Screening of the gene encoding the alpha'-subunit of cone cGMP-PDE in patients with retinal degenerations.

PURPOSE: To screen the exons of the gene encoding the alpha'-subunit of cone cyclic guanosine monophosphate (cGMP>phosphodiesterase (PDE6C) for mutations in a group of 456 unrelated patients with various forms of inherited retinal disease, including cone dystrophy, cone-rod dystrophy, macular dystrophy, and simplex/multiplex and autosomal recessive retinitis pigmentosa. METHODS: The 22 exons of the PDE6C gene were screened for mutations either by denaturing gradient gel electrophoresis and single-strand conformation polymorphism electrophoresis (SSCP) or by SSCP alone; variants were sequenced directly. RESULTS: Although many sequence variants were found, none could be associated with disease. CONCLUSIONS: The results show that PDE6C was not the site of the amutations responsible for the types of inherited retinal degenerations analyzed in the large population of patients 'in the present study. The types of degeneration included those that predominantly affect cone-mediated function (cone and cone-rod dystrophies) or rod-mediated function (retinitis pigmentosa) or that have a predilection for disease in the macula (macular dystrophies).     

Symptomatic compression of the optic nerve by the carotid artery: clinical profile of 18 patients with 24 affected eyes identified by magnetic resonance imaging.

OBJECTIVE: To characterize the clinical features and course of patients with magnetic resonance imaging (MRI)-defined optic nerve compression by the supraclinoid carotid artery. DESIGN: Retrospective, observational case series. PARTICIPANTS: Eighteen patients with 24 affected eyes were identified by reviewing case records from the author's referral-based neuro-ophthalmology practice. Predetermined inclusion and exclusion criteria were applied to potential participants. MAIN OUTCOME MEASURES: The following variables were abstracted from the medical record: age, gender, presenting symptoms, past medical problems, visual acuity, color vision, visual field, pupillary reactions, optic disc appearance, other neurologic signs, and previously documented and follow-up examinations. RESULTS: There were eight women and ten men ranging in age from 28 to 86 years (median age, 72 years) at the time of diagnosis. Ten (56%) of 18 patients had hypertension. Twelve patients had unilateral optic neuropathy, whereas 6 patients had bilateral optic neuropathy. One patient presented with subacute superior orbital fissure syndrome due to mass effect of a dolichoectatic carotid artery. Another patient had oculomotor nerve palsy with signs of aberrant regeneration due to intracavernous mass effect of a dolichoectatic carotid artery. One patient had a bitemporal hemianopia associated with bilateral compression of the immediate prechiasmatic optic nerves by dolichoectatic carotid arteries. The predominant pattern of visual field loss in most patients reflected nerve fiber bundle injury. A central scotoma or absolute central visual field loss was noted in only 6 (25%) of 24 affected eyes. Most patients demonstrated saucerlike excavation of the optic disc. Progression of visual acuity loss occurred at a relatively slow rate. CONCLUSIONS: Although uncommon, intracranial compression of the optic nerve by the carotid artery should be considered in a patient with unexplained or progressive unilateral or bilateral optic neuropathy. This entity can be diagnosed using clinical skills to exclude more common causes of optic nerve injury and coronal-oriented MRI to confirm anatomic compression of the symptomatic optic nerve. Although many affected patients have excavation of the optic disc and nerve fiber bundle visual field defects, most have additional signs atypical for glaucoma, minimizing the potential for diagnostic confusion between the two disorders.     

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A1 receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A1 receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25-100 microg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75-200 microg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A receptors appear to be involved.     

Emergency medicine at the Mount Sinai School of Medicine

Emergency medicine became the twenty-third specialty by the American Board of Medical Examiners in 1979. Emergency physicians are specialists in the stabilization and resuscitation of medical and surgical emergencies in patients of all ages; they are experts in triage and in prioritization of resources. Emergency physicians provide the "safety net" for the American health care system, and they are the facilitators between the community and health care systems, and between primary care physicians and specialists. The emergency department is an ideal environment in which to teach the assessment and management of patients presenting with undifferentiated processes. Emergency physicians possess a unique set of clinical and research skills that have made them valuable members of the medical school academic community. Presented is a historical perspective on the specialty of emergency medicine and its evolving role at the Mount Sinai School of Medicine. Included are discussions on innovations in teaching developed by the emergency medicine faculty, including applications of computer-assisted instruction and the Internet.     

Epidural and intravenous bolus morphine for postoperative analgesia in infants

Purpose

To compare two doses of bolus epidural morphine with bolus iv morphine for postoperative pain after abdominal or genitourinary surgery in infants.

Methods

Eighteen infants were randomly assigned to bolus epidural morphine (0.025 mg · kg^?1 or 0.050 mg · kg^?1) or bolus iv morphine (0.050–0.150 mg · kg^?1). Postoperative pain was assessed and analgesia provided, using a modified infant pain scale. Monitoring included continuous ECG, pulse oximetry, impedance and nasal thermistor pneumography. The CO₂ response curves and serum morphine concentrations were measured postoperatively.

Results

Postoperative analgesia was provided within five minutes by all treatment methods. Epidural groups required fewer morphine doses (3.8 ± 0.8 for low dose [LE], 3.5 ± 0.8 for high dose epidural [HE] vs. 6.7 ± 1.6 for iv, P < 0.05) and less total morphine (0.11 ± 0.04 mg · kg^?1 for LE, 0.16 ± 0.04 for HE vs 0.67 ± 0.34 for iv, P < 0.05) on POD1 Dose changes were necessary in all groups for satisfactory pain scores. Pruritus, apnoea, and haemoglobin desaturation occurred in all groups. CO₂ response curve slopes, similar preoperatively (range 36–41 ml · min^?1 · mmHg ETco ₂ ^?1 · kg^?1) were generally depressed (range, 16–27 ml · min^?1 · mmHg ETco ₂ ^?1 · kg^?1) on POD1. Serum morphine concentrations, negligible in LE (<2 ng · ml^?1), were similar in the HE and iv groups (peak 8.5 ± 12.5 and 8.6 ± 2.4 ng · ml^?1, respectively).

Conclusion

Epidural and iv morphine provide infants effective postoperative analgesia, although side effects are common. Epidural morphine gives satisfactory analgesia with fewer doses (less total morphine); epidural morphine 0.025 mg · kg^?1 is appropriate initially. Infants receiving epidural or iv morphine analgesia postoperatively need close observation in hospital with continuous pulse oximetry.     

Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.

We have studied the influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. In a double-blind, placebo-controlled trial of immunotherapy in 40 adult hay fever sufferers, clinical improvement was accompanied by a decrease in the size of the late-phase skin response. When the immunotherapy-treated group was compared with the placebo group, analysis of skin biopsies obtained 24 h after intradermal allergen revealed a significant reduction in the number of infiltrating CD3+ (P = 0.04) and CD4+ (P = 0.009) cells and a trend for a decrease in EG2+ eosinophils (P = 0.08). Treatment did not influence allergen-induced recruitment of CD8+ cells, neutrophils, or macrophages. Unexpected increases in expression of CD25 (P = 0.006) and HLA-DR (P = 0.007) were observed in the actively treated group. In situ hybridization using a panel of riboprobes demonstrated "TH2-type" (IL-4, IL-5) cytokine mRNA responses in both groups of patients. In contrast, significant hybridization for IL-2 (8/16 patients, P = 0.02) and for interferon-gamma (6/16 patients, P = 0.04) was observed only in the actively treated group. These findings indicate that immunotherapy is associated with suppression of allergen-induced CD4+ T lymphocyte infiltration, but among the cells that are recruited, there is upregulation of CD25 and HLA-DR. At least in this model, immunotherapy does not appear to affect expression of TH2-pattern cytokines in response to allergen exposure, but expression of mRNA for Th1-type cytokines was enhanced in half of the patients. The results support the view that immunotherapy may possibly be working through induction of T cell tolerance.     

Neuroaxonal dystrophy in HTLV-1-associated myelopathy/tropical spastic paraparesis: neuropathologic and neuroimmunologic correlations

Summary Detailed neuropathologic and immunohistologic analysis of a case of serologically and polymerase chain reaction-confirmed human immunodeficiency virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is reported in a 73-year-old North American black woman. In addition to the usual neuropathologic features of HAM/TSP, including tractal degeneration of the spinal cord, leptomeningeal and perivascular fibrosis, perivascular demyelination and chronic inflammation, neuroaxonal spheroids were prominent in the spinal cord. Neuroaxonal dystrophy was characterized by neurofilamentous masses that were immunoreactive for phosphorylated neurofilament epitopes, but not ubiquitin. Neuroimmunologic analysis of the inflammatory reaction revealed a prevalence of CD8⁺ T cells and class I major histocompatibility molecules (MHC) (HLA-ABC and 2-microglobulin), but very few CD4⁺ T cells. Microglia were highly reactive for class II MHC (HLA-DR) and this was attributed to activation, rather than CD4 interaction, since CD4 presence was minimal. Inflammatory cytokine immunoreactivity was also detected in glia. It is concluded that the cumulative effects of cytotoxic T cell (CD8) infiltration and the possible involvement of cytokines were responsible for the unusual degree of neuroaxonal dystrophy and vascular fibrosis, as well as the observed demyelination in this case.Supported in part by grants NS 07098, NS 08952, NS 11920 and MH 47667 from the NIH; and RG 1001-G-7 from the National Multiple Sclerosis Society.     

Medical malpractice in California: recent trends and future prospects

For many years, California court decisions and legislation have often presaged national trends. The expected debate over medical malpractice should be no exception. Thus, the court decisions on third party liability and the outcome of the MICRA negotiations are important both for California and as a harbinger of future national trends.     

Clinical experience with intraurethral alprostadil (MUSE) in the treatment of men with erectile dysfunction. A retrospective study. Medicated urethral system for erection

OBJECTIVE: The Food and Drug Administration (USA) approved the transurethral administration of prostaglandin (alprostadil in January 1997), which had an efficacy of approximately 50% in clinical trials. We studied its effectiveness in clinical practice. METHODS: Patient and partner education was followed by an initial office trial of a medicated urethral system for erection (MUSE) after other medical risk factors were corrected during a 2- to 4-month period. The initial titration dose of alprostadil was usually 125 or 250 microg. Further titration, if needed, was instituted by the patient at home. Success was determined as the satisfactory completion of sexual intercourse in more than 66% of attempts, with a minimum of two being required. RESULTS: Two hundred and seventy patients entered the trials, and follow-up information was available in 229 (85%). The overall success rate was 56%. The dose required was 500 microg in 49.2% and 1,000 microg in 42.2%. Of the 44% in whom treatment failed, 61.4% did so because of lack of efficacy and 38.6% because of side effects (genital pain or urethral bleeding). Minor urogenital symptoms, which did not interfere with treatment, occurred in an additional 40% of patients. CONCLUSIONS: The efficacy of transurethral administration of alprostadil (56%) is higher than the initial published clinical trial data and higher than recent reported clinical experiences, although higher doses were required in our study. Men over 50 years of age, having an organic cause for erectile dysfunction, had better responses. Patient and partner education is important for successful treatment, and the in-office initial titration is an integral part of this success. Prior correction of medical risk factors may enhance the success rate.