BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A.

The breast cancer specific tumour suppressor protein, BRCA1 (refs 1,2), activates transcription when linked with a DNA-binding domain and is a component of the RNA polymerase II (Pol II) holoenzyme. We show here that RNA helicase A (RHA) protein links BRCA1 to the holoenzyme complex. The region of BRCA1 which interacts with RHA and, thus, the holoenzyme complex, corresponds to subregions of the BRCT domain of BRCA1 (ref. 9). This interaction was shown to occur in yeast nuclei, and expression in human cells of a truncated RHA molecule which retains binding to BRCA1 inhibited transcriptional activation mediated by the BRCA1 carboxy terminus. These data are the first to identify a specific protein interaction with the BRCA1 C-terminal domain and are consistent with the model that BRCA1 functions as a transcriptional coactivator.

UME6, a negative regulator of meiosis in Saccharomyces cerevisiae, contains a C-terminal Zn2Cys6 binuclear cluster that binds the URS1 DNA sequence in a zinc-dependent manner.

UME6 is a protein of 836 amino acids from Saccharomyces cerevisiae that acts as a repressor and activator of several early meiotic genes. UME6 contains, near the C-terminus, the amino acid sequence-771C-X2-C-X6-C-X6-C-X2-C-X6-C-, in which the spacings of the six Cys residues are identical to those found in 39 N-terminal Cys-rich DNA binding subdomains of fungal transcription factors. This sequence has been shown in GAL4 and other proteins to form a zinc binuclear cluster. In spite of the different location, the C-rich sequence, cloned and over-produced within the last 111 amino acid residues of UME6, UME6(111), forms a binuclear cluster and exhibits a Zn-dependent binding to the URS1 DNA sequence. The latter, TAGCCGCCGA, is required for the repression or activation of meiosis-specific genes by UME6. UME6(111) contains 1.8 +/- 0.4 mol Zn/mol protein and the Zn can be exchanged for Cd to yield a protein containing 1.9 +/- 0.1 mol Cd/mol protein. At 5 degrees C, 113Cd2UME6(111) shows two 113Cd NMR signals, with chemical shifts of 699 and 689 ppm, similar to those observed for 113Cd2GAL4(149). The magnitude of these chemical shifts suggests that each 113Cd nucleus is coordinated to four -S- ligands, compatible with a 113Cd2 cluster structure in which two thiolates from bridging ligands. The entire UME6 gene has been cloned and overexpressed and binds more tightly to the URS1 sequence than the zinc binuclear cluster domain alone. DNase I footprints of UME6 on URS1-containing DNA show that the protein protects the phosphodiesters of the 5'-CCGCCG-3' region within the URS1 sequence.

The anger recall interview and cardiovascular reactivity in women: an examination of context and experience.

Recent research has focused on the role of hostility as a risk factor for coronary heart disease. Hostility has been linked independently to cardiovascular mortality and, as a component of Type A behavior, to atherogenesis and myocardial infarction; however, the mechanisms by which hostility manifests its effects on the cardiovascular system have not been determined. In addition, hostility has been evaluated as a trait measure, with little emphasis on how anger-provoking episodes may be perceived by individuals. The present study seeks to evaluate the affective experience of hostility, through an anger recall interview, and relate qualities of that experience to one potential mechanism of cardiovascular risk, cardiovascular reactivity. Fifty-eight women, classified by structured interview as Type A or B, participated in an anger recall interview while their heart rate and blood pressure were monitored. Type A women manifested greater systolic reactivity when their anger was in response to frustration of autonomy needs, while Type B women exhibited greater heart rate reactivity in response to frustration of affiliation needs. All women who suppressed anger expression experienced higher pressor responses than women who expressed anger assertively. Future investigations may find the content of an interview as useful as the procedure itself in studies of cardiovascular reactivity.

Family history of hypertension: a psychophysiological analysis.

Family history of hypertension (positive and negative) and gender groups were compared on cardiovascular responses at rest, during stressors and during recovery. Two tasks were employed, mental arithmetic and an anger recall interview. Both levels and reactivity measures of blood pressure, heart rate, cardiac output and total peripheral resistance were included. In addition, participants filled out several questionnaires measuring state feelings during the task and recovery periods, trait anger/hostility and emotions. Both men and women with a positive family history of hypertension exhibited higher tonic levels of blood pressure and heart rate at rest, recovery and during both tasks. They also exhibited greater heart rate reactivity during the mental arithmetic task and greater blood pressure reactivity to both tasks when post-math recovery, but not initial rest, was used as a covariate. Positive family history individuals reported less trust and gregariousness, more depression and aggression, less awareness of somatic responses to the tasks and less effort to relax during the post-task rest periods. Finally, significant correlations were found between low anger expression how anger experience and high anger control and task SBP levels in positive family history individuals.

Iodine-125 plaque radiotherapy of choroidal hemangioma.

BACKGROUND: Circumscribed choroidal hemangioma (CCH) is a benign vascular tumor that is not associated with systemic abnormalities and its pathogenesis is unknown. Most choroidal hemangiomas remain stable in size, and treatment is periodic observation unless complicated by an overlying serous retinal detachment. CASE REPORT: A 43-year-old white man came to our clinic reporting decreased vision in the left eye for 1 year. On funduscopic evaluation, a large elevated nonpigmented red-orange lesion, just temporal to the fovea of the left eye, was observed with surrounding areas of subretinal fluid. On the basis of findings obtained through ophthalmoscopy, fluorescein angiography, and ultrasonography, the patient was diagnosed with a circumscribed choroidal hemangioma. Treatment of the CCH was with iodine-125 plaque radiotherapy, which significantly reduced the tumor size and improved vision. CONCLUSION: CCH is a benign vascular tumor that is characteristically nonprogressive, but in cases of vision loss caused by serous detachment of the fovea, argon laser photocoagulation or radiotherapy is the treatment of choice. Recent studies indicate that iodine-125 plaque radiotherapy is indicated for large choroidal hemangiomas involving the macula or with associated retinal detachment. The main goal of treating CCH is to preserve vision and to prevent the progression of vision loss.

Bilateral occipital lobe stroke with inferior altitudinal defects.

BACKGROUND: Cerebrovascular disease is the most common cause of neurological disability in Western countries. Patients who survive cerebrovascular accidents exclusive to the occipital lobe often have no significant neurological deficits other than visual-field loss. Visual-field defects from occipital lobe stroke typically include congruous homonymous hemianopsias or quadranopsias, with or without macular sparing. CASE REPORT: A 61-year-old white man came to us with symptoms of sudden loss of vision and difficulty reading. Visual-field testing revealed a bilateral inferior altitudinal defect with normal optic nerve and fundus appearance in both eyes. On radiological examination, he was found to have had a bioccipital lobe cerebrovascular accident secondary to complete occlusion of the left vertebral artery. An embolic event causing the artery occlusion, in combination with bilaterally compromised cerebellar and posterior cerebral arteries, presumably caused the bilateral stroke. After appropriate medical and neurological consultation, optometric management consisted of maximizing the patient's remaining vision with a prismatic spectacle correction. DISCUSSION/CONCLUSION: Patients with infarction exclusive to the occipital lobe typically have no other neurological deficits except visual-field loss and are often easier to manage than patients with infarctions to other areas of the cerebral cortex or multiple infarctions. Visual-field loss from occipital lobe damage can be successfully managed with optical systems and/or visual rehabilitation. Factors related to management include location and extent of visual-field damage, functional visual needs, and both personal and health concerns of the patient. A discussion is presented on cerebrovascular disease, occipital lobe infarction, imaging techniques, and visual rehabilitation.

Suprasellar squamous papillary craniopharyngioma: a case report.

BACKGROUND: Craniopharyngiomas are benign neoplasms that are usually suprasellar in origin. They are considered a type of pituitary tumor that can cause hyposecretion of anterior pituitary hormones or hypopituitarism. Clinically, they may cause visual and endocrine deficiencies similar to pituitary adenoma. Histopathologically, they are distinct from pituitary adenoma and are generally classified as either adamantinomatous or squamous papillary. Adamantinomatous tumors are more common in children, whereas the squamous papillary type is found almost exclusively in adults. CASE REPORT: A 45-year-old white man came to our clinic with a history of decreased vision in his left eye for the previous five months that fluctuated. Magnetic resonance imaging of the brain revealed a suprasellar multilobular mass, which was distinguishable from the pituitary gland. The patient underwent a right frontotemporal craniotomy for resection of the tumor. Histopathological analysis showed a benign squamous epithelial-lined mass consistent with squamous papillary craniopharyngioma. CONCLUSION: Craniopharyngiomas are generally considered to be adamantinomatous or squamous papillary in origin. Recently, magnetic resonance imaging has been used to distinguish between these two types of tumors, although clinically no significant difference has been found with respect to resectability. Clinical presentation, treatment options, recurrence, and differential diagnosis of craniopharyngiomas are discussed.

Case presentations of retinal artery occlusions.

BACKGROUND: Retinal artery occlusions typically result in sudden, unilateral painless loss of vision and may have varying presentations. They are associated with systemic diseases such as atherosclerosis, hypertension, and valvular heart disease. Additional risk factors include diabetes mellitus, cigarette smoking, giant-cell arteritis, and hyperlipidemia. They most often occur in persons 60 to 80 years of age. METHODS: Four patients have come to our clinics with varying degrees of visual loss as a result of retinal artery occlusions. The types of arteriolar occlusions presented include: precapillary arteriole occlusion, cilioretinal artery occlusion, branch retinal artery occlusion, and central retinal artery occlusion. RESULTS: Patients were followed for their ocular involvement, but also included was medical management of the underlying systemic disease condition. Workup of retinal artery occlusion included laboratory testing, carotid duplex scans, and echocardiograms to uncover the possible systemic etiologies of the artery occlusion. CONCLUSION: Optometrists should recognize the signs and symptoms of the various arterial obstructions and refer patients for systemic treatment as indicated. Patients who manifest retinal or pre-retinal artery occlusions should undergo thorough systemic evaluations for vascular disease, including: atherosclerotic disease, hypertension, and valvular heart disease.

Mooren's ulcer.

BACKGROUND: Mooren's ulcer is a rapidly progressive, painful, ulcerative keratitis which initially affects the peripheral cornea and may spread circumferentially and then centrally. Mooren's ulcer can only be diagnosed in the absence of an infectious or systemic cause and must be differentiated from other corneal abnormalities, such as Terrien's degeneration. Although the etiology remains unknown, recent research has proposed an underlying immune process and a possible association with the hepatitis C virus. The response to medical and surgical intervention is typically poor, and the visual outcome can be devastating. CASE SERIES: Three patients presented to our clinic with inferior peripheral corneal defects characteristic of Mooren's ulceration. The first patient, a 67-year-old white male, presented with an area of progressive peripheral thinning of the left inferior cornea 1 week after a preoperative skin cleanser was inadvertently splashed in both eyes. This occurred during a surgical procedure to remove a basal cell carcinoma. The second patient, a 56-year-old white male, was treated for a recurrent left inferior corneal ulcer with impending risk of perforation. The third patient was a 68-year-old white male referred for a painful left inferior peripheral ulcer, which rapidly progressed into a bilateral corneal melt disorder. All patients were diagnosed with Mooren's ulcerative keratitis after they underwent extensive medical and laboratory testing to rule out an infectious or systemic cause of their corneal melt. The first patient was treated with oral steroids, as well as doxycycline, to control his acne rosacea. The second patient responded to aggressive treatment with topical steroid therapy. This patient also tested positive for hepatitis C. The third patient rapidly developed a perforated left cornea and was treated with a penetrating keratoplasty after a patch graft had failed. DISCUSSION: Mooren's ulcer is an idiopathic, painful, progressive ulceration of the peripheral cornea. These ulcers usually respond poorly to conventional therapy, as there is limited knowledge of the pathophysiology of the disease. Evidence of an autoimmune component advocates the use of steroids and immunosuppressive agents. With further research and understanding of Mooren's ulcer, better treatment options may be available in the future.

Conformational changes of HIV reverse transcriptase subunits on formation of the heterodimer: correlation with kcat and Km.

The reverse transcriptase (RT) from the human immunodeficiency virus (HIV) is initially expressed as a 66-kDa protein and is subsequently proteolytically processed in vivo to form a 66-kDa/51-kDa heterodimer. Comparison of circular dichroism spectra of the 66-kDa, 51-kDa, and heterodimeric forms of RT indicates that the conversion is accompanied by dramatic changes in subunit conformation. The mean residue ellipticity per subunit at 220 nm decreases from -10.7 x 10(3) deg cm2 dmol-1 for the 66-kDa protein to -6 x 10(3) deg cm2 dmol-1 for the heterodimer. The same loss of ellipticity is observed whether the heterodimer is produced by proteolysis or by mixing a separately-expressed cloned 51-kDa subunit with the 66-kDa protein. Comparison with the spectrum of the cloned 51-kDa protein suggests that much of the conformational change arises from formation of the 51-kDa subunit but substantial changes occur in the remaining 66-kDa subunit as well. A kinetic analysis was performed to correlate these conformational changes with changes in enzyme function. Application of an integrated Michaelis-Menten equation to the catalysis of poly(dT) formation using a d(pT)20-poly(rA) primer-template shows that the kcat for the heterodimer is approximately half that of the 66 kDa enzyme, decreasing from 2.9 to 1.2 nucleotides/s upon formation of the heterodimer. However, km values for the primer-template decrease from 0.54 to 0.12 microM upon heterodimer formation. Thus, kcat/Km is 2-fold larger for the heterodimer, giving it a distinct catalytic advantage at undersaturating concentrations of enzyme and primer-template.(ABSTRACT TRUNCATED AT 250 WORDS)

Relapsing polychondritis.

BACKGROUND: Relapsing polychondritis (RPC) is a rare, chronic, and potentially fatal multisystemic inflammatory disorder targeting cartilaginous structures. This disorder is frequently associated with rheumatoid arthritis, systemic vasculitis, connective tissue diseases, and/or hematologic disorders. RPC afflicts patients with recurrent and often progressive episodes of inflammation with the potential for destruction of the affected structures. Tissues involved include the ears, joints, nose, larynx, trachea, eyes, heart valves, kidneys,and skin. Ocular manifestations commonly include episcleritis, scleritis, conjunctivitis, iridocyclitis, chorioretinitis, and proptosis. Lid edema, orbital inflammation, muscle palsies, and corneal melting may also occur. CASE REPORT: An 83-year-old man previously diagnosed with RPC presented to our clinic with acute unilateral chemosis, conjunctivitis, lid edema, proptosis, and extraocular muscle restriction. After orbital cellulitis was ruled out, further evaluation revealed posterior scleritis with choroidal detachment OS. A course of oral indomethacin and topical antibiotic-steroid combination drops was implemented in the treatment of the ocular manifestations. The quick positive response to the anti-inflammatory agents confirmed the diagnosis of ocular complications secondary to RPC. DISCUSSION: The presenting ocular signs and symptoms of RPC often resemble other commonly encountered ocular conditions. It is important for the eye care practitioner to be familiar with the ocular manifestations of RPC because the eyes are sometimes the initial site of involvement and may be a marker of severity. Early diagnosis and intervention may significantly improve the patient's outcome. This case report with literature review will hopefully bring to light features of this disease which will help the eye care practitioner in the diagnosis and management of this condition.

Orbital fibrous histiocytoma: case report and literature review.

BACKGROUND: Fibrous histiocytomas are a diverse group of soft tissue tumors classified histiologically as benign, locally aggressive, and malignant. These tumors are found throughout the body, but seem to have an affinity for the periorbital area. They account for one percent of all ocular masses and are the most common primary mesenchymal tumor of the orbit. Associated ocular signs and symptoms include decreased visual acuity, proptosis, diplopia, pain, restricted extraocular muscle movement, swelling of the eyelids, and conjunctiva, as well as disk edema. CASE REPORT: A case of a benign orbital fibrous histiocytoma is presented. The patient reported intermittent pain and occasional diplopia; severe edema of the right upper eyelid; and proptosis and inferior vertical displacement of the right globe were observed. Computed tomography revealed a well-defined mass that was subsequently surgically removed and histopathological results from the Armed-Forces Pathology Institute confirmed the diagnosis. CONCLUSIONS: Orbital fibrous histiocytomas are rare periocular tumors that can manifest multiple ocular signs and symptoms. Careful histologic examination is necessary for diagnosis, since these tumors have a wide range of morphology. Differential diagnoses include orbital masses with similar radiologic or histologic findings.

Central serous chorioretinopathy complicated by subsequent occipital lobe infarction and sinusitis in a drug abuser.

BACKGROUND: The presence of multiple occurring, simultaneously complicated clinical findings can be challenging. METHODS: A 39-year-old white male presented initially with central serous chorioretinopathy. Later, the patient reported a great deal of pain over his left eye with nasal vision loss. Comprehensive ophthalmic evaluation and neurologic consultation were invaluable in the diagnosis and management of the patient. RESULTS: Neurologic consultation along with computed tomography (CT) of the head with and without contrast enhancement along with magnetic resonance imaging (MRI) with and without gadolinium revealed lesions in the left occipital lobe, right cerebellum, and left thalamus area. In addition, bilateral maxillary and ethmoidal sinusitis were observed. CONCLUSIONS: Multiple events affecting vision are often related, sometimes not. However, co-existing factors can confound and obscure accurate diagnoses. Careful patient clinical and laboratory investigations are frequently necessary to elucidate correct diagnosis.

Bilateral disc edema in retinitis pigmentosa.

Retinitis pigmentosa (RP), one of the most common forms of hereditary retinal degeneration, is characterized by night blindness and constricted visual fields. In addition to bone spicule pigmentation, other ocular findings may include posterior subcapsular cataracts, cystoid macular edema, and hyaline bodies or drusen of the optic nerve. Rarely, optic nerve head (ONH) edema has been reported to be associated with RP. A 44-year-old white male with RP and neurosensory hearing loss (Usher's syndrome type II) presented to our clinic for routine examination. A dilated fundus examination revealed bone spicule pigmentation, vessel attenuation, several flame hemorrhages on or adjacent to the nerves, and ONH edema in the right eye. B-scan ultrasonography revealed drusen of the right ONH but not of the left. Late stage fluorescein angiography showed hyperfluorescence and dye leakage from both optic discs which was more pronounced in the right eye than the left. Computed tomography (CT) of the head and orbits and cerebrospinal fluid (CSF) examination by lumbar puncture were normal. The differential diagnosis of bilateral ONH edema in this case included ONH drusen or papilledema secondary to increased intracranial pressure. This patient was found to have RP with asymmetric, bilateral ONH edema of unknown cause. One theory regarding the cause of the ONH edema is disc vessel leakage secondary to an inflammatory reaction caused by rapid photoreceptor and retinal pigment epithelium (RPE) degeneration.

Paraocular sinus mucoceles.

BACKGROUND: Patients with paraocular sinus masses may manifest ocular complications, including orbital displacement, proptosis, diplopia, restricted extraocular muscles, decreased vision, chemosis, pain, and optic neuritis. METHODS: Two patients with paraocular sinus masses came to our clinic for examination. One had proptosis and orbital displacement and a chief symptom of increasing diplopia, along with dull brow pain and sudden decreased vision of the left eye. He was diagnosed with polypoid disease and mucoceles of the ethmoidal and frontal sinuses. The second patient experienced pain and swelling under his left eye. He had an upper respiratory tract infection with sinusitis, which in turn increased the size of the sinus cyst. RESULTS: Computed tomography (CT) of the sinuses and orbits was ordered for both patients and confirmed the presence of mucoceles in each case. The first patient's signs and symptoms decreased over 2 weeks, so surgical intervention at that time was not necessary. The second patient was treated with 60-mg pseudoephedrine q.i.d. and 250-mg amoxicillin/potassium clavulanate q.i.d. CONCLUSIONS: Mucoceles are slow-growing polyp-like cysts of the sinuses; these cysts may be sterile in composition or harbor purulent infection (mucopyocele). In either case; they are space-occupying lesions that increase in size as mucus secretions continue, and can be exacerbated by active sinusitis. Differential diagnosis includes thyroid eye disease, orbital pseudotumor, infection, trauma, benign or malignant tumors, encephalocele, or meningiocele.

Circumscribed choroidal hemangioma.

BACKGROUND: Circumscribed or solitary choroidal hemangioma is a relatively rare, benign vascular tumor. Because its appearance may mimic more serious intraocular lesions, eye care practitioners should be familiar with differential diagnosis and treatment options. METHODS: A patient presented with an asymptomatic, elevated, red-orange lesion above the macula in the right eye and a history of longstanding unexplained visual acuity loss in the eye. Intraocular lesions such as amelanotic melanoma, metastatic tumor, choroidal osteoma, disciform scar, serous detachment, and central serous chorioretinopathy can appear similar to circumscribed choroidal hemangioma (CCH) on ophthalmoscopy, but may be differentially diagnosed with fluorescein angiography, ultrasonography, and periodic observation. RESULTS: CCH requires various therapeutic options. Until the patient becomes symptomatic from visual loss secondary to serous macular detachment or subretinal neovascular membrane formation, no treatment is necessary. Laser photocoagulation is the preferred therapeutic intervention, and most patients will require a minimum of two sessions. A small percentage of individuals will progress to complete retinal detachment with profound visual loss regardless of therapy. Most CCHs remain stable in size and do not undergo malignant transformation. CONCLUSIONS: CCHs may be overlooked because of their initial subtle clinical appearance with no associated cutaneous or systemic anomaly. Even though CCH is a benign tumor, it may mimic more serious intraocular lesions and require a combination of ancillary tests for proper diagnosis. Depending on visual symptoms or potential threat to vision, management options include periodic observation, laser photocoagulation, cryotherapy, microwave therapy, and possible enucleation. CCH has little or no growth potential, but visual prognosis remains guarded due to significant secondary retinal changes that can occur over the tumor's surface. CCH must be considered in the differential diagnosis of an elevated intraocular lesion.

Gender differences in patterns of dynamic cardiovascular regulation.

The purpose of this research was to examine the role of gender in hemodynamic response patterns to stress. Sixty-four male and 55 female young adults were administered a protocol of rest, mental arithmetic, video game, and anger recall interview while blood pressure, heart rate, and cardiac impedance measures were obtained. Men had higher levels of systolic blood pressure and cardiac output and greater reactivity to tasks, indexed by increases in cardiac output and diastolic blood pressure. Extreme groups of myocardial and vascular reactors were formed from cardiac output and total peripheral resistance change scores during mental arithmetic. The myocardial reactors exhibited greater sensitivity to task demands, whereas vascular reactors exhibited comparable total peripheral resistance increases to all tasks. Vascular reactors exhibited greater diastolic blood pressure reactivity than myocardial reactors. Future studies should address the predictive validity of these reactor patterns for the subsequent development of coronary heart disease.

The normal optic nerve head.

BACKGROUND: The normal optic nerve head varies from one person to another, and there is often intraindividual variation as well. Factors such as race and age play an important role in distinguishing what may be considered normal variations in optic nerve head appearance. METHODS: A literature search and review of the latest studies on the optic nerve head was conducted. RESULTS: Results of recent studies showed that variations in the average cup-to-disc ratio exist for different races, and with age there is a gradual loss of nerve fibers leading to an overall increase in the cup-to-disc ratio. There is also evidence that congenitally larger optic nerves have larger cup-to-disc ratios and more nerve fibers. Smaller optic nerves, in contrast, have smaller cup-to-disc ratios and fewer nerve fibers. These findings are presented along with sample photographs depicting the normal variations in optic nerve head appearance. CONCLUSION: Over the past 30 years, technology has allowed for changing views about what may be considered normal in reference to the optic nerve head. This information is valuable to the eye care practitioner in helping to make appropriate patient care management decisions.