Thomas B. Connor

Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye.

Approximately 1 out of every 10 eyes undergoing surgery for retinal detachment develops excessive intraocular fibrosis that can lead to traction retinal detachment and ultimate blindness. This disease process has been termed proliferative vitreoretinopathy (PVR). The ability to monitor and grade this fibrotic response accurately within the eye as well as the ability to aspirate vitreous cavity fluid bathing the fibrotic tissue makes this an ideal setting in which to investigate the development of fibrosis. Although laboratory studies have recently shown that transforming growth factor-beta (TGF-beta) can enhance fibrosis, little clinical evidence is yet available correlating the level of this or other growth factors with the degree of fibrosis in a clinical setting. We have found that vitreous aspirates from eyes with intraocular fibrosis associated with PVR have more than three times the amount of TGF-beta (1,200 +/- 300 pM [SEM]) found in eyes with uncomplicated retinal detachments without intraocular fibrosis (360 +/- 91 pM [SEM]). Using an in vitro assay, 84-100% of the TGF-beta activity could be blocked with specific antibodies against TGF-beta 2, whereas only 10-21% could be blocked by specific antibodies against TGF-beta 1. TGF-beta 1 was used in an animal model of traction retinal detachment. Since beta 1 and beta 2 have essentially identical biologic effects and only human beta 1 was available in quantities required, beta 1 was chosen for these in vivo studies. The injection of TGF-beta1 plus fibronectin (FN) but not TGF-beta1 alone into the vitreous cavity of rabbits resulted in the increased formation of intraocular fibrosis and traction retinal detachments as compared to control eyes. In previous studies, intravitreal FN levels were also found to be elevated in eyes with intraocular fibrosis.

Gene therapy for red–green colour blindness in adult primates

Red–green colour blindness, which results from the absence of either the long- (L) or the middle- (M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here we explore the possibility of curing colour blindness using gene therapy in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that the treatment of congenital vision disorders would be ineffective unless administered to the very young. However, here we show that the addition of a third opsin in adult red–green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.

UNILATERAL RENAL DISEASE AS A CAUSE OF HYPERTENSION: ITS DETECTION BY URETERAL CATHETERIZATION STUDIES

Excerpt It has been amply demonstrated experimentally that renal ischemia can result in hypertension1-3and that, in man, reduced arterial flow toonekidney may produce a clinical picture indistingui...

STUDIES OF ANTIRICKETIC ACTIVITY IN SERA FROM PATIENTS WITH DISORDERS OF CALCIUM METABOLISM AND PRELIMINARY OBSERVATIONS ON THE MODE OF TRANSPORT OF VITAMIN D IN HUMAN SERUM

Proof of the curative action of vitamin D for rickets was established by the studies of many investigators (1, 2). It is now known that therapeutic doses of this vitamin bring about increased calcium absorption from the intestinal tract (3), while massive doses induce hypercalcemia (4) and, experimentally at least, a combination of skeletal resorption and vigorous bone-matrix formation (5-7). Also, in the hypoparathyroid individual, administration of vitamin D results in an increased excretion of phosphorus and usually of calcium (8, 9). Knowledge of the biochemical or enzymatic means by which vitamin D induces the foregoing effects would greatly enhance our understanding of mineral and bone metabolism. An approach to the study of this problem was afforded by the reports of Warkany and his co-workers (10-12) on bioassays of vitamin D in sera of animals and humans. Vitamin D in aqueous solution, however, is known to be readily oxidized and thereby rendered inactive (13). This suggests that the vitamin, as it exists in serum, is in some manner protected and may not be in a free or unaltered state. Therefore, in our initial studies on vitamin

Hypocalcemia Precipitating Congestive Heart Failure

CALCIUM ions have a key role in the excitation as well as the contraction of cardiac muscle fibers.1 2 3 Calcium also influences the renal excretion of sodium.4 , 5 The importance of sodium retenti...

Hypercalcemic Crisis Due to Hyperparathyroidism

Abstract A potentially fatal course characterized by rapidly progressive nausea, vomiting, lethargy and azotemia is occasionally encountered in patients with hyperparathyroidism. Three such patients having these manifestations are reported. In two, recognition was sufficiently prompt, and an emergency removal of a parathyroid adenoma resulted in a successful outcome in each. In the third patient the correct diagnosis was suspected only two hours before death. Similar clinical manifestations occur with marked hypercalcemia of any etiology. Although the pathogenesis of this syndrome is not clearly understood, successful treatment seems dependent on prompt reduction of the high serum calcium concentrations.

Circulating thyroid hormone changes in acute trauma: prognostic implications for clinical outcome.

Alterations in circulating thyroid hormone concentrations occur in a variety of nonthyroidal disease states. In the present study, thyroid hormone levels were measured every 8 to 12 hours in 19 otherwise healthy individuals suffering acute severe trauma necessitating admission to the Maryland Institute for Emergency Medical Services Systems. Four fatalities occurred within 48 hours of admission. The mean total T3 level fell rapidly after the onset of trauma and remained low throughout the observation period. Reverse T3 rose concurrent with the fall in T3 but gradually returned to normal in the survivors. Total and free T4 levels remained normal in the survivors but fell below normal in the fatalities on the samples obtained preceding death. Changes in free T4 were consistent in three separate radioimmunoassay systems. Pharmacologic doses of glucocorticoids administered to seven of the 15 survivors and to the four fatalities did not result in an acute depression in total and free T4 levels in the survivors. Post-mortem examination of three fatalities did not reveal evidence of significant thyroid or pituitary disease. These results suggest that in acutely traumatized patients: 1) T3 declines rapidly and remains depressed throughout the illness; 2) continued fall of T4 to subnormal levels is associated with a poor prognosis; and 3) steroid therapy alone cannot explain the acute changes observed in hormone levels.

Subtenon’s depot corticosteroid injections in patients with a history of corticosteroid-induced intraocular pressure elevation☆

PURPOSE To determine whether a history of intraocular pressure elevation from local corticosteroid administration could predict subsequent intraocular pressure elevation after posterior subtenons corticosteroid injection. METHODS A retrospective review was performed of 64 consecutive patients (64 eyes) receiving posterior subtenons corticosteroid injection. Patients were categorized as either historical corticosteroid responders or nonresponders based on intraocular pressure response to topical corticosteroid drops in the same eye or to previous posterior subtenons corticosteroid injection of the fellow eye. Historical responders were defined as having a relative intraocular pressure increase of 5 mm Hg and absolute intraocular pressure greater than 24 mm Hg with an anatomically open angle. Relative risk of intraocular pressure elevation was evaluated based on historical response and presenting diagnosis. RESULTS Nine eyes were historical responders, and 55 eyes were historical nonresponders. A higher rate of recurrent intraocular pressure elevation developed in historical responder eyes (4 of 9, 44%) compared with nonresponders (7 of 55, 13%) after posterior subtenons injection (P = .04, Fishers test; P = .07, Kaplan-Meier analysis). Historical responders with uveitis were at significantly higher risk of intraocular pressure elevation than nonresponders without uveitis (hazard ratio = 10.8, P = .04, Cox proportional hazards). All but one eye that developed intraocular pressure elevation from posterior subtenons injection was adequately controlled with topical antiglaucoma therapy. CONCLUSION In nonglaucomatous eyes, a previous history of corticosteroid-induced intraocular pressure elevation is a relative, not absolute, contraindication to posterior subtenons corticosteroid injection, because the risk of intraocular pressure elevation is not absolute, and because it can usually be well controlled with topical antiglaucoma therapy.

Relationship Between Foveal Cone Specialization and Pit Morphology in Albinism

PURPOSE Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism. METHODS We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured. RESULTS We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism. CONCLUSIONS Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue.

Diagnostic considerations in hypercalcemia; with a discussion of the various means by which such a state may develop.

DESPITE knowledge that hypercalcemia, regardless of cause, is injurious and potentially lethal, there is wide variation in the diligence with which its presence or absence is determined in patients...