Changing trends in postoperative cataract care: impact of electronic patient records in optometrist-delivered shared care.

BACKGROUND: This study evaluates a community optometrist-delivered postoperative care scheme in patients discharged from the hospital ophthalmology department following uncomplicated cataract surgery. AIM: The aim of this study is to assess the efficacy of electronic patient records (EPR) in facilitating co-managed cataract care. METHODS: We performed a retrospective analysis of a prospectively maintained Medisoft EPR database of postoperative cataract review data at a single centre, Sligo University Hospital (SUH), which serves a large and predominantly rural catchment area. All patients undergoing cataract surgery at SUH from October 2012 to September 2013 were included in this study. A total of 39 optometric practices, all with access to the Medisoft EPR software, participated in this pilot co-management scheme. RESULTS: One thousand four hundred and twenty-two cataract surgeries were performed in SUH (55% female, 45% male); 1011 patients (71%) were discharged to the community on the day of cataract surgery. Complete postoperative feedback (i.e. data on refraction, visual acuity and intraocular pressure) was available in 97% of these patients compared to 50% of patients reviewed in the hospital. Patients followed up by optometrists were twice as likely to have complete postoperative clinical details (RR = 1.934, 95% CI: 1.759-2.126, p < 0.0001). Overall, 65% of operations were performed on first eyes. Hospital doctors were more likely to document requirement for second eye surgery compared to community optometrists (RR = 1.434, 95% CI: 1.302-1.580, p < 0.0001). CONCLUSIONS: Optometrists provided an excellent postoperative care service with superior postoperative feedback rates compared to hospital doctors. EPRs facilitate a postoperative shared-care pathway that is of high quality and efficiency with major economic advantages.

Treatment of clinical insulin resistance in children: a systematic review.

The objective of this study was to evaluate the effectiveness of interventions aimed at improving clinical insulin resistance and/or pre-diabetes in children. This study is a systematic review and meta-analysis. Five electronic databases were searched for randomized controlled trials of at least 2-months' duration. The outcomes were fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI) and adverse outcomes. Four randomized controlled trials were identified. All compared the effect of 6 months of metformin plus or minus lifestyle intervention with placebo plus or minus lifestyle intervention. After pooling results from three trials, the mean difference after 6 months favoured the intervention with a statistically significant mean decrease in fasting insulin, HOMA-IR and BMI of 9.6 µU mL(-1) (95% confidence interval [CI]: 6.3, 13.0 µU mL(-1) ; I(2) = 76%), 2.7 (95% CI: 1.7, 3.6; I(2) = 74%) and 1.7 kg m(-2) (95% CI: 1.1, 2.3 kg m(-2) ; I(2) = 75) respectively. Mild gastrointestinal symptoms were reported in 19% (2-29%; median and range) of participants taking metformin. Metformin improves markers of insulin sensitivity and reduces BMI in children and adolescents with clinical insulin resistance or pre-diabetes. Stronger evidence from high-quality studies of longer duration and larger sample size are required before clinical conclusions about the optimal treatment protocol in this population can be drawn.

Autosomal dominant brachydactyly, coloboma and anterior segment dysgenesis.

A three-generation family presenting with ocular developmental abnormalities, including anterior segment dysgenesis and coloboma, associated with brachydactyly and clinodactyly is presented. Several conditions incorporating ocular and bony limb abnormalities have been described. However, we believe that this family manifests a previously undescribed syndrome due to autosomal dominant or possibly x-linked inheritance with variable expression.

Regulation of immunoglobulin G2 production by prostaglandin E(2) and platelet-activating factor.

Patients with localized juvenile periodontitis (LJP) have elevated levels of immunoglobulin G2 (IgG2) in their sera. This is also observed in vitro when peripheral blood leukocytes from LJP patients are stimulated with pokeweed mitogen. In previous studies, we showed that lymphocytes from subjects with no periodontitis (NP subjects) produced substantial amounts of IgG2 when they were cultured with monocytes from LJP patients (LJP monocytes). These observations indicate that monocytes or monocyte-derived mediators are positive regulators of the production of IgG2. The present study was initiated to determine if secreted factors from LJP monocytes were capable of enhancing IgG2 production and to determine if prostaglandin E2 (PGE(2)), which LJP monocytes produce at elevated levels, enhances IgG2 production. Experiments in a transwell system and with monocyte-conditioned media indicated that cell-cell contact was not necessary for LJP monocytes to augment the production of IgG2 by T and B cells from NP subjects. Moreover, the production of IgG2 was selectively induced by the addition of PGE(2) or platelet-activating factor (PAF), another lipid cytokine, which can elevate PGE(2) synthesis. Furthermore, IgG2 production was abrogated when cells were treated with indomethacin, a cyclooxygenase inhibitor that blocks the synthesis of PGE(2), or the PAF antagonists CV3988 and TEPC-15. The effects of indomethacin were completely reversed by PGE(2), indicating that this is the only prostanoid that is essential for the production of IgG2. Similarly, PGE(2) reversed the effects of a PAF antagonist, suggesting that the effects of PAF are mediated through the induction of PGE(2) synthesis. Together, these data indicate that PGE(2) and PAF are essential for the production of IgG2.

Lineage restriction of neuroepithelial precursor cells from fetal human spinal cord.

In the presence of epidermal growth factor (EGF) and/or fibroblast growth factor 2 (FGF2), neuroepithelial precursor cells from dissociated fetal human spinal cord are mitotically active and form free-floating spheres of undifferentiated cells. Proliferating cells were obtained in approximately 40% of preparations with each mitogen, were immunoreactive for the intermediate filament nestin, and did not express neuronal- or glial-specific markers. Early passage neuroepithelial precursor cells were pluripotent and differentiated into neurons expressing MAP2a,b, NF-M, and TuJ1, and GFAP-positive astrocytes; however, oligodendrocytes were never seen. As the cells were passaged from P0 to P4, the percentage of differentiating neurons significantly decreased and the prevalence of astrocytes significantly increased. While the majority of cell populations from individual preparations stopped proliferating between 3 and 6 passages, two expanding cell lines have been successfully expanded in EGF and FGF2 for over 25 passages and have been maintained in culture for over one year. These cells express nestin and not other cell-specific lineage markers. When differentiated, these neuroepithelial cell lines differentiate only into astrocytes, showing no expression of any neuronal marker. These data suggest that continued passage under these conditions preferentially selects for spinal cord neural precursors that are restricted to the astrocytic lineage. Despite the lineage restriction of later passage cell populations, these results provide a rationale for future investigation into the lineage potential of these cells in vivo following transplantation into the adult CNS, potentially as a therapeutic approach for traumatic injury and neurodegenerative disease.

Minor modifications of a cholecystokinin-B/gastrin receptor non-peptide antagonist confer a broad spectrum of functional properties.

The development of non-peptide agonists for peptide hormone receptors would markedly expand the treatment options for a large number of diseases. However, difficulty in identifying non-peptide molecules which possess intrinsic activity has been a major obstacle in achieving this goal. At present, most of the known non-peptide ligands for peptide hormone receptors appear in standard functional assays to be antagonists. Here, we report that a constitutively active mutant of the human cholecystokinin-B/gastrin receptor, Leu325 --> Glu, offers the potential to detect even trace agonist activity of ligands which, at the wild type receptor isoform, appear to lack efficacy. The enhanced functional sensitivity of the mutant receptor enabled us to detect intrinsic activity of L-365,260, an established non-peptide antagonist for the cholecystokinin-B/gastrin receptor. Extending from this observation, we were able to demonstrate that minor structural modifications could convert L-365, 260 into either: (i) an agonist or (ii) an inverse agonist (attenuates ligand-independent signaling). The ability to confer functional activity to small non-peptide ligands suggests that the properties of endogenous peptide hormones can be mimicked, and even extended, by considerably less complex molecules.

The influence of smoking and race on adult periodontitis and serum IgG2 levels.

Smoking is a known risk factor for developing periodontal diseases, but the risk appears to be greater for white smokers than black smokers. Furthermore, it has been reported that young white subjects have significantly lower levels of serum IgG2 than their non-smoking counterparts while young black adult subjects are generally not affected by smoking. These relationships prompted the hypothesis that adult white subjects, including periodontitis subjects, who smoked would have more attachment loss than adult black subjects and that smoking would be associated with lower serum IgG2 levels in adult white subjects but not in adult black subjects. Smoking status was established from serum cotinine levels determined by radioimmunoassay. Serum IgG subclass levels were determined using radial immunodiffusion. White adult periodontitis (AP) and non-periodontitis (NP) subjects who smoked had greater mean attachment loss per site than their non-smoking counterparts. Furthermore, smoking white AP subjects and their age-matched NP controls had substantially less IgG2 in their serum. In marked contrast, we were unable to detect any increase in periodontal destruction or a significant decrease in serum IgG2 levels in smoking black AP subjects or their age-matched controls. However, IgG1 and IgG4 levels were reduced in smoking black AP subjects. IgG3 was the only subclass in adults that was unaffected by smoking. IgG2 can be a good opsonin and may help control periodontitis-associated bacteria in adults. Even though a cause-and-effect relationship has not been established, the association between a smoking-related decrease in serum IgG2 and an increase in periodontal destruction in white subjects is striking.

The effect of smoking on individuals with minimal periodontal destruction.

Recent studies have demonstrated that smoking is associated with periodontal destruction. The majority of these studies have focused on periodontal disease groups with moderate or severe periodontal destruction. Additionally, there have been few reports investigating the relationship between smoking and gingival recession. The goal of this report was to investigate the effect of smoking on periodontal destruction and recession in subjects with minimal or no interproximal attachment loss. This is a cross-sectional study of 142 non-smoking subjects and 51 smoking subjects. Subjects could have no more than one tooth with a site of interproximal attachment loss > or =2 mm. Subjects could, however, have attachment loss associated with recession. For three different methods of summarizing attachment loss measurements at a subject level, including average attachment loss, percentage of teeth with one site of 2 mm of attachment loss, and the percentage of teeth with one site of 5 mm of attachment loss, smoking subjects had approximately twice as much attachment loss than their non-smoking counterparts. Smoking subjects also had significantly greater recession (P < 0.05) [0.056+/-0.017 mm] than non-smoking subjects (0.025+/-0.005 mm). Recession sites occurred primarily on the facial surface of maxillary molars and bicuspids and mandibular central incisors and bicuspids. The results suggest a strong association between smoking and both attachment loss and recession in subjects who have minimal or no periodontal disease.

The effect of smoking on serum IgG2 reactive with Actinobacillus actinomycetemcomitans in early-onset periodontitis patients.

High titers of serum IgG2 reactive with Actinobacillus actinomycetemcomitans are present in early-onset periodontitis (EOP) patients and it appears that anti-A. actinomycetemcomitans may be protective. Smoking is associated with increased periodontal disease severity in generalized early-onset periodontitis (G-EOP) patients, but is not associated with periodontal disease severity in patients with localized juvenile periodontitis (LJP). Furthermore, smoking is associated with reduced serum IgG2 levels in black patients with G-EOP but not in those with LJP. Based on this selective effect of smoking, we hypothesized that smoking would be associated with a reduction of specific IgG2 reactive with A. actinomycetemcomitans in black G-EOP patients but not black LJP patients. In addition, we examined IgG2 responses to carbohydrate antigens from non-periodontal pathogens including Haemophilus influenzae b oligosaccharide antigen (Hib) and the Streptococcus pneumoniae antigen phosphocholine (PC). Smoking status was assessed from serum cotinine levels, and IgG2 specific for A. actinomycetemcomitans, Hib, and PC was assessed by ELISA. Our study revealed that smoking was correlated with a dramatic reduction in serum IgG2 anti-A. actinomycetemcomitans in G-EOP smokers but not in LJP smokers. In contrast, anti-Hib IgG2 and anti-PC IgG2 were not affected in either G-EOP or LJP patients. In short, these results indicate that smoking is associated with a reduction in serum IgG2 anti-A. actinomycetemcomitans in black G-EOP subjects, but IgG2 reactive with other antigens may not be reduced in G-EOP smokers.

Inter- and intraspecies polymorphisms in the cholecystokinin-B/gastrin receptor alter drug efficacy.

The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major target for drug development because of its postulated role in modulating anxiety, memory, and the perception of pain. Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype. These drugs include the peptide-derived compound PD135,158 as well as the nonpeptide benzodiazepine-based ligand, L-740,093 (S enantiomer). We now report that the maximal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among species homologs of the CCK-BR. Further analysis reveals that the observed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective species homologs. This interspecies variability in ligand efficacy introduces the possibility of species differences in receptor-mediated function, an important consideration when selecting animal models for preclinical drug testing. The finding that even single amino acid substitutions can significantly affect drug efficacy prompted us to examine ligand-induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; 288E --> K). When examined using the 288E --> K receptor, the efficacies of both PD135,158 and L-740, 093 (S) were markedly increased compared with values obtained with the wild-type human protein. These observations suggest that functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects.

The effect of race, smoking and immunoglobulin allotypes on IgG subclass concentrations.

In previous studies we have demonstrated that serum IgG subclass concentrations are influenced by both race and periodontal disease diagnosis. Furthermore, we have shown that smoking habits modify the concentrations of some IgG subclasses in specific racial and diagnostic groups. In view of a large amount of data showing strong associations between immunoglobulin allotypes and IgG subclass concentrations we have investigated the effects of race, smoking and IgG allotype on IgG subclass concentration in a population of subjects with or without various forms of periodontitis. The results indicated that there are complex relationships between these factors in their effects on individual IgG subclass levels, and that effects unique to black or white subject groups, or to specific periodontal diagnostic groups and racial subgroups, were evident. In blacks with chronic adult periodontitis IgG1 was lower in smokers, while in generalized early-onset periodontitis patients IgG2 was lower in smokers. IgG4 was independently affected by gender (males higher), smoking (smokers lower) and GM23 (GM23 positive subjects higher), in black subjects only. In white subjects, complex relationships between smoking and allotypic markers were noted but no influence of periodontal diagnosis was found. White GM23 negative subjects who smoked had lower levels of IgG1 than GM23 positive subjects. White GM2 negative subjects who smoked had lower levels of IgG2, than did those who did not smoke. In contrast, smoking had no effect on IgG2 levels in GM2 positive subjects. Thus, in addition to immunoglobulin allotype, smoking is associated with IgG subclass concentrations; furthermore, in black subjects, periodontal diagnosis, gender and smoking all influence IgG subclass concentrations. These results demonstrate that genetic and environmental factors can interact to influence levels of individual subclasses.

Influence of smoking and race on immunoglobulin G subclass concentrations in early-onset periodontitis patients.

Recent data indicate that smoking is an important risk factor for the development of periodontitis. Smoking is also known to reduce serum immunoglobulin G (IgG) levels. Interestingly, patients with the localized form of early-onset periodontitis (LJP) have elevated levels of serum IgG2, and those who smoke are not clinically different from nonsmoking LJ subjects. In contrast, patients with the generalized form of early-onset periodontitis (G-EOP) who smoke have more extensive destruction than their nonsmoking counterparts. Given the effects of smoking on EOP and the association of IgG2 with less severe disease, we hypothesized that smoking might reduce serum IgG2 and that this might be most apparent in G-EOP. We therefore examined the effects of smoking on serum IgG subclass concentrations in race-matched groups: LJP, G-EOP, and age-matched periodontally healthy controls (NPs). Smoking status was established from serum cotinine levels, and serum IgG subclass concentrations were determined by using radial immunodiffusion. The data indicated that the effects of smoking were remarkably selective with respect to both IgG subclass and race. Smoking did not appear to have any effect on the concentration of IgG1 or IgG3 in either black or white subjects. In contrast, smoking was associated with depressed serum IgG2 concentrations in both white NP and G-EOP subgroups. Serum IgG2 levels in black subjects did not appear to be depressed by smoking, with the single striking exception of the black G-EOP subgroup which also had depressed serum IgG4 levels. The results here confirm that smoking has effects on serum immunoglobulin levels, but the effects were both race and serum IgG subclass specific. Furthermore, the periodontal diagnosis of EOP subjects appeared to be important, as indicated by the fact that IgG2 and IgG4 levels were reduced in smoking black G-EOP subjects whereas the IgG2 and IgG4 levels in black LJP and NP subjects were not reduced by smoking.

Hyper-immunoglobulin G2 production by B cells from patients with localized juvenile periodontitis and its regulation by monocytes.

Localized juvenile periodontitis (LJP) runs in families, and a predisposition to develop disease appears to be inherited in an autosomal dominant fashion. Patients with LJP have elevated levels of serum immunoglobulin G2 (IgG2), and this is most striking in black LJP patients. We hypothesized that the markedly elevated serum IgG2 levels related to LJP status and race may be attributable to a fundamental difference in the response of black LJP leukocytes. To test this possibility, leukocytes from black LJP patients, black non-periodontitis (NP) controls, and white NP controls were cultured with a nonspecific mitogen (pokeweed mitogen) which stimulates immunoglobulin production. The levels of IgG2 produced were measured using an enzyme-linked immunosorbent assay. The results revealed that the serum IgG2 level differences among black LJP patients and white and black NP subjects were reproducible in peripheral blood leukocytes in vitro. Analysis revealed that B cells from the LJP patients appeared to be predisposed to produce high levels of IgG2. Further analysis supported the concept that the high IgG2 responses of B cells from black LJP patients were regulated by monocytes. Replacing the monocytes in cultures from white NP subjects with LJP monocytes from black patients resulted in production of IgG2 at levels that were comparable with those produced by the LJP B cells from black patients. In short, B cells from black LJP patients produce elevated levels of IgG2 in vitro, and at least part of this elevation appears to be attributable to regulation via the LJP monocytes.

Genetic segregation analyses of serum IgG2 levels.

Summary : The aim of this study was to determine whether there was evidence for a genetic component in the immune response as measured by IgG2 levels. The study was motivated by our studies of early-onset periodontitis (EOP), a group of disorders characterized by rapid destruction of the supporting tissues of the teeth in otherwise healthy individuals. EOP has two subforms, localized juvenile periodontitis (LJP) and a generalized form (G-EOP). IgG2 levels are elevated in LJP but not G-EOP individuals; and African-American IgG2 levels are higher than Caucasian levels regardless of EOP status. IgG2 levels were determined in 123 EOP families and in 508 unrelated non-EOP control individuals. Segregation analysis under the regressive model approach of Bonney was used to analyze IgG2 levels for evidence of major locus segregation. After adjusting for LJP status, race, sex, and age, the best fitting model was an autosomal codominant major locus model (accounting for approximately 62% of the variance in IgG2), plus residual parent/offspring and spousal correlations. Smoking and GM23 are also known to affect IgG2 levels. If additional adjustments are made for smoking and GM23, the best-fitting model is still a codominant major locus but with no significant residual correlations.

The role of the cholecystokinin-B/gastrin receptor transmembrane domains in determining affinity for subtype-selective ligands.

We have examined the role of transmembrane domain amino acids in conferring subtype-selective ligand affinity to the human cholecystokinin-B (CCK-B)/gastrin receptor. Fifty-eight residues were sequentially replaced by the corresponding amino acids from the pharmacologically distinct CCK-A receptor subtype. 125I-CCK-8 competition binding experiments were performed to compare all mutant CCK-B/gastrin receptor constructs with the wild type control. Affinities for the nonselective agonist, CCK-8, as well as the subtype-selective peptide (gastrin), peptide-derived (PD135,158), and nonpeptide (L365,260) and L364,718) ligands were assessed. All of the mutants retained relatively high affinity for CCK-8, suggesting that the tertiary structure of these receptors was well maintained. Only eight of the amino acid substitutions had a significant effect on subtype selective binding. When compared with the wild type, single point mutations in the CCK-B/gastrin receptor decreased affinity for gastrin, L365,260, and PD135,158 up to 17-,23-, and 61-fold, respectively. In contrast, the affinity for L364,718 increased up to 63-fold. None of the single amino acid substitutions, however, was sufficient to fully account for the subtype selectivity of any tested compound. Rather, CCK-B/gastrin receptor affinity appears to be influenced by multiple residues acting in concert. The 8 pharmacologically important amino acids cluster in the portion of the transmembrane domains adjacent to the cell surface. The spatial orientation of these residues was analyzed with a rhodopsin-based three-dimensional model of G-protein coupled receptor structure (Baldwin, J.M. (1993) EMBO J. 12, 1693-1703). This model predicts that the 8 crucial residues project into a putative ligand pocket, similar to the one which is well established for biogenic amine receptors (Caron, M. G., and Lefkowitz, R.J. (1993) Recent Prog. Horm. Res. 48, 277-290; Strader, C.D., Sigal, I.S., and Dixon, R.A. (1989) Trends Pharmacol. Sci. 10, Dec. Suppl., 26-30).

A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists.

The brain cholecystokinin-B/gastrin receptor (CCK-B/gastrin) has been implicated in mediating anxiety, panic attacks, satiety, and the perception of pain. The canine and human CCK-B/gastrin receptors share 90% amino-acid identity and have similar agonist affinities. These receptors can be selectively blocked by the non-peptide benzodiazepine-based antagonists L365260 (ref. 8) and L364718 (ref. 9); however, the binding of these antagonists to the human and canine receptors differs by up to 20-fold, resulting in a reversal of affinity rank order. Here we report the identification of a single amino acid in the sixth transmembrane domain of the CCK-B/gastrin receptor that corresponds to valine 319 in the human homologue and which is critical in determining the binding affinity for these non-peptide antagonists. We show that it is the variability in the aliphatic side chain of the amino acid in position 319 that confers antagonist specificity. Substitution of valine 319 with a leucine residue decreases the affinity for L365260 20-fold while concomitantly increasing the affinity for L364718. An isoleucine in the same position of the human receptor selectively increases affinity for L364718. Interspecies differences in the aliphatic amino acid occupying this single position selectively affect antagonist affinities without altering the agonist binding profile. We therefore conclude that the residues underlying non-peptide antagonist affinity must differ from those that confer agonist specificity. To our knowledge, these findings are the first example in which a critical antagonist binding determinant for a seven-transmembrane-domain peptide hormone receptor has been identified.

O-linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b.

By transfecting the full-length cDNA for human von Willebrand factor (vWf) into a line of Chinese hamster ovary cells with a defect in carbohydrate metabolism, we have prepared recombinant vWf specifically lacking O-linked carbohydrates. We have compared this under-glycosylated protein to fully glycosylated recombinant vWf with respect to several structural and binding properties. vWf deficient in O-linked glycans was synthesized, assembled into multimers, and secreted in an apparently normal manner and was not prone to degradation in the extracellular milieu. It did not differ from fully glycosylated vWf in ability to bind to heparin or to collagen type I but did interact less well with glycoprotein 1b on formalin-fixed platelets. This decreased interaction was evidenced in both a lessened overall binding to platelets and in diminished capacity to promote platelet agglutination, in the presence of ristocetin. In contrast, no difference was seen in platelet binding in the presence of botrocetin. These data indicate a possible role for O-linked carbohydrates in the vWf-glycoprotein 1b interaction promoted by ristocetin and suggest that abnormalities in carbohydrate modification might contribute to the altered ristocetin-dependent reactivity between vWf and platelets described for some variant forms of von Willebrand disease.