High mortality in displaced populations of northern Uganda.
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Cause of Death↗
Biomedical subjects
S Lake
Publications and source records attributed to S Lake.
Outcome of ICG-assisted ILM peel in macular hole surgery.
PURPOSE: To investigate whether indocyanine green (ICG) staining of the internal limiting membrane (ILM) improves surgical outcome. METHODS: A total of 34 patients were identified who underwent macular hole surgery with ILM peeling augmented with ICG. These were matched retrospectively with 34 patients who underwent macular hole surgery without the use of ICG. Closure rates from primary and secondary procedures were compared, as were changes in Snellen and Logmar visual acuity. RESULTS: There was no significant difference between the two groups with reference to demographic features of age, sex, staging of the macular holes, and the proportion subsequently undergoing cataract surgery. The mean follow-up period was 7.7 months in the ICG group and 6.3 months in the non-ICG group. Closure rates from primary surgery were 91.2% in the ICG group and 73.5% in the non-ICG group (P = 0.056), whereas overall closure rates following further surgery were similar in both groups (94.1 and 91.2%, respectively). Logmar visual improvement above baseline was achieved in 53% of the non-ICG group compared to 82% of the ICG group (P = 0.01). Where primary hole closure occurred, there was no statistically significant difference in visual outcome between the two groups. CONCLUSION: ICG-assisted ILM peel in macular hole surgery is associated with a higher closure rate following a single surgical procedure. This difference was found to approach statistical significance (P = 0.056). Overall visual improvement was greater in the ICG group (P = 0.01); however, this reflected the higher closure rates. Visual outcomes between the two groups were comparable where primary hole closure occurred.
Aged↗
Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans.
There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.
Adult↗
Normal tension glaucoma is not associated with the common apolipoprotein E gene polymorphisms.
BACKGROUND: /aims: In normal tension glaucoma (NTG) factors other than raised intraocular pressure have a role in the pathogenesis of the optic neuropathy. Because particular apolipoprotein E (ApoE) gene polymorphisms have been associated with cell death and survival in neurological degenerative diseases, the purpose of this study was to determine the ApoE allele frequencies in patients with normal tension glaucoma. METHODS: The apolipoprotein E genotype of 155 patients with normal tension glaucoma was compared to that of 349 non-affected, control subjects from the same geographical area. A similar comparison was made between 53 patients with normal tension glaucoma who demonstrated progressive visual field loss, and control subjects. The frequencies of genotypes was compared with the chi(2) test and Mantel-Haenszel coefficent. RESULTS: There was no significant difference in the frequency of ApoE alleles or genotypes in the normal tension glaucoma population compared to the control group. The ApoE alleles and genotypes in NTG patients with progressive disease were not different from the control group. CONCLUSION: ApoE gene polymorphisms are not linked to normal tension glaucoma, suggesting that this gene does not have a role in the pathogenesis of optic neuropathy in this disease.
Adult↗
Open sky Müller's muscle-conjunctiva resection for ptosis surgery.
PURPOSE: We describe a surgical technique for ptosis correction in moderate to good levator function involving resection of Müller's muscle of the upper eyelid. This is a substantial modification of the technique described by Putterman. We then present our experience of and the results from this method. METHODS: A subtotal resection of Müller's muscle plus underlying conjunctiva is performed under direct visualisation. The muscle stump is reattached to the tarsus and the sutures passed through to the skin crease. In those cases where the phenylephrine test was positive to a level less than the desired lid height, a 1 mm of strip of tarsus is included in the tissue resection. The sutures are removed between 5 days and 3 weeks postoperatively allowing control over lid height and contour. A total of 61 eyes of 48 patients underwent this procedure. RESULTS: Of 61 eyelids, 56 undergoing this procedure were within 0.5 mm of the desired end point, giving a success rate of 92%. Of 61 eyelids, 60 were within 1 mm of the desired height. Preoperative phenylephrine 10% was highly predictive of postoperative lid height (58/61). An excellent lid contour was noted in all cases (61/61). CONCLUSIONS: We present a new approach to ptosis correction using Müller's muscle. It has a high success rate and good cosmetic outcome. It is technically straightforward and easy to learn.
Adolescent↗
Analysis of insulin signaling pathways through comparative genomics. Mapping mechanisms for insulin resistance in type 2 (non-insulin-dependent) diabetes mellitus.
The precise molecular cause of insulin resistance has not yet been elucidated. Resistance to the normal action of insulin contributes to the pathogenesis of a number of common human disorders, including type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, hypertension, and the Metabolic Syndrome X, thus constituting a major public health problem. A disease program aimed at combating this disorder should focus on the identification of targets for therapeutic intervention which may overcome insulin resistance and hence the associated metabolic consequences characteristic of the Metabolic Syndrome. Although the primary defect in the pathogenesis of type 2 diabetes is unknown, genetic and environmental factors are likely to contribute to the manifestation of this progressive metabolic disorder, which is usually not clinically apparent until mid-life. Defects at the level of glucose uptake/phosphorylation characterize insulin resistance in skeletal muscle of type 2 diabetic patients. Identification of putative components of the insulin receptor-signaling pathway may offer insights into mechanisms involved in insulin resistance. Enhanced flux of free fatty acids due to impaired lipid metabolism may contribute to impaired insulin secretion and peripheral insulin resistance. Genes regulating lipolysis are prime candidates for susceptibility towards the metabolic syndrome. Here we describe pathways constituting complex interactions that control glucose homeostasis. We will be considering (1) regulation of glucose uptake by the insulin receptor signaling pathway, and (2) control of adipogenesis and insulin sensitivity by the sterol response element binding protein (SREBP) pathway.
Diabetes Mellitus, Type 2↗
Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans.
AIM/HYPOTHESIS: Insulin receptor substrate (IRS) proteins play important roles in insulin action and pancreatic beta-cell function. At least four mammalian IRS molecules have been identified. Although genes and cDNAs encoding human IRS-1, IRS-2, and IRS-4 have been cloned, IRS-3 has been identified only in rodents. Thus, we have attempted to clone the human IRS-3 gene. METHODS: Insulin-stimulated rat or human adipocytes were subjected to Western blot analysis to assess IRS-3 tyrosine phosphorylation. Human liver and adipose cDNA libraries were screened in an effort to clone IRS-3 cDNA. A PCR-based approach was designed to amplify IRS-3 cDNA. Reverse transcription PCR was carried out using mRNA from adipose tissue, liver, and skeletal muscle as templates in combination with an in silico screen using mouse IRS-1, IRS-2 and IRS-3 in a tblastn search of the draft public human genome. RESULTS: In human adipocytes we did not detect a M(r) 60 000 phosphoprotein corresponding to IRS-3, whereas in rat adipocytes IRS-3 protein and insulin-stimulated tyrosine phosphorylation was readily observed. None of the molecular approaches provided evidence for a functional IRS-3gene in human tissue. Two deletions in human IRS-3 gene were identified using bioinformatics. The human IRS-3 gene product is predicted to lack a phosphotyrosine binding domain and also the sequence corresponding amino acid 353-407 of murine IRS-3. The contiguous sequence of genomic DNA between these two homologous regions does not have the coding information for human IRS-3. CONCLUSION/INTERPRETATION: In silico screening of the human IRS-3 genome region, combined with further biological and molecular validation, provides evidence against a functional IRS-3 in humans.
Adipocytes↗
Strategies for promoting equity: experience with community financing in three African countries.
Although the need for a pro-poor health reform agenda in low and middle income countries is increasingly clear, implementing such policy change is always difficult. This paper seeks to contribute to thinking about how to take forward such an agenda by reflection on the community financing activities of the UNICEF/WHO Bamako Initiative. It presents findings from a three-country study, undertaken in Benin, Kenya and Zambia in 1994/95, which was initiated in order to better understand the nature of the equity impact of community financing activities as well as the factors underlying this impact. The sustained relative affordability gains achieved in Benin emphasise the importance of ensuring that financing change is used as a policy lever for strengthening health service management in support of quality of care improvements. All countries, however, failed in protecting the most poor from the burden of payment, benefiting this group preferentially and ensuring that their views were heard in decision-making. Tackling these problems requires, amongst other things, an appropriate balance between central and local-level decision-making as well as the creation of local decision-making structures which have representation from civil society groups that can voice the needs of the most poor. Leadership, strategy and tactics are also always important in securing any kind of equity gain-such as establishing equity goals to drive implementation. In the experiences examined, the dominance of the goal of financial sustainability contributed to their equity failures. Further research is required to understand what equity goals communities themselves would prefer to guide financing policy.
Benin↗
Twenty-four hour intraocular pressure reduction with latanoprost compared with pilocarpine as third-line therapy in exfoliation glaucoma.
PURPOSE: To compare the 24 hour efficacy of latanoprost 0.005% given every evening with that of pilocarpine 4% given four times daily as third-line therapy in patients with exfoliation glaucoma receiving timolol 0.5% and dorzolamide 2% each given twice daily. METHOD: We enrolled 30 patients with exfoliation glaucoma not adequately controlled on timolol maleate 0.5% and dorzolamide 2%. Each patient underwent a baseline 24 hour intraocular pressure curve testing at 06:00, 10:00, 14:00, 18:00, 22:00 and 02:00 hours. Patients were randomised to receive either latanoprost 0.005% or pilocarpine 4% for a minimum of 8 weeks and were then crossed over to the opposite therapy. Diurnal curve testing was repeated at the end of each treatment. RESULTS: There was a significant decrease from baseline in intraocular pressure at each timepoint for both study medicines (p < 0.016). Latanoprost provided better intraocular pressure control than pilocarpine at daytime measuresments (17.4 vs 19.7 mmHg at 06:00 hours, p < 0.001; 17.8 vs 19.1 mmHg at 10:00 hours, p = 0.04). However, pilocarpine reduced the pressure more than latanoprost at 22:00 hours (18.4 vs 19.5 mmHg, p = 0.016). Overall, the diurnal intraocular pressure was reduced from a baseline of 21.5 +/- 3.7 mmHg to 18.8 +/- 3.1 mmHg on pilocarpine and to 18.0 +/- 3.0 mmHg on latanoprost (p = 0.06). In addition, mean peak pressure was similar between pilocarpine (21.0 +/- 2.9 mmHg) and latanoprost (20.5 +/- 3.8 mmHg) (p = 0.20). Side-effects were similar with the exception of blurred vision, which was only found with pilocarpine (10%). Compliance was more difficult with pilocarpine. CONCLUSION: In exfoliation glaucoma, as a third-line adjunctive therapy added to timolol and dorzolamide, latanoprost and pilocarpine have similar diurnal efficacy. However, latanoprost provides a greater morning pressure reduction.
Aged↗
Latanoprost-induced increase of tyrosinase transcription in iridial melanocytes.
PURPOSE: Latanoprost, the active principle of Xalatan eye drops, has been shown to cause increased iridial pigmentation as a side-effect in some patients. The purpose of the present study was to investigate whether latanoprost affects tyrosinase, the rate limiting enzyme in melanogenesis, at the gene transcription level in the iridial melanocytes. METHODS: Four cynomolgus monkeys were treated unilaterally with 3 or 11 microg latanoprost once daily for 10 days. The contralateral eye received the vehicle only. Tyrosinase mRNA was visualized by in situ hybridization using radio-labelled riboprobes. The transcription of tyrosinase was also studied in vitro using cultivated human iridial melanocytes. Tyrosinase RNA was quantified by Northern blotting. RESULTS: In the monkeys transcription of tyrosinase was found to be increased in iridial melanocytes of the treated eyes compared to the control eyes. Increased transcription of tyrosinase was in addition found in the iridial pigment epithelium and in melanocytes of the anterior choroid. Latanoprost was also found to increase the transcription of tyrosinase in melanocytes isolated from at least one human eye. CONCLUSIONS: Although the tyrosinase enzyme has to undergo complex post-translational modification to become biologically active, which we have not studied, it appears that latanoprost treatment may increase the transcription of the tyrosinase gene in some individuals, consistent with increased melanogenesis in the iridial melanocytes leading to darker eye colour.
Animals↗
Induction of VEGF and VEGF receptors in the spinal cord after mechanical spinal injury and prostaglandin administration.
Vascular endothelial growth factor (VEGF) is an angiogenetic factor that promotes endothelial cell proliferation during development and after injury to various types of tissue, including the central nervous system (CNS). Using immunohistochemical and in situ hybridization methods we have here demonstrated that VEGF and its receptors Flk-1, Flt-1 and Neuropilin-1 mRNAs and proteins are induced after incisions in the rat spinal cord. The inducible enzyme for prostaglandin synthesis cyclooxygenase-2 (COX-2) is known to be upregulated after spinal injury, cerebral ischemia and to stimulate angiogenesis. To test the hypothesis that prostaglandins may be involved in the VEGF response after lesion we investigated whether intraspinal microinjections of prostaglandin F2alpha (PGF2alpha) alters VEGF expression in the spinal cord. Such treatment was followed by a strong upregulation of VEGF mRNA and protein in the injection area. Finally, by use of an in vitro model with cell cultures of meningeal fibroblast and astrocyte origin, resembling the lesion area cellular content after spinal cord injury but devoid of inflammatory cells, we showed that VEGF is expressed in this in vitro model cell system after treatment with PGF2alpha and prostaglandin E2 (PGE2). These data suggest that cells within a lesion area in the spinal cord are capable of expressing VEGF and its receptors in response to mechanical injury and that prostaglandins may induce VEGF expression in such cells, even in the absence of inflammatory cells.
Animals↗
Pneumoperitoneum following Jacuzzi usage.
A 56-year-old woman presented with abdominal pain after using a Jacuzzi hours earlier. Abdominal radiographs revealed intra-peritoneal free gas and, as she presented symptomatically, a laparotomy was performed. This revealed fluid and gas but no visceral perforation or intra-abdominal pathology to account for this. Peritoneal lavage was performed and the patient made an unremarkable recovery. Various causes of pneumoperitoneum have been described in the literature and both conservative and operative treatment recommended. We are unaware of any other reports of Jacuzzi-induced pneumoperitoneum and describe it as an entity to be considered in abdominal pain secondary to the use of similar types of device.
Female↗
Zambia: the role of aid management in sustaining visionary reform.
As part of its ongoing reform of the health sector, Zambia has developed a number of systems and structures to coordinate and manage external resources. With increasing attention being given to the potential for sector-wide approaches (SWAps) to enhance the efficiency and effectiveness of health systems in low-income countries, Zambia provides an interesting case study of how this is emerging in practice over time. The paper outlines the different coordination mechanisms and assesses them in terms of selected criteria of effectiveness, finding that the potential to meet reform objectives is currently not being met. Factors influencing the effectiveness of these mechanisms are identified as falling into categories around personalities and human interaction, the nature of reform processes, and the impact of broader context. The need to maintain dialogue in the face of external constraints and uncertainties is stressed.
Developing Countries↗
Applying performance measurement to a nursing service.
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Efficiency↗
Rapid metabolic responses to prostaglandins in cultured cells expressing the FP-receptor.
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Animals↗
The molecular biology and ocular distribution of prostanoid receptors.
Enormous progress has been made in the characterization of prostanoid receptors during the past five years. Molecular biological studies have enabled structural identification of all the human prostanoid receptors that had been proposed according to pharmacological criteria. The pharmacological classification proposed different receptor subtypes for prostaglandins D2, E2, F2 alpha, I2 and thromboxane A2 which were termed DP, EP, FP, IP and TP, respectively. Further subdivision for only the EP receptor has been reported and EP1, EP2, EP3, and EP4 subtypes have been unequivocally identified. The molecular structure of all prostanoid receptors is typical of that for G protein-coupled receptors and consists of seven alpha-helical transmembrane domains, three extracellular loops and an amino terminus, and three intracellular loops and a carboxyl terminus. Interestingly, mRNA alternative splice variants of the carboxyl termini have been found to determine G protein interactions for the EP3 receptor. Application of molecular biological techniques is beginning to make an impact in ocular research, where precise localization of receptors is difficult by more traditional methods because of the diminutive size of most ocular tissues. In situ hybridization and immunohistochemical studies using antibodies against the cloned human FP receptor have already suggested an unexpectedly wide distribution in the monkey eye. Transgenic studies involving FP receptor knock-out animals may provide future insight into the role of this receptor in glaucoma. However, since prostaglandins are extraordinarily effective in reducing intraocular pressure, it follows that traditional physiological and pharmacological studies retain a key role in glaucoma research. Studies in perfused human anterior segment organ culture have revealed that although prostaglandin F2 alpha does not facilitate trabecular aqueous humor outflow, prostaglandin E1 does increase trabecular outflow. Thus, different prostanoids may lower intraocular pressure by distinctly different mechanisms of action. Recent studies also indicate that prostanoids may exert a beneficial effect on retinal blood perfusion and may even act as neuroprotective agents.
Animals↗
Localization of the prostaglandin F2 alpha receptor in rat tissues.
The localization of the prostaglandin F2alpha (FP) receptor was examined in rat tissues by immunohistochemistry and in situ hybridization. Immunohistochemistry on paraffin sections was performed with a rabbit polyclonal antiserum raised against a synthetic peptide derived from the rat FP receptor sequence. In situ hybridization on cryosections was done with 35S-labelled rat FP receptor antisense and sense riboprobes. The most intense FP receptor-like immunoreactivity was observed in granulosa luteal cells, muscle and epithelial cells, e.g. cardiac, skeletal and smooth muscle, and hepatocytes. Weaker immunoreactivity was found in connective tissue fibroblasts. In the eye, intense immunostaining was associated with the corneal and conjunctival epithelium and moderate staining with the ciliary body, retina, iris and connective tissues. In situ hybridization generally confirmed the results. The riboprobe hybridized weakly with the heart, skeletal muscle, uterus, liver, lung and corpus luteum. Thus, the prostaglandin FP receptor was found to be widely distributed in rat tissues.
Animals↗
Localization of the prostaglandin F2 alpha receptor messenger RNA and protein in the cynomolgus monkey eye.
PURPOSE: To determine the distribution of the prostaglandin F2 alpha (FP) receptor within the monkey eye. METHODS: The expression and localization of the FP receptor was studied by in situ hybridization and immunohistochemistry. Cryosections of the eye were hybridized with a 35S-labeled FP receptor riboprobe, and paraffin sections were immunostained with polyclonal antibodies against an FP receptor peptide. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on cultured cell populations from the eye. RESULTS: Results of the three methods largely correlated with each other. The highest expression of FP receptor mRNA and protein was found in the corneal, conjunctival, and iridial epithelium, the ciliary muscle, and ciliary processes. Iridial and choroidal melanocytes, the retina, and the optic nerve expressed lower levels of both FP receptor message and protein. Using immunohistochemistry, the FP receptor protein was found in connective tissue fibroblasts, the corneal endothelium, and the vasculature; however, FP receptor expression was not detected using in situ hybridization. With RT-PCR, cultured retinal pigment epithelial and ciliary muscle cells from the cynomolgus monkey eye were found to express the FP receptor. CONCLUSIONS: The FP receptor was found to be distributed widely in the ocular tissues, suggesting an array of autocrine and paracrine functions of PGF2 alpha in the eye.
Amino Acid Sequence↗