An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I.

The insulin-like growth factors IGF-I and IGF-II circulate in blood bound to carrier proteins. The higher molecular mass IGF-binding protein complex (150 kDa) is composed of subunits, and one subunit that forms this complex is growth hormone dependent. In addition, many cell types and tissues secrete another form of IGF binding protein that is not growth hormone dependent. Both forms of the IGF binding protein are believed to inactivate the IGFs and to function as delivery systems to tissues. This conclusion was based on studies that determined the effects of impure preparations of these binding proteins or that examined the effect of these proteins only on the insulin-like actions of the IGFs. We report here that a pure preparation of the extracellular form of the IGF binding protein (purified from human amniotic fluid) markedly potentiated replication of several cell types in response to human IGF-I. Secondary cultures of human, mouse, and chicken embryo fibroblasts as well as porcine aortic smooth muscle cells showed marked enhancement of their DNA synthesis response (2.8- to 4.4-fold increases) to IGF-I in the presence of this protein. These responses were synergistic since the sum of the responses to either IGF-I or to the binding protein alone was between 8 and 17% of the increase obtained in cultures exposed to both peptides. The binding protein not only potentiated the DNA synthesis response but also enhanced the increase in cell number in response to IGF-I. This stimulation is specific for growth factors that bind to the binding protein since incubation with insulin, which binds to the type I IGF receptor but not to the binding protein, did not result in potentiation of this response. We conclude that a form of IGF binding protein that is present in extracellular fluids and is secreted by many types of cells can markedly potentiate the cellular response to IGF-I.     

Effect of lisinopril on renal tissue damage in unilateral ureteral obstruction in rats

In this study, it was aimed to investigate apoptosis in renal injury and the effect of lisinopril in rat model, which constitute unilateral ureteral obstruction. The retroperitoneal ureter was ligated with a 4.0 silk for the experimental model of ureteral obstruction in Wistar albino rats. Untreated group (n = 20) received no treatment. For the lisinopril-treated group (n = 20), 20 mg/kg/day of drug was given orally. Ultrastructural differences were analyzed using electron microscopic technique; apoptotic distribution was analyzed using the TUNEL method. After electron microscopic evaluation, on the 4th and 14th day in the untreated group, edema in the glomeruli, loss of microvillus and apoptotic cells in proximal tubule cells and sclerosis in the glomeruli were detected. On the 4th day in the lisinopril-treated group, the kidney was ultrastructurally normal and a less number of apoptotic cells were only observed on the 14th day. On light microscopic examination on the 4th and 14th day in the untreated group, while the glomeruli were normal in structure, the boundary of the proximal tubule was disrupted and some picnotic cells in both the proximal and collecting tubules were observed. In both 4th and 14th day of the lisinopril-treated group, kidney showed normal structure, although in some places picnotic cells in the collecting tubules were observed. In conclusion, lisinopril was effective and it may prevent early renal damage in the direct obstruction model.     

Cardiac-Targeted Transgenic Mutant Mitochondrial Enzymes: mtDNA Defects, Antiretroviral Toxicity and Cardiomyopathy

Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs ( approximately 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass ( approximately 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.     

Peripapillary and macular choroidal vascularity index in patients with clinically unilateral pseudoexfoliation syndrome

PurposeTo investigate choroidal vascular changes using an image binarization tool in patients with clinically unilateral pseudoexfoliation syndrome (XFS).MethodsThis cross-sectional study included 150 eyes of 100 patients. The eyes were divided into three groups: (1) 50 affected eyes of patients with clinically unilateral XFS; (2) 50 unaffected fellow eyes; and (3) 50 healthy control eyes. Enhanced depth imaging optical coherence tomography scans of the macula and peripapillary regions were acquired. Images were binarized using ImageJ software (National Institutes of Health, Bethesda, MD, USA). The choroidal vascularity index (CVI) was defined as proportion of the luminal area to the total circumscribed choroidal area.ResultsHorizontal and vertical scans revealed that the macular CVI values of the affected eyes (60.08 ± 2.06 and 62.21 ± 2.10, respectively) were lower compared with control eyes (67.31 ± 2.24; p = 0.001 and 68.11 ± 2.36; p < 0.001, respectively). Conversely, no significant difference in the macular CVI was found between unaffected fellow and control eyes (p = 0.094 and p = 0.120, respectively). The mean peripapillary CVI values of the temporal (58.73 ± 3.15), superior (59.84 ± 3.09), and inferior (56.94 ± 2.47) sectors were significantly lower in affected eyes compared to control eyes (63.21 ± 3.00, 62.07 ± 3.05, and 60.78 ± 2.88, respectively; p < 0.05 for all). In addition, the unaffected fellow eyes had significantly lower CVI values in the temporal (61.42 ± 3.07) and inferior (57.61 ± 2.56) peripapillary sectors compared with the control eyes (p = 0.007 and p = 0.005, respectively).ConclusionsThese findings suggest that XFS is associated with decreased macular and peripapillary choroidal vascularity. Furthermore, the unaffected eyes of patients with unilateral XFS may show vascularity changes in the peripapillary choroid.Subject terms: Eye diseases, Biomarkers     

Corneal biomechanical properties measured by the ocular response analyzer in acromegalic patients

Purpose

To investigate the effect of acromegaly on corneal biomechanical parameters.

Methods

This cross-sectional, comparative clinical study included 34 acromegalic patients and 30 age-matched and sex-matched healthy controls. Corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated and corneal-compensated intraocular pressure (IOPg and IOPcc, respectively) were measured using the Ocular Response Analyzer. Central corneal thickness (CCT) was determined with the ultrasonic pachymeter.

Results

The mean duration of disease for the acromegalic patients was 5.3 years. There was no significant difference between the groups regarding mean CH, CRF, IOPg and IOPcc values. The respective mean values in patients with acromegaly and controls were 10.3?±?2.2 and 9.5?±?1.5 mmHg (p?=?0.13) for CH; 10.5?±?2.4 and 9.7?±?1.7 mmHg (p?=?0.16) for CRF, 16.1?±?3.6 and 15.5?±?2.9 mmHg (p?=?0.49) for IOPg, 16.8?±?3.4 and 17.0?±?2.8 mmHg (p?=?0.82) for IOPcc, and 544.8?±?32.2 and 530.7?±?22.9 μm (p?=?0.05) for CCT. A significant moderate correlation was detected between the duration of acromegaly and IOPg OD (r?=?0.430, p?=?0.01). There was no significant correlation between other ocular parameters and levels of GH and IGF-1 at the time of diagnosis, the status of control, adenoma type, radiotherapy treatment, and drug usage.

Conclusions

In acromegalic patients, the duration of disease was correlated with IOPg OD level. Corneal biomechanical parameters and CCT values were not significantly different than those in age-matched and sex-matched healthy individuals.     

Relationship between central corneal thickness and parameters of optic nerve head topography in healthy subjects

PURPOSE: To investigate the relationship between central corneal thickness (CCT) and topographic parameters of optic nerve head (ONH) in healthy eyes. METHODS: Right eyes of 208 healthy subjects between 40 and 59 years of age with refractive error less than 1 D were enrolled in this cross-sectional study. Ultrasonic pachymeter was used to measure CCT, and the ONH parameters were obtained by using confocal scanning laser ophthalmoscope. Relationship of various topographic parameters to age and sex were also investigated. For statistical analysis Student t test, analysis of variance, Pearson and Spearman test, and partial correlation coefficients were used. RESULTS: Mean CCT of subjects was 540.71+/-35.53 micronm (462-621 micronm), and the mean disc area was 2.37+/- 0.44 mm2 (1.28-3.66 mm2). CCT showed negative correlations to disc area, rim area, rim volume, and retinal nerve fiber layer (RNFL) area. These correlations were found to be stronger in females. Negative correlations were demonstrated between age and the mean cup depth, maximum cup depth, RNFL thickness, and RNFL cross sectional area. Women had lesser rim volumes, but bigger cup to disk (C/D) area and linear C/D ratios compared to those of men. CONCLUSIONS: In addition to its effect in the accuracy of intraocular pressure measurements, CCT has a structural relationship with the ONH in healthy nonglaucomatous eyes. Therefore, its effect on disc area might be especially important to explain the structural strength of the ONH in the pathogenesis of glaucoma.     

A method for determination of the in situ distribution of chromosomal proteins.

A technique has been developed for "staining" cytological preparations by indirect immunofluorescent methods that permits determination of the in situ distribution of chromosomal proteins. The method is particularly oriented to the use of polytene chromosome squashes from Drosophila salivary glands. Control experiments indicate that the fixation methods used allow little or no extraction or rearrangement of the chromosomal proteins. The results obtained demonstrate the specific in vivo chromosomal locations of nonhistone proteins purified from isolated chromatin. The technique is apparently capable of resolution at the level of the chromomere or band, the unit of genetic organization in Drosophila.     

The fourth chromosome of Drosophila melanogaster: interspersed euchromatic and heterochromatic domains

The small fourth chromosome of Drosophila melanogaster (3.5% of the genome) presents a puzzle. Cytological analysis suggests that the bulk of the fourth, including the portion that appears banded in the polytene chromosomes, is heterochromatic; the banded region includes blocks of middle repetitious DNA associated with heterochromatin protein 1 (HP1). However, genetic screens indicate 50-75 genes in this region, a density similar to that in other euchromatic portions of the genome. Using a P element containing an hsp70-white gene and a copy of hsp26 (marked with a fragment of plant DNA designated pt), we have identified domains that allow for full expression of the white marker (R domains), and others that induce a variegating phenotype (V domains). In the former case, the hsp26-pt gene shows an accessibility and heat-shock-inducible activity similar to that seen in euchromatin, whereas in the latter case, accessibility and inducible expression are reduced to levels typical of heterochromatin. Mapping by in situ hybridization and by hybridization of flanking DNA sequences to a collection of cosmid and bacterial artificial chromosome clones shows that the R domains (euchromatin-like) and V domains (heterochromatin-like) are interspersed. Examination of the effect of genetic modifiers on the variegating transgenes shows some differences among these domains. The results suggest that heterochromatic and euchromatic domains are interspersed and closely associated within this 1.2-megabase region of the genome.