration. In vitro, deoiled soybean lecithin added to hay increased (P less than .05) total VFA concentration but had no effect on fiber digestion in four of five trials. Purified phospholipid (synthetic phosphatidylethanolamine), however, had little effect on in vitro hay fermentation when tested at four levels (0, 10, 20 or 30 mg) in three separate trials. Deoiled soybean lecithin disappeared in vitro at two rates, 12.9 and .66%/h for the fast- and slow-degrading fractions, respectively. Compared with 2.4% corn oil supplements, 5.2% soybean lecithin added to sheep diets (56% concentrate) reduced (P less than .05) energy, fiber and nitrogen digestibilities. Crude lecithin reduced (P less than .05) energy digestibility more than deoiled lecithin. Both types of lecithin increased (P less than .05) serum nonesterified fatty acid concentrations but had no effect on serum glucose, cholesterol or triglyceride concentrations compared with the corn oil diet. In summary, phospholipids had different effects on ruminal fermentation, depending on their source. None had a beneficial effect on fiber digestion. Phospholipids are degraded in the rumen and inhibit digestion in a manner similar to that of the commercial fats and oils.

The interaction of the nitroimidazole-aziridines RSU-1069 and RSU-1131, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH 7 results in strand breakage. The yields of DNA single strand breaks (ssb), "alkali-labile" damage and DNA crosslinks induced by these alkylating agents have been assessed. It is shown that DNA crosslinks are induced only by the reduced nitro-compounds. RSU-1069, as parent or reduced compound, is more efficient at producing these effects than the equivalent form of RSU-1131. Further, RSU-1069 is about 2 X more susceptible to nucleophilic attack by inorganic phosphate and deoxynucleotides than RSU-1131. RSU-1069 also shows greater selectivity for reaction with the nucleotide base moiety than does the less-reactive monomethyl analogue, RSU-1131. The yields of ssb and "alkali-labile" damaged sites induced by the two agents reflect their respective chemical reactivities and appear largely to determine their aerobic cytotoxicities. In contrast, the yield of DNA crosslinks induced by the reduced compounds appears to correspond rather better with the observed hypoxic cytotoxicities. From these findings it is suggested that the induction of DNA crosslinks by these agents may play a major role in their effectiveness as hypoxia-selective cytotoxins.

The interaction of a series of nitroimidazole-aziridine radiosensitisers, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH7 results in strand breakage. The efficiency of strand breakage substantially increases on reduction of the nitroimidazole analogues. The rate of production of strand breaks decreases on interaction with both parent and reduced nitroimidazole analogues as the aziridine moiety is deactivated through alkyl-substitution. These variations in efficiency are reflected in changes in the toxicity towards both oxic and hypoxic cells and in the decrease in toxicity with progressive substitution of the aziridine moiety. The stabilities of these nitroimidazoles in aqueous solution at pH7 have also been determined. However, these stabilities do not parallel the variations in the alkylating efficiency of DNA by the aziridine moiety. These results have been discussed in terms of the relative reactivities of the nitroimidazoles with plasmid DNA and their ability to act as cytotoxic agents, especially following bioreduction and how the findings may relate to the radiosensitising properties of these agents.

RSU 1069 is a substantially more efficient sensitizer than misonidazole when hypoxic Chinese hamster V79 cells are irradiated in vitro at room temperature; such that for 0.5 mmol dm-3 sensitizer an ER of 3.0 is obtained for RSU 1069 whereas an ER of only 1.6 is obtained for misonidazole. However, when irradiation is done at 4 degrees C, the radiosensitization caused by RSU 1069 is reduced to a level close to that obtained with misonidazole, the action remaining unaltered at the lower temperature. This temperature dependent component of sensitization for RSU 1069 suggests the involvement of a slow biochemical process that has an appreciable activation energy. The RSU 1069 analogue RB 7040 is a more efficient radiosensitizer than RSU 1069 particularly at lower concentrations. This compound has a pKa value of 8.45, in contrast to that of RSU 1069 which is 6.04. Weak bases with pKa values in excess of average intra-cellular pH can be taken up preferentially into cells from medium at pH 7.4. It is shown that RB 7040 has a 4 X higher intracellular concentration than RSU 1069 for a similar extracellular concentration. This will explain, at least in part, the greater sensitizing efficiency of this compound when compared to RSU 1069 in vitro.

Two groups of patients, one under 40 years of age and the other 40 years and over, were divided into subgroups according to whether they had symptoms associated with near vision. A method developed in 'signal detection theory' was used to determine whether a value could be found for heterophoria, or associated heterophoria, which would predict which patients had symptoms due to decompensated heterophoria in normal routine investigation. Receiver operator characteristic curves (ROC curves) were constructed to look for these cut-off values between patients with, and without, symptoms. No value for dissociated heterophoria was found that would discriminate between the symptomatic and asymptomatic patients. It is concluded that heterophoria measurement is not useful as a routine procedure. In the case of associated heterophoria, for the under 40 years age group, patients with a value of 1 prism dioptre or more are more likely to have symptoms than not, and one-third of patients with close work problems have a value of 2 prism dioptres or more. It was rare to find any asymptomatic patient with a value as high as this. In the 40 years and over age group those with an associated heterophoria of 2 prism dioptres or more are more likely to have symptoms than not. One-third of patients in the latter age group, with symptoms, have a value of 3 prism dioptres or more whilst it is rare to find an asymptomatic patient with a value as large as this.

RSU-1069 is one of a group of compounds of particular interest in radiobiology, since it combines the nitroimidazole ring with a side chain bearing a monofunctional alkylating agent. This compound has been shown to be a potent radiosensitizer both in vitro and in vivo. Furthermore, it has recently been shown to be an effective hypoxic cell cytotoxin in vitro. Our studies have been carried out using the SCCVII squamous carcinoma implanted subcutaneously in C3H mice, using a technique we recently developed which facilitates isolation of tumor cell subpopulations from known locations relative to the tumor blood supply. The response of the separated tumor subpopulations was assessed using a soft agar clonogenic assay. For radiosensitization studies, RSU-1069 was administered i.p. at 0.5 mumol/g 20 min before irradiation and the tumors excised 20 min after irradiation. For toxicity studies, tumors were excised 16-18 hr after RSU-1069 administration. The results obtained to date clearly demonstrate that RSU-1069 is an efficient hypoxic cell radiosensitizer and cytotoxin in this murine tumor and has little effect on well perfused (i.e., oxic) cells.

The ability of the evoked potential to predict conventional visual acuity, as measured with a Landolt C test, was investigated for subjects with normal acuities. Both peak-to-trough and Fourier-analysed amplitudes were used. The extrapolation technique assumed curvilinear regression and produced correlations no better than did a method employing amplitude measurements of a single check size of 5.5 min arc (r = 0.67). Assessment of Landolt C acuity by subjective use of the evoked potential stimulus was unable to produce a higher correlation.

A series of nitroimidazoles containing aziridine and alkyl-substituted aziridine functions has been synthesized. The 2-nitroimidazole compounds examined all show greater radiosensitizing efficiency in vitro than misonidazole. The 4- and 5-nitroimidazole analogues are also more efficient than equivalent compounds which do not contain the alkylating aziridine moiety. All the compounds show increased toxicity towards hypoxic cells relative to aerobic cells, but this toxicity is reduced by alkyl-substitution of the aziridine ring. In vivo toxicity can also be reduced by modification of the aziridine function, but such alterations appear to have less effect upon the high radiosensitizing efficiency of these compounds in vivo. As a consequence of this study, compounds of potentially improved therapeutic utility compared to RSU-1069, the first reported member of this class, have been identified.

Two trials ascertained whether feeding fatty acids as preformed calcium soaps would permit normal digestibility of fiber without reducing availabilities of fatty acids or energy. Six diets contained no added fat (control) or the equivalent of 4.5% added fatty acids as tallow or soy fatty acids, tallow or soy calcium soaps, or tallow combined with the nonnutritive carrier verxite. Six cows were fed each diet in trial 1 to ascertain digestibilities of total nutrients, whereas control, tallow fatty acid, and tallow soap diets were fed to steers with duodenal cannulae in trial 2 to evaluate effects of fat source on rumen fermentation. Digestibility of total fiber in trial 1 was reduced 13% by tallow fatty acids. In trial 2, tallow fatty acids markedly reduced digestibility of dry matter and fiber in the rumen. Diets supplemented with tallow calcium soaps had normal digestibilities of fiber in the rumen and totally, but digestibility of fatty acids was reduced 6% and digestibility of energy reduced 3% compared to feeding tallow fatty acids. Efficiency of synthesis of microbial protein was 39% higher for tallow fatty acids than for control. Feeding tallow verxite also permitted normal digestibility of fiber in trial 1 but caused reduced availabilities of fatty acids and energy.(ABSTRACT TRUNCATED AT 250 WORDS)

The records of treatment by the after-image transfer method of 21 children, mainly with strabismus amblyopia, were examined to evaluate the acuity improvement in the short term. There was no significant improvement in 15 cases. In several other patients, an immediate response to the after-image method occurred, but these patients' binocular vision and acuity had deteriorated following previous improvement achieved by other orthoptic methods.

Diets with and without added fat and with different amounts of soluble and insoluble calcium were fed to rumencannulated cows to determine roles of fat and calcium in formation of insoluble calcium soaps in the rumen. Percent of total fatty acids in soap was increased only by addition of soluble calcium (CaCl2). The amount of fatty acid in soap was highly dependent on amount of fat in the rumen and was not changed by calcium addition. Concentration of ionized calcium in rumen content was halved by fat addition and was inversely correlated with rumen pH, whereas proportion of fatty acid in soap was directly related to pH. Rumen pH was lower 8 to 12 h postfeeding when calcium was added to the diet, which was related nonsignificantly with total volatile fatty acid concentration. Addition of fat to diets tended to lower the ratio of acetic to propionic acids in the rumen; this trend was reversed by calcium addition. Beneficial effects of added calcium in high fat diets were not caused by increased calcium soap formation in the rumen.

Fixation disparity has been taken as a sign of stress on binocular vision because it is established that prism stress creates fixation disparity. This paper looks at the effect on fixation disparity of the stress caused by requiring subjects to read in inadequate illumination. It is found that the reduction in illumination does not in itself immediately change the magnitude of the fixation disparity. There is, however, an increase in the mean slope of the central part of the fixation disparity curve which suggests that when the effect of reduced illumination is added to prism stress, fixation disparity is increased. The stress created by asking subjects to read in reduced illumination for half an hour resulted in the mean associated heterophoria being increased, and over half the subjects reported symptoms of stress. It is concluded that fixation disparity is changed by this type of visual stress in some subjects, and in near vision is increased to a more marked degree of exo-disparity. Most of this increase occurs in the first ten minutes.

1. Using unscheduled DNA synthesis as an index, the possible interaction of a number of substituted nitroimidazoles, e.g. misonidazole, with cellular DNA has been investigated. Transformed (JB1), non-transformed (BL8) rat liver epithelial derived cell lines and freshly prepared rat hepatocytes have been used. 2. Under anaerobic or aerobic conditions, relative to cells exposed to a nitroquinoline-N-oxide standard, misonidazole and related nitroimidazoles were very poor at stimulating unscheduled DNA synthesis in JB1 or BL8 cells or in hepatocytes, even at the highest concentrations tested (10 mM). Under anaerobic conditions, metabolic activation did occur as judged from the time-dependent depletion of cellular reduced glutathione in all three cell types. 3. It was concluded that in hypoxic cells an important mode of action of such nitroimidazoles as chemotherapeutic sensitisers may be by their interaction with cellular thiols rather from their interaction with DNA. 4. Functionalisation of the nitroimidazole ring with a side chain containing an aziridine function, e.g. RSU-1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol), results in the induction of unscheduled DNA synthesis in cells exposed under both aerobic and anaerobic conditions. On a molar basis, however, this induction was not so great as that caused by the simple monofunctional alkylating agent 1-aziridineethanol itself. Methyl-substitution of the aziridine ring in RSU-1069 reduced the extent of unscheduled DNA synthesis. 5. With all the compounds tested, unscheduled DNA synthesis was greater in JB1 cells than in BL8s or in hepatocytes.

Rate of gain by final weight response surfaces for gain of empty body water, protein, lipid and ash were defined with data from 62 male Sprague-Dawley rats. Rats were fed for 21 days at 100, 88, 76, 64, 52 or 40% of ad libitum intake within each of five initial weight groups ranging from 84 to 286 g. Forty additional rats were killed at the beginning of the growing period to provide initial estimates of amount and composition of empty body weight. Water in the gain decreased (P less than 0.05) and lipid increased (P less than 0.05) with increasing final weight. Gains of protein and ash were not significantly affected by final weight. Gains of water, protein and lipid increased (P less than 0.05) linearly with increasing rates of gain. The relationship between rate of gain and composition of gain was not affected by different final weights. Averaged across final weight, at all rates of gain each gram of gain was composed of about 66.9% water, 18.8% protein, 10.6% lipid and from 1.0 to 2.5% ash. Thus, each additional unit of gain per unit time was composed of the same amount of water, protein, lipid and about the same amount of ash. Therefore, over the stage of growth examined, these results demonstrate that the rates at which rats grow do not influence the composition of their gain to a particular weight.