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Biomedical subjects

R Silverman

Publications and source records attributed to R Silverman.

At least 19 recordsLinked to original sources
PubMed2002

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.

Adenine Nucleotides↗
PubMed2001

Small bowel perforation from a migrated biliary stent.

Stenting of the biliary tract is performed for a variety of benign and malignant disorders. Although uncommon, proximal and distal migration of these stents is known to occur. We report a case of jejunal perforation from a distally migrated biliary stent.

Biliary Tract Surgical Procedures↗
PubMed2001

The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Adolescent↗
PubMed2001

Elevated concentration of intraocular cortisol obtained by sequential parabulbar injection in rabbit model.

BACKGROUND: Parabulbar injections of corticosteroids yield a high intraocular concentration, but the half-life is short. We determined the concentration of cortisol that might be obtained by sequential parabulbar infusions of hydrocortisone. MATERIALS AND METHODS: Single parabulbar injections of hydrocortisone sodium succinate were made in a rabbit model and the time of maximum concentration and half-life determined in the retina-choroid, vitreous, serum, and the tissues of the paired eye by radio-immune assay. Based upon the half-life, sequential injections were made at 3 hour intervals to obtain a steady concentration. RESULTS: The maximum concentration of cortisol in the ocular tissues occurred two hours after a single injection and was 98 times greater in the choroid-retina and 72 times greater in the optic nerve than in the paired eye and the serum. The half-life of cortisol was 15 minutes. Elevated levels could be sustained by sequential injections at 3 hour intervals. CONCLUSION: Sequential injections of hydrocortisone through a retained parabulbar catheter could make it possible to titrate and maintain a therapeutic level of cortisol in the eyes of patients with posterior uveitis or optic neuritis.

Animals↗
PubMed2001

Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome.

BACKGROUND: Tacrolimus is a macrolide immunosuppressant approved in oral and intravenous formulations for primary immunosuppression in liver and kidney transplantation. Topical 0.1% tacrolimus ointment has recently been shown to be effective in atopic dermatitis for children as young as 2 years of age, with minimal systemic absorption. We describe 3 patients treated with topical 0.1% tacrolimus who developed significant systemic absorption. OBSERVATION: Three patients previously diagnosed as having Netherton syndrome were treated at different centers with 0.1% tacrolimus ointment twice daily. Two patients showed dramatic improvement. All patients were found to have tacrolimus blood levels within or above the established therapeutic trough range for oral tacrolimus in organ transplant recipients. None of these patients developed signs or symptoms of toxic effects of tacrolimus. CONCLUSIONS: Patients with Netherton syndrome have a skin barrier dysfunction that puts them at risk for increased percutaneous absorption. The Food and Drug Administration recently approved 0.1% tacrolimus ointment for the treatment of atopic dermatitis. Children with Netherton syndrome may be misdiagnosed as having atopic dermatitis. These children are at risk for marked systemic absorption and associated toxic effects. If topical tacrolimus is used in this setting, monitoring of serum tacrolimus levels is essential.

Administration, Cutaneous↗
PubMed2000

Internal sphincterotomy is superior to topical nitroglycerin in the treatment of chronic anal fissure: results of a randomized, controlled trial by the Canadian Colorectal Surgical Trials Group.

PURPOSE: This was a multicenter, randomized, controlled trial to compare the effectiveness of topical nitroglycerin with internal sphincterotomy in the treatment of chronic anal fissure. METHODS: Patients with symptomatic chronic anal fissures were randomly assigned to 0.25 percent nitroglycerin tid or internal sphincterotomy. Both groups received stool softeners and fiber supplements and were assessed at six weeks and six months. RESULTS: Ninety patients were accrued, but 8 were excluded from the analysis because they refused internal sphincterotomy after randomization (6), the fissure healed before surgery (1), or a fissure was not observed at surgery (1). There were 38 patients in the internal sphincterotomy group (22 males; mean age, 40.3 years) and 44 patients in the nitroglycerin group (15 males; mean age, 38.7 years). At six weeks 34 patients (89.5 percent) in the internal sphincterotomy group compared with 13 patients (29.5 percent) in the nitroglycerin group had complete healing of the fissure (P = 5x10(-8)). Five of the 13 patients in the nitroglycerin group relapsed, whereas none in the internal sphincterotomy group did. At six months fissures in 35 (92.1 percent) patients in the internal sphincterotomy group compared with 12 (27.2 percent) patients in the nitroglycerin group had healed (P = 3x10(-9)). One (2.6 percent) patient in the internal sphincterotomy group required further surgery for a superficial fistula compared with 20 (45.4 percent) patients in the nitroglycerin group who required an internal sphincterotomy (P = 9x10(-6)). Eleven (28.9 percent) patients in the internal sphincterotomy group developed side effects compared with 37 (84 percent) patients in the nitroglycerin group (P<0.0001). Nine (20.5 percent) patients discontinued the nitroglycerin because of headaches (8) or a severe syncopal attack (1). CONCLUSIONS: Internal sphincterotomy is superior to topical nitroglycerin 0.25 percent in the treatment of chronic anal fissure, with a high rate of healing, few side effects, and low risk of early incontinence. Thus, internal sphincterotomy remains the treatment of choice for chronic anal fissure.

Administration, Topical↗
PubMed2000

Therapeutic drug monitoring of once daily gentamicin in serum and saliva of children.

UNLABELLED: Gentamicin is widely used in paediatric medicine and therapeutic monitoring is mandatory due to the narrow margin of safety. Saliva sampling may be of potential interest, especially in children in whom blood sampling is often difficult. Experience with once daily intravenous administration of aminoglycosides has grown in recent years. Gentamicin levels were measured in serum and saliva of 55 children treated with the drug (5 mg/kg per day), administered intravenously in three different regimens: thrice (n = 19), twice (n = 18), and once daily (n = 18). No correlation was found between serum gentamicin concentrations and saliva levels when the drug was administered twice or thrice daily, however, there was good correlation when the drug was administered once daily (r2 = 0.96, P < 0.0001). CONCLUSION: In children with uncomplicated infections treated with once daily gentamicin, trough concentrations of the drug can be monitored in saliva.

Child↗
PubMed2000

Treatment of acute asthma. A new look at the old and at the new.

beta-Agonists remain the mainstay of therapy for acute asthma and, for most patients, standard doses are acceptable. Although the onset of action of systemic steroids is still not clear, steroids promote recovery and should be given to patients with acute illness. Intravenous magnesium sulfate appears to improve pulmonary function in the most severely ill patients but is not useful in patients with more moderate episodes. Ipratropium bromide is a weak bronchodilator that still needs to be tested as an adjunct to standard treatment regimens before its role in adults with asthma can be determined; given its ease of use and favorable safety profile it could be considered for patients with more severe acute illness. Aminophylline has not been found by most studies to improve outcomes and the narrow therapeutic range and unfavorable safety profile relegate it to a last-line agent or no use at all. Helium-oxygen mixtures currently have no role in moderately ill patients but have a theoretical advantage as a temporizing measure in severely ill patients. Drugs used in the management of chronic asthma, such as inhaled steroids and leukotriene-modifying agents, are making their way into the acute treatment arena, and other newly developed specific mediator inhibitors or blockers deserve attention. The use of isomers of beta-agonists is another area that is attracting attention and study. Systemic steroids are used to prevent relapse after emergency department discharge and the addition of other agents such as leukotriene-modifying agents or inhaled steroids may further prevent the need for urgent visits or hospitalization. The search for optimal treatment strategies for acutely ill patients is challenging and exciting and, with more attention and resources being devoted to this area, newer treatments will be found that will eventually have a greater impact on the high morbidity associated with acute asthma.

Adrenergic beta-Agonists↗
PubMed2000

The mode selection trial (MOST) in sinus node dysfunction: design, rationale, and baseline characteristics of the first 1000 patients.

BACKGROUND: More than 200,000 permanent pacemakers will be implanted in the United States in 2000 at a cost of more than $2 billion. Sick sinus syndrome (SSS) will likely account for approximately half of all cases necessitating implantation. Pacemaker technology permits the selection of ventricular (single-chamber) or dual-chamber devices. However, clinical and outcomes data are inadequate to support a clear recommendation that one or the other type of device be used. METHODS: The Mode Selection Trial (MOST) is a single-blind study supported by the National Heart, Lung, and Blood Institute designed to enroll 2000 patients with SSS. All patients will receive a DDDR pacemaker programmed to VVIR or DDDR before implantation. The average time of follow-up will be 3 years. MOST has a >90% power to detect a 25% reduction in the primary end point-nonfatal stroke or total (all cause) mortality-in the DDDR-treated group. Secondary end points will include health-related quality of life and cost effectiveness, atrial fibrillation, and development of pacemaker syndrome. Prespecified subgroups for analysis will include women and the elderly. Enrollment was completed in October 1999, with a total of 2010 patients. RESULTS: The median age of the first 1000 enrolled patients is 74 years, with 25% of patients 80 years or older. Women comprise 49%, and 17% are nonwhite, predominantly black (13%). Before pacemaker implantation, 22% of patients reported a history of congestive heart failure, 11% coronary angioplasty, and 25% coronary bypass surgery. Supraventricular tachycardia including atrial fibrillation was present in 53% of patients. A prior stroke was reported by 12%. Antiarrhythmic therapy was in use in 18% of patients. CONCLUSIONS: MOST will fill the clinical need for carefully designed prospective studies to define the benefits of dual-chamber versus single-chamber ventricular pacing in patients with SSS. The MOST population is typical of the overall pacemaker population in the United States. Thus the final results of MOST should be clinically generalizable.

Aged↗
PubMed2000

Heterotopic pregnancy presenting as an acute abdomen: a diagnostic masquerader.

Simultaneous intrauterine and extrauterine pregnancy is called heterotopic pregnancy. It is a rare complication of pregnancy, especially in the absence of predisposing factors. It is known to present with a variety of symptoms and signs often leading to a delay in establishing the correct diagnosis. We report the case of a 29-year-old woman, known to be 14 weeks pregnant, presenting with acute abdominal pain. The confirmation of a viable intrauterine pregnancy led to a general surgery consultation. A heterotopic ruptured right ectopic tubal pregnancy was found. Right salpingectomy was performed. The patient recovered uneventfully. The intrauterine pregnancy was not affected. This case illustrates the variable presentation of heterotopic pregnancy and the need for general surgeons to be suspicious of pregnancy related complications, even in the presence of a viable intrauterine pregnancy.

Abdomen, Acute↗
PubMed1999

En passant synaptic varicosities form directly from growth cones by transient cessation of growth cone advance but not of actin-based motility.

Formation of terminal synapses at sites such as the neuromuscular junction involves transformation of the motile growth cone into the nonmotile synaptic terminal. However, transformation does not need to be the mechanism when a neurite forms multiple widely spaced synaptic varicosities along a target in an en passant configuration. Synaptic varicosities could form here by specialization of the neurite after the growth cone has advanced past the site. We examined this issue by using cocultures of identified sensory (SN) and motor (L7) neurons from Aplysia. Living SNs were labeled with fluorescent dye and their neurites were observed at high resolution every few minutes growing along the axon of L7, allowing a fine-grained analysis of the behavior of the growth cone at the sites of synapse formation. All varicosities whose formation was observed indeed developed from the growth cone. Sensory varicosities were shown by electron microscopy to contain features characteristic of active zones for transmitter release within a day of their formation on the motor axon. Growth cone advance slowed or stopped transiently during varicosity formation, but the motile activity of the peripheral region of the growth cone (veils and filopodia) was maintained. These results suggest that target "stop signals" involved in the formation of synapses, at least of the en passant variety, may be of a different type from the growth inhibitory molecules, such as the collapsins, which guide axons to their targets.

Actins↗
PubMed1999

Contemporaneous positron emission tomography and MR imaging at 1.5 T.

Simultaneous acquisition of positron emission tomography (PET) and magnetic resonance (MR) images using an MR-compatible PET system will obviate the need for image registration and will allow unique studies of structure and function of living organisms in one setting. Here we report on simultaneous acquisition of PET and MR images on a clinical 1.5 T system using a 54 mm diameter prototype MR-compatible PET system (McPET). Phantom experiments were performed in order to determine the effect of the McPET system on MR images. The results demonstrated the system to be fully MR compatible, in both its detector head construction and operation. The McPET construction offers a promising method for design of a large-scale MR-compatible PET system that will be useful in functional studies of the brain.

Artifacts↗
PubMed1999

Intravitreal gas injection diminishes hyaluronic acid.

OBJECTIVES: To determine if compression of the vitreous by an intraocular gas bubble diminishes the concentration of hyaluronic acid (NaHA). MATERIALS AND METHODS: Eighteen albino rabbits had air, xenon or perfluoroethane (C2F6) injected into the vitreous to displace 12.5% to 90% of the vitreous volume. After the gas was absorbed, the vitreous was analyzed for NaHA by the Carbazole method (1, 13). RESULTS: A 90% displacement diminished the NaHA concentration by 18.6%. Lesser displacements caused a lesser loss, but the differences are not significant. CONCLUSION: Intraocular gas injections, both large and small, reduce the concentration of NaHA and destabilize the vitreous structure.

Air↗
PubMed1999

Internal fixation of phalangeal fractures using titanium miniplates.

Although widely utilized in the treatment of metacarpal fractures, plate fixation in phalangeal fractures remains controversial. Increased potential for infection, breakage, and added soft-tissue trauma leading to increased joint stiffness have been cited as important negative factors. A retrospective analysis of titanium plate fixation of phalangeal fractures over a 7-year period is presented. From 1991 to 1998, 16 fractures (13 men, 3 women; age range, 19-70 years) were managed with plate fixation using the Profyle titanium plating system as the primary modality of treatment. All plates were seated dorsally using an extensor tendon-splitting approach. The average follow-up period after surgery was 5 months (range, 3-28 months). Fracture patterns varied: 31% (5 of 16) were open fractures and 69% (11 of 16) were closed. Complications occurred in 25% of patients (4 of 16) and consisted of pain or other trigger that required removal of hardware, flexion contracture at the proximal interphalangeal joint, and extensor lag. There were no instances of hardware failure, infection, or malunion. The quality of recovery of joint motion was assessed using the Total Active Flexion Scale: nine digits were graded excellent, another six were categorized as good, and only one digit was judged as poor. A review of the current literature is presented along with suggested guidelines for the application of miniplate fixation for fractures of the phalanges.

Adult↗
PubMed1998

Research fundamentals: II. Choosing and defining a research question.

This is the second in a series of articles developed by members of the SAEM Research Committee to describe a stepwise approach to the research process. This series is aimed at junior academic emergency physicians (EPs), as well as nonacademic EPs with an interest in the research process. This article describes the development of a testable research hypothesis. While a multitude of sources provide interesting questions for consideration, choosing and refining the research question, so that it can be tested adequately and answered completely, are difficult tasks.

Emergency Medicine↗