Biomedical subjects
Publications and source records attributed to P M Holland.
The substrate specificities of protein kinases have been found, in many cases, to be determined at least in part by short regions within the substrate known as docking sites. Docking sites are specific and modular, and can dramatically increase the efficiency of phosphorylation.
Stimulation of the high affinity IgE receptor (FC epsilonRI) as well as a variety of stresses induce activation of c-Jun N-terminal protein kinases (JNKs) stress-activated protein kinases in mast cells. At least three distinct signaling pathways leading to JNK activation have been delineated based on the involvements of Bruton's tyrosine kinase (Btk), protein kinase C (PKC), and the JNK-activating cascades composed of multiple protein kinases. The PKC-dependent pathway, which is inhibited by a PKC inhibitor Ro31-8425 and can be activated by PMA, functions as a major route in FC epsilon RI-stimulated mast cells derived from btk gene knockout mice. On the other hand, wild-type mouse-derived mast cells use both PKC-dependent and PKC-independent pathways for JNK activation. A PKC-independent pathway is regulated by Btk and SEK1 via the PAK-->MEKK1-->SEK1-->JNK cascade, and is sensitive to phosphatidylinositol 3-kinase inhibitors, wortmannin and LY-294002, while the PKC-dependent pathway is affected to a lesser extent by both wortmannin treatment and overexpression of wild-type and dominant negative mutant SEK1 proteins. Another PKC-independent pathway involves Btk and MKK7, a recently cloned direct activator of JNK. Among the stresses tested, UV irradiation seems to activate Btk and JNK via the PKC-independent pathways.
Exposure of mammalian cells to stressful stimuli results in activation of the c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinases (SAPKs), a family of protein kinases related to mitogen-activated protein (MAP) kinase. JNK/SAPKs are activated by specific MAP kinase kinases (MKKs), one of which, MKK4/SEK1, has been characterized extensively. In Drosophila, the JNK/SAPK Basket (Bsk) and the MKK Hemipterous (Hep), are important for embryonic development. Loss of function of either gene inhibits dorsal closure, a morphogenetic movement in which the edges of the embryonic ectoderm move together over the amnioserosa. There is evidence that the Rho GTPases Rac and Cdc42 are also required for dorsal closure, suggesting that Rac or Cdc42 may regulate Hep and Bsk. We have identified MKK7, a murine homolog of Hep. MKK7 functionally rescues hep mutant flies. In fibroblasts, MKK7 is activated by stress and by the GTPase Rac1. MKK7 directly phosphorylates and activates JNK/SAPK. Thus, MKK7 is a homolog of hep and functions in a conserved signaling pathway involving JNK/SAPK and the GTPase Rac1.
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The 5'----3' exonuclease activity of the thermostable enzyme Thermus aquaticus DNA polymerase may be employed in a polymerase chain reaction product detection system to generate a specific detectable signal concomitantly with amplification. An oligonucleotide probe, nonextendable at the 3' end, labeled at the 5' end, and designed to hybridize within the target sequence, is introduced into the polymerase chain reaction assay. Annealing of probe to one of the polymerase chain reaction product strands during the course of amplification generates a substrate suitable for exonuclease activity. During amplification, the 5'----3' exonuclease activity of T. aquaticus DNA polymerase degrades the probe into smaller fragments that can be differentiated from undegraded probe. The assay is sensitive and specific and is a significant improvement over more cumbersome detection methods.
Cystoid macular edema typically manifests 4 to 16 weeks after ocular surgery. It has only rarely been documented with an onset more than 2 years postoperatively. We report four patients who developed clinically significant cystoid macular edema between 7 and 16 years after initially successful surgery. Two patients had undergone intracapsular cataract extraction, one extracapsular cataract extraction, and one a scleral buckling procedure. Although such cases of "very late onset" cystoid macular edema are uncommon, it should be considered in patients who suffer visual loss many years after ocular surgery.
A 57-year-old patient underwent a scleral buckle operation for a rhegmatogenous bullous retinal detachment. An episcleral buckle and cryotherapy were used. Drainage of subretinal fluid was performed beneath the buckle as well as posterior to the buckle, close to the posterior pole. The postoperative course was unremarkable. Eight months later, the patient developed a subretinal neovascular membrane at the drain site posterior to the buckle. This was documented by fluorescein angiography. Such membranes have not been previously documented at retinal drain sites in an ophthalmic journal.
A 58-year-old hypertensive male developed a superior temporal branch vein occlusion in the left eye in 1979. Fluorescein angiography documented the venous occlusion, as well as normal arterial flow. Subsequent laser photocoagulation was performed for cystoid macular edema. In 1981 the patient developed a pre- and sub-retinal hemorrhage in the left eye due to a retinal arterial macroaneurysm in the superior temporal quadrant. Fluorescein angiography documented normal retinal arterial blood flow in the affected vessel at the time of development of the macroaneurysm, but the vessel subsequently occluded. This case adds to the scant literature documenting the evolution of a retinal arterial macroaneurysm.
One of us (T.R.S.) operated on 24 patients with 26 retinal detachments caused by giant tears between 1969 and 1975 with the use of a broad silicone implant and diathermy. Minimum follow-up was six months. The technique included a scleral dissection extending at least three circumferential rows of diathermy posterior to the folded edge of the retinal flap, up onto the ora serrata, and two hours of the clock beyond each end of the tear. The retina was intentionally incarcerated on the buckle when subretinal fluid was drained. Sixty-nine percent of the cases were successfully reattached. If those patients with radial tears extending from the circumferential tears to the disk were excluded, the success rate rose to 75%. Seventeen percent of the successful reattachments required a second scleral buckle operation. Giant tears with radial tears extending to the disk, tears greater than 180 degrees, and immobile posteriorly everted flaps were poor prognostic signs. Thirty-five percent of the eyes with giant tears and a detachment had other holes or tears in the retina of that eye.
Two 4-year-old boys, one white and one black, had unilateral extensive myelinization of retinal nerve fibers associated with severe myopia, esotropia, and amblyopia. The finding of unilateral extensive myelinization of the nerve head and retinal fibers in a child may indicate a potentially remediable anisometropic amblyopia.
Since growth hormone has been implicated as a possible etiologic factor in the development of diabetic retinopathy, we examined growth hormone levels in two groups of growth-onset diabetics matched for age and duration of disease. The experimental group had definite proliferative diabetic retinopathy; the control group of growth-onset diabetics had no significant retinopathy. Basal and levodopa-stimulated levels of growth hormone were determined for each group. Growth hormone response could not be correlated with the presence or absence of diabetic retinopathy (P less than .05).
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The results of automated multiphasic health testing (AMHT) were evaluated with special attention to diagnoses made by physicians and to false positive results, as well as to laboratory test results. The study population consisted of 1,157 patients at the Health Evaluation Center of the Public Health Service Hospital in Baltimore. Although 95 percent of the patients had at least one newly diagnosed disease or condition., the percentage dropped to 78 percent when dental abnormalities were excluded and to 70 percent when dental, vision, and hearing abnormalities were excluded. Abnormal laboratory test results were observed for 98 percent of the patients, and 36 percent had at least one false positive test result. The study results indicated that AMHT is a highly productive method for comprehensive medical testing with a variety of uses other than mass screening. The productive diagnostic yield combined witha high percentage of false positive results dictate the need for careful planning for followup care, strict attention to quality control, and excellent communication between the AMHT center and the practicing physician.