Use of botulinum toxin in small-angle heterotropia and decompensating heterophoria: a review of the literature.

Botulinum toxin has been used extensively in strabismus management. However, less is published regarding its use in small-angled manifest deviations or decompensating heterophorias, where an alternative to surgery is required. The aim of this review is to look at the use and effectiveness of botulinum toxin in managing small-angled manifest deviations, both constant and intermittent, and decompensating heterophorias. These types of strabismus can prove difficult to manage, as the angle present is often too small for surgery to be advised, but it may still cause a cosmetic or symptom-producing problem. A search of the English speaking literature was undertaken using Medline facilities as well as a limited manual search of non-Medline journals and transactions. A brief overview is provided for mechanisms of action, complications and dose effects, and diagnostic and therapeutic uses of botulinum toxin. The main reported complications are those of ptosis, induced vertical deviation and subconjunctival haemorrhage. The higher the dose, the greater the risk of complications. In small-angle strabismus, botulinum toxin is reported as particularly useful in cases of acquired and acute-onset esotropia in aiding maintenance of binocular vision. It is useful for additional management of surgically under- or over-corrected esotropia, particularly for those with potential for binocular vision. Less effect is reported in primary exotropia versus primary esotropia. It is the management of choice for consecutive exotropia, particularly when patients have had previous multiple surgery and where there is a risk for postoperative diplopia. Botulinum toxin has a specific role in decompensated heterophoria, allowing the visual axes a chance to 'lock on' and subsequently maintain binocular vision. Successful outcomes are reported after 1-2 injections only but the results are best in cases of heterophoria with little near-distance angle disparity.

Optical quality of the nasendoscope with and without the endosheath.

With the increasing use of the endosheath in clinical practice, we set out to investigate the quality of the nasendoscope image produced with and without an endosheath. It has been suggested by some users that the endosheath degrades the image. We used a spectrophotometer to assess the optical transmission of the endosheath and found no selective chromatic absorption. However, on requesting nine experienced users to document whether they could differentiate between the sheathed and unsheathed endoscope, a significantly correct answering pattern was obtained in repeated blinded experiments. This suggests that individuals can distinguish between the sheathed and unsheathed nasendoscope view and that the image is indeed altered when an endosheath is employed.

The distribution of cement penetration into bovine acetabular bone utilising various pressurisation techniques.

Most mechanical failures of acetabular fixation within ten years of primary cemented hip replacement are attributable to a failure to achieve good initial fixation of bone and cement. Several studies have suggested that to achieve good fixation between bone and cement between 3 mm and 5 mm of cement penetration into bone is desirable. Whilst several acetabular cement pressurisation systems exist, little is known about the effects of cement pressurisation on the pattern of penetration of cement into cancellous bone within the pelvis. The current paper assesses the penetration of bone cement into bovine acetabular bone by various pressurisation techniques. We found that pressurisation with the use of a swab in glove or the DePuy pressuriser led to improvement in cement penetration both in terms of maximum depth and also percentage cover of the cup by cement (p<0.05). There was no significant difference in mean maximal penetration between the use of the pressuriser and the swab in a glove technique (p=0.3). If only a plain cup was used as a pressuriser, the penetration achieved was significantly lower in comparison to use of a pressuriser (p<0.02). When compared to previously documented acrylic models, the pattern of intrusion noted in the bovine model was different: penetration was lower at the equatorial and base regions of the acetabulum.

The femoral cement mantle in three total hip replacements.

We measured the size and volume of the femoral broaches and stems supplied with three commercial total hip replacement (THR) systems (JRI Furlong, Biomet Stanmore, and Howmedica Exeter). Using an in vitro method, we created cement mantles that could be directly measured. The broaches supplied with the Biomet Stanmore and the Howmedica Exeter systems allowed the creation of significantly thicker cement mantles than the JRI broaches and stems (Stanmore mean thickness = 1.7 mm, defects at 3% of measurement sites; Exeter mean thickness = 2.0 mm, no defects; JRI mantles mean thickness = 0.9 mm, cement defects at 29% of measurement sites). We conclude that, in vivo, the broaches supplied with the Stanmore and Exeter systems are significantly larger than the corresponding stems, and will excavate a cavity large enough to accommodate the appropriate femoral stem surrounded by an intact cement mantle.

Assessment of colour vision as a screening test for sight threatening diabetic retinopathy before loss of vision.

AIM: To assess the effects of sight threatening diabetic retinopathy (STDR) on colour vision and to evaluate automated tritan contrast threshold (TCT) testing for STDR screening before significant visual loss. METHOD: Patients were recruited from a hospital based photographic screening clinic. All subjects underwent best corrected Snellen visual acuity (BCVA) and those with 20/30 vision or worse were excluded. Automated TCT was performed with a computer controlled, cathode ray tube based technique. The system produced a series of sinusoidal, standardised equiluminant chromatic gratings along a tritan confusion axis. Grading of diabetic retinopathy was made by one of the team of experienced ophthalmic registrars (SpR) using slit lamp biomicroscopy and a 78D lens; HbA(1c) and urine albumin were also tested. RESULTS: Patients with STDR had significantly worse TCT despite normal BCVA (p<0.0001). TCT yielded a sensitivity of 100% for detecting diabetic maculopathy and 94% for STDR with a specificity of 95%. Logistic regression analyses showed that TCT (p<0.001) and HbA(1c) (p<0.05) correlated significantly with the presence of STDR but duration of diabetes, urine albumin counts, and BCVA failed to show any significant correlation. No associations between TCT and duration of disease, TCT and HbA(1c), and TCT and urine albumin counts were found. CONCLUSION: Tritan colour vision deficiency was observed in patients with STDR despite their normal BCVA. These results indicate that automated TCT assessment is an effective and clinically viable technique for detecting STDR, particularly diabetic maculopathy, before visual loss.

Production, characterization, and cross-reactivity studies of monoclonal antibodies against the coccidiostat nicarbazin.

A cELISA was developed for the coccidiostat nicarbazin. On the basis of previous computer-assisted molecular modeling studies, p-nitrosuccinanilic acid (PNA-S) was selected as a hapten to produce antibodies to 4,4'-dinitrocarbanilide (DNC), the active component of the coccidiostat nicarbazin. Synthesis is described for the hapten [p-nitro-cis-1,2-cyclohexanedicarboxanilic acid (PNA-C)] used in a BSA conjugate as a plate coating antigen. Monoclonal antibodies (Mabs) were isolated that compete with nicarbazin, having IgM(kappa) isotype. Because of the lack of water solubility of nicarbazin, N,N-dimethylformamide (DMF) (3%, v/v) and acetonitrile (ACN) (10%, v/v) were added to the assay buffer to achieve solubility of nicarbazin and related compounds. The Nic 6 Mabs had an IC(35) value for nicarbazin of 0.92 nmol/mL, with a limit of detection of 0.33 nmol/mL. Nic 6 exhibited high cross-reactivity for PNA-S and PNA-C, and 3-nitrophenol, 4-nitrophenol, and 1-(4-chlorophenyl)-3-(4-nitrophenyl) urea. However, Nic 6 had little or no cross-reactivity with 15 other related compounds.

Chromatic contrast thresholds as a prognostic test for visual improvement after macular hole surgery: color vision and macular hole surgery outcome.

PURPOSE: To evaluate the relationship between preoperative chromatic contrast thresholds, postoperative visual acuities (VA), and visual improvement after macular hole surgery. METHODS: A consecutive series of patients with Stage II to IV macular holes was studied before macular hole surgery. Preoperative chromatic contrast thresholds, VA, and reading acuity were analyzed in relation to the postoperative visual function. The chromatic contrast thresholds were measured using a computerized cathode ray tube-based system along red-green and tritan confusion axes. RESULTS: Preoperative and postoperative chromatic contrast thresholds were elevated significantly in affected eyes (P < 0.001). Preoperative VA showed a strong correlation with postoperative VA (r = 0.66, P < 0.001) but a weak correlation with visual improvement (r = -0.33, P = 0.03). Red-green contrast threshold correlated strongly with both the distance visual improvement (r = -0.77, P < 0.001) and reading visual improvement (r = -0.61, P < 0.001). Tritan contrast threshold, however, showed a slightly weaker correlation (distance: r = -0.63, P < 0.001; reading: r = -0.47, P < 0.005). CONCLUSIONS: These results suggest that chromatic contrast thresholds, especially the red-green contrast threshold, represent a better prognostic guide for visual improvement after macular hole surgery than VA measurement.

Screening for CMV retinitis using chromatic discrimination thresholds and achromatic contrast sensitivity.

BACKGROUND: Many patients with cytomegalovirus retinitis (CMVR) are unaware of visual disturbance so screening is advocated for patients with HIV and low CD4 counts. Many tests of retinal function have been recommended but few are effective at detecting CMVR. We assess the potential of chromatic discrimination thresholds and achromatic contrast sensitivity as screening tests for patients with CMVR. METHOD: 11 HIV+ patients with CMVR, 16 age matched HIV+ patients, and 29 age matched controls were recruited. Visual acuity, chromatic discrimination thresholds, and achromatic contrast sensitivity were measured. Fundal examination was performed by slit lamp biomicroscopy for HIV+ patients. Those with CMVR were photographed and the CMVR graded from the photographs. RESULTS: Loss of chromatic discrimination was found in patients with CMVR (tritan p<0.0005, red/green p<0.05). The same group had deterioration in achromatic contrast sensitivity at 2.2, 3.4, and 10 cpd (p<0.05). There was correlation between the zone of CMVR with chromatic gratings (tritan r=0.83, p<0.005). No statistically significant difference was found between the HIV+ patients and the controls for all tests (p>0.1). CONCLUSIONS: HIV+ patients with CMVR have a loss of chromatic discrimination and achromatic contrast sensitivity and this may be used to screen HIV+ patients for CMVR.

Predictability of mutant sequences. Relationships between mutational mechanisms and mutant specificity.

Spontaneous mutations are rare and are produced by multiple biochemical mechanisms. Nonetheless, studies of these mechanisms have revealed striking examples in which mutational specificity can be regularly related to a characteristic of the surrounding DNA sequence and/or the enzymes participating in mutagenesis. Thus, to an increasing degree the DNA sequences of mutants are "predictable." This report considers some examples of predictable sequence changes, evidence for their contribution to mutagenesis in populations, and how the predictability of mutant sequences may be useful to improve our interpretation of the molecular course of evolution from DNA sequence comparisons.

Primer-template misalignments during leading strand DNA synthesis account for the most frequent spontaneous mutations in a quasipalindromic region in Escherichia coli.

Spontaneous mutant sequences which differ from the starting DNA sequence by the specific correction of quasipalindromic to perfect palindromic sequence are hallmarks of mutagenesis mediated by misalignments directed by palindromic complementarity. The mutant sequences are specifically predicted by templated, but ectopic, DNA polymerization on a misaligned DNA substrate. In a previous study, we characterized a spontaneous frameshift hotspot near a 17 bp quasipalindromic DNA sequence within the mutant chloramphenicol acetyl transferase (CAT) gene of plasmid pJT7. A one base-pair insertion hotspot, ectopically templated by misalignment mediated by palindromic complementarity, was shown to occur more frequently during synthesis of the leading than the lagging DNA strand. Here we analyze the misalignment mechanisms that can account for the DNA sequences of 123 additional spontaneous frameshift mutations (22 distinct genotypes) occurring in the same quasipalindromic DNA region in plasmids pJT7 and p7TJ (a pJT7 derivative with the CAT gene in the inverse orientation). Approximately 80% of the small frameshift mutants in each plasmid are predicted by palindromic misalignments of the leading strand. Smaller numbers of mutations are consistent with other DNA misalignments, including those predicted by simple slippage of the nascent DNA strand on its template. The results show that remarkable changes in the mutation spectra of a reporter gene may not be revealed by measurements of mutation frequency.

The spectrum of acridine resistant mutants of bacteriophage T4 reveals cryptic effects of the tsL141 DNA polymerase allele on spontaneous mutagenesis.

Mutations in the ac gene of bacteriophage T4 confer resistance to acridine-inhibition of phage development. Previous studies had localized the ac gene region; we show that inactivation of T4 Open Reading Frame 52.2 confers the Acr phenotype. Thus, 52.2 is ac. The resistance mechanism is unknown. The ac gene provides a convenient forward mutagenesis assay. Its compact size (156 bp) simplifies mutant sequencing and diverse mutant types are found: base substitutions leading to missense or nonsense codons, in-frame deletions or duplications within the coding sequence, deletion or duplication frameshifts, insertions, complex mutations, and large deletions extending into neighboring sequences. Comparisons of spontaneous mutagenesis between phages bearing the wild-type or tsL141 alleles of DNA polymerase demonstrate that the impact of the mutant polymerase is cryptic when total spontaneous mutant frequencies are compared, but the DNA sequences of the ac mutants reveal a substantial alteration of fidelity by the mutant polymerase. The patterns of base substitution mutagenesis suggest that some site-specific mutation rate effects may reflect hotspots for mutagenesis arising by different mechanisms. A new class of spontaneous duplication mutations, having sequences inconsistent with misaligned pairing models, but consistent with nick-processing errors, has been identified at a hotspot in ac.

Chromatic-contrast threshold impairment in diabetes.

A prospective study was carried out to investigate acquired colour-vision deficits in diabetics using an automated, computer-controlled, cathode-ray-tube based test of chromatic contrast. Chromatic-contrast thresholds estimates were measured along both a red/ green (constant S-cone) confusion axis and a tritan (constant M/L-cone) confusion axis for 305 eyes of 305 diabetics. The diabetic data were partitioned into groups based on a clinical categorisation of retinopathy. The diabetic data were compared with both age-matched and 'lens-equated' control data obtained from a bank of 347 normal subjects. Further analysis of differences between diabetic-status groups was performed. Associations between chromatic contrast threshold estimates and age, duration of disease, and severity of both macular oedema and ischaemia were investigated. The diabetic group was found to have significantly reduced chromatic-contrast threshold estimates when compared with normal controls, even in the absence of retinopathy. This reduction in chromatic contrast was predominantly tritanopic in nature. Interestingly, no reduction in red/green chromatic-contrast threshold estimate was found in diabetics without retinopathy. The tritan deficit seen in diabetics without retinopathy was strongly correlated with duration of disease, but when adjustments were made to account for the effects of duration-dependent lens yellowing, the tritan deficit was no longer apparent. A correlation between both the severity of macular oedema and severity of ischaemia with chromatic-contrast loss was established. Acquired reductions in both red/green and tritan chromatic-contrast threshold estimates seen in diabetics are strongly correlated with the severity of retinopathy. The results provide evidence that the specific tritan deficits seen in diabetics can be explained by the effects of lens yellowing rather than by selective damage of the blue cone system as has been hypothesised by other groups. The results provide support for the potential use of automated CRT-based tests of colour vision in diabetic retinopathy screening protocols.

Colour vision in diabetic and normal pseudophakes is worse than expected.

Automated colour vision testing in pseudophakes showed unexpected results. Chromatic discrimination sensitivity was measured in 22 diabetic pseudophakes with no retinopathy, 23 diabetic pseudophakes with background retinopathy and 34 non-diabetic pseudophakes. These results were compared with those in age-matched normal and diabetic phakic subjects, all of whom had good vision. The diabetics were also matched for retinopathy grading and duration of diabetes. In all three groups, red-green discrimination sensitivity was worse in the pseudophakes when compared with the corresponding phakic subjects (normals, p < 0.001; no retinopathy, p = 0.467; background retinopathy, p = 0.057). However, tritan vision was marginally worse in the normal pseudophake group but was better in the two diabetic pseudophake groups, when compared with phakic controls. This may be due to a reduction in tritan sensitivity in age-matched phakic controls from the effects of increased lens yellowing with age.

DNA nick processing by exonuclease and polymerase activities of bacteriophage T4 DNA polymerase accounts for acridine-induced mutation specificities in T4.

Acridine-induced frameshift mutagenesis in bacteriophage T4 has been shown to be dependent on T4 topoisomerase. In the absence of a functional T4 topoisomerase, in vivo acridine-induced mutagenesis is reduced to background levels. Further, the in vivo sites of acridine-induced deletions and duplications correlate precisely with in vitro sites of acridine-induced T4 topoisomerase cleavage. These correlations suggest that acridine-induced discontinuities introduced by topoisomerase could be processed into frameshift mutations. The induced mutations at these sites have a specific arrangement about the cleavage site. Deletions occur adjacent to the 3' end and duplications occur adjacent to the 5' end of the cleaved bond. It was proposed that at the nick, deletions could be produced by the 3'-->5' removal of bases by DNA polymerase-associated exonuclease and duplications could be produced by the 5'-->3' templated addition of bases. We have tested in vivo for T4 DNA polymerase involvement in nick processing, using T4 phage having DNA polymerases with altered ratios of exonuclease to polymerase activities. We predicted that the ratios of the deletion to duplication mutations induced by acridines in these polymerase mutant strains would reflect the altered exonuclease/polymerase ratios of the mutant T4 DNA polymerases. The results support this prediction, confirming that the two activities of the T4 DNA polymerase contribute to mutagenesis. The experiments show that the influence of T4 DNA polymerase in acridine-induced mutation specificities is due to its processing of acridine-induced 3'-hydroxyl ends to generate deletions and duplications by a mechanism that does not involve DNA slippage.

Automated achromatic contrast and chromatic discrimination sensitivity testing in dysthyroid optic neuropathy.

Our experience of patients with dysthyroid eye disease shows that normal chromatic discrimination sensitivity precludes the diagnosis of optic nerve compression (31 patients), and that clinically confirmed optic nerve compression is invariably associated with decreased chromatic discrimination sensitivity thresholds (8 patients). Dysthyroid patients enrolled in this study underwent automated achromatic contrast and chromatic discrimination sensitivity testing on presentation, with repeat assessment of those patients suspected of developing optic nerve compression. If chromatic discrimination sensitivity was decreased, patients were followed up more frequently. If abnormal chromatic discrimination sensitivity was accompanied by a relative afferent pupillary defect (RAPD) or decreased Snellen visual activity (VA), then optic nerve decompression was performed. The automated chromatic discrimination sensitivity test described represents a quick, reproducible and cheap clinical test which we feel is of value in assessing patients with dysthyroid eye disease. We suggest that sequential chromatic discrimination sensitivity assessment is a sensitive and effective way of monitoring patients at risk of dysthyroid optic neuropathy.

Prospective analysis of uncemented and hybrid primary porous coated anatomic total hip arthroplasties in a community setting.

One hundred thirty-four consecutive primary total hip arthroplasties, with 100 uncemented and 34 hybrid cemented femoral components, were performed in 119 patients in a community hospital setting, and the patients were followed for between 2 and 4 years. Two-year followup mean Harris hip ratings were 88 for the hybrid group and 90 for the porous coated group. The pain score was 43 for both groups. The incidence of thigh pain was 9% at 1 year, 6% at 2 years, and 5% at 3 years in the porous coated group; none of the pain was disabling. A persistent limp was noted in 19% of patients: 18% of the porous coated group and 22% of the hybrid group. Limp was believed to be related to the number of prior hip surgeries, preoperative leg length discrepancy greater than 2.7 cm, and comorbid musculoskeletal diseases, and not to utilization of the modified direct lateral approach. Radiographic zonal analysis revealed that 99 of the porous coated femoral components had a stable implant fixation with bone ingrowth; one component was stabilized by fibrous ingrowth. The average femoral size used was two sizes larger than those used elsewhere, when the same prosthesis was used during the same time interval. These results obtained in a community hospital setting using either modern cemented or porous-coated insertion techniques are similar to those achieved in major medical centers.

Automated tritan discrimination sensitivity: a new clinical technique for the effective screening of severe diabetic retinopathy.

We have developed and extensively assessed an automated chromatic discrimination test which can be used to screen effectively a diabetic population for sight threatening diabetic eye disease. Equiluminant, sinusoidal, low spatial frequency, chromatic gratings are produced along a tritan confusion axis under computer software control on a high resolution CRT. The correct position of the tritan axis in colour space was calibrated using subjects whilst they were transiently tritanopic. The minimum amplitude about a neutral "grey point" along the tritan confusion axis at which a subject can just distinguish a grating is found using a double staircase reversal algorithm. This measure is taken as the Tritan Discrimination Sensitivity and it is this that we use to flag those diabetics with severe diabetic retinopathy. This computerised tritan discrimination test is quick, non-invasive, easy to operate, inexpensive and reliable. The test-retest reliability coefficient (rho) is 0.92. The tritan discrimination test effectively identifies those diabetics who have or are most at risk of developing severe diabetic retinopathy. The sensitivity of the test for the detection of maculopathy, ischaemic retinopathy (pre-proliferative), and proliferative retinopathy is 97%, 65%, and 93%, respectively. The corrected specificity of the test is 83%. We conclude that the tritan discrimination test has potential for use as a valuable screening tool for the early detection and treatment of severe diabetic retinopathy.

Deletion and duplication sequences induced in CHO cells by teniposide (VM-26), a topoisomerase II targeting drug, can be explained by the processing of DNA nicks produced by the drug-topoisomerase interaction.

Frameshift mutations induced by acridines in bacteriophage T4 have been shown to be due to the ability of these mutagens to cause DNA cleavage by the type II topoisomerase of T4 and the subsequent processing of the 3' ends at DNA nicks by DNA polymerase or its associated 3' exonuclease followed by ligation of the processed end to the original 5' end. An analysis of the ability of nick-processing models is presented here to test the ability of nick processing to account for the DNA sequences of duplications and deletions induced in the aprt gene of CHO cells by teniposide (VM-26) [Han et al. (1993) J. Mol. Biol., 229, 52]. Although teniposide is not an acridine, it induces topoisomerase II-mediated DNA cutting in aprt sequences in vitro and mutagenesis in vivo. Although the previous study noted a correlation between mutation sites and nearby DNA discontinuities induced by the enzyme in vitro, neither the nick-processing model responsible for T4 mutations, nor double-strand break models alone were able to account for most of the mutant sequences. Thus, no single model explained the correlation between teniposide-induced DNA cleavage and mutagenic specificity. This report describes an expanded analysis of the ways that nick-processing models might be related to mutagenesis and demonstrates that a modified nick-processing model provides a biochemical rationale for the mutant specificities. The successful nick-processing model proposes that either 3' ends at nicks are elongated by DNA polymerase and/or that 5' ends of nicks are subject to nuclease activity; 3'-nuclease activity is not implicated. The mutagenesis model for nick-processing of teniposide-induced nicks in CHO cells when compared to the mechanism of nick-processing in bacteriophage T4 at acridine-induced nicks provides a framework for considering whether the differences may be due to cell-specific modes of DNA processing and/or due to the precise characteristics of topoisomerase-DNA intermediates created by teniposide or acridine that lead to mutagenesis.

DNA sequence effects on single base deletions arising during DNA polymerization in vitro by Escherichia coli Klenow fragment polymerase.

Most single base deletions detected after DNA polymerization in vitro directed by either Escherichia coli DNA polymerase I or its Klenow fragment are opposite Pu in the template. The most frequent mutations were previously found to be associated with the consensus template context 5'-PyTPu-3'. In this study, the predictive power of the consensus sequence on single base deletion frequencies was directly tested by parallel comparison of mutations arising in four related DNAs differing by a single base. G, a deletion hotspot within the template context 5'-TTGA-3', was substituted by each of the 3 other bases. Previous studies had shown that deletions opposite the G were frequent but that deletions opposite its neighboring A were never detected. Based on the predictions of the consensus, the substitution of T for G should produce frequent deletions opposite the neighboring A due to its new 5'-TTTA-3' template context. This prediction was fulfilled; no deletions of this A were detected in the other templates. The consensus further predicted that deletions opposite template C would be lower than those opposite either A or G at the same site and this prediction was also fulfilled. The C substitution also produced a new hotspot for 1 bp deletions 14 bp away. The new hotspot depends on quasi-palindromic misalignment of the newly synthesized DNA strand during polymerization; accurate, but ectopically templated synthesis is responsible for this mutagenesis. Mutations templated by quasi-palindromic misalignments have previously been recognized when they produced complex sequence changes; here we show that this mechanism can produce frequent single base deletions. The unique stimulation of misalignment mutagenesis by the C substitution in the template is consistent with the singular ability of C at that site to contribute to extended complementary pairing during the DNA misalignment that precedes mutagenesis.