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PubMed2001

Epidemiology and clinical features of HIV-1 associated neuropathies.

Peripheral neuropathy is common in human immunodeficiency virus type-1 (HIV-1) infection. Peripheral neuropathies complicate all stages of the HIV-1 disease and cause considerable morbidity and disability in HIV-1 infected individuals and acquired immunodeficiency syndrome (AIDS) patients. Whereas symptomatic neuropathies occur in approximately 10% to 15% of HIV-1-infected patients overall, pathologic evidence of peripheral nerve involvement is present in virtually all end-stage AIDS patients. There are 6 major clinical types of HIV-associated neuropathies that are regularly seen in large HIV-1 clinics. Distal sensory polyneuropathy (DSP) is the most common among the HIV-1-associated neuropathies. DSP generally occurs in later stages of HIV-1 infection and it follows an indolent and protracted clinical course. The dominant clinical features in DSP include distal pain, paresthesia and numbness in a typical length-dependent fashion with proximal to distal gradient. Whereas toxic neuropathies--secondary to certain antiretroviral agents--are clinically similar to DSP, their temporal relation to neurotoxic medication helps distinguish them from other HIV-1-associated neuropathies. DSP and toxic neuropathy may coexist in a single patient. Acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP) produce global limb weakness. AIDP may occur at seroconversion and it can therefore be the initial manifestation of HIV-1 infection. CIDP generally occurs in the mid to late stages of HIV-1 infection. Progressive polyradiculopathy (PP) occurs in patients with advanced immunodeficiency and is generally caused by the opportunist cytomegalovirus (CMV) infection. Mononeuropathy multiplex (MM) in early stages of HIV-1 infection is immune mediated, whereas in advanced AIDS it is caused by the CMV infection. Finally, subclinical autonomic nervous system involvement is common in all stages of HIV-1 infection. Because HIV-1-associated neuropathies are diverse in their etiology and pathogenesis, a precise clinical diagnosis is required to formulate a rational therapeutic intervention.

HIV Infections↗

PubMed2003

Biomarkers in Barrett's esophagus.

This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.

Adenocarcinoma↗

PubMed1992

A prospective randomized study comparing aspiration only with aspiration and flushing for transvaginal ultrasound-directed oocyte recovery.

OBJECTIVE: To compare aspiration only with aspiration and flushing of ovarian follicles during transvaginal ultrasound (US)-directed oocyte recovery. DESIGN: Prospective randomized study. PATIENTS: One hundred patients who were undergoing an in vitro fertilization (IVF) treatment cycle. INTERVENTIONS: All patients underwent pituitary desensitization before the administration of gonadotropins. Monitoring of ovarian stimulation and the criteria for the administration of human chorionic gonadotropin were similar in both groups. In patients in whom aspiration alone was used, each follicle was aspirated until it was empty. The US probe was then rotated until every drop of follicular fluid had been aspirated before the next follicle was aspirated and the procedure repeated. For patients who had aspiration and flushing, each follicle was aspirated and then flushed up to a maximum of six times before moving to the next follicle. In both groups, all follicles greater than 10 mm were aspirated. RESULTS: The indication for IVF and mean age of the patients were comparable in the two groups. There were no significant differences between the aspiration and the aspiration and flushing groups in terms of the number of oocytes retrieved (11 versus 9), the oocyte recovery rates (77.5% versus 77.0%), the fertilization rates (55.6% versus 60.0%), the number of embryos transferred (2 versus 2), or the number of clinical pregnancies (12 versus 13). The time taken for oocyte recovery was significantly shorter (15 versus 30 minutes, P less than 0.00001), and the dose of pethidine required significantly less (50 mg versus 100 mg, P less than 0.00001) in the aspiration only group. CONCLUSIONS: Aspiration alone produces comparable oocyte recovery rates as aspiration and flushing while significantly reducing the length of the procedure and the dose of analgesia required. Aspiration alone suffices for virtually all cases during transvaginal US-directed oocyte recovery.

Adult↗

PubMed1999

Mental health nursing policy - an exploratory qualitative study of managers' opinions.

During the 1990s, much of the legislation and policy that pertains to mental health services has sought to direct them towards a virtually exclusive concern with the seriously mentally ill, typified by the following recommendation from a recent Department of Health review of mental health nursing that stated: 'The essential focus for the work of mental health nurses lies in working with people with serious or enduring mental illness'. On the other hand, pressure from the primary health care sector suggests the need for services to be provided for the less seriously mentally ill, particularly through the auspices of general practice fundholders. Following a review of the literature, a small-scale, exploratory study was initiated to seek answers to the following research question: How is the policy focus urging reorientation to the severely mentally ill viewed by nurse managers who have a responsibility through Mental Health Resource Centres and Community Mental Health Teams, to provide mental health services? The study was based within a Welsh National Health Service (NHS) Trust that employed six nurse managers of Community Mental Health Teams (CMHTs). Four of the managers additionally had responsibility for Community Mental Health Resource Centres (CMHRCs). Of the population of six managers, four composed the sample for the investigation. A qualitative research approach was employed, utilizing semistructured interviews as the data collection tool. Analysis of the data revealed that managers were finding creative solutions in order to meet the conflicting demands placed upon them. The research findings also indicated that many of the obstacles to providing a needs-led service were structural in origin, and could be resolved by central strategic intervention.

Attitude of Health Personnel↗

PubMedDate not supplied

Prevention of child sexual abuse.

Efforts to prevent child sexual abuse have taken a distinctly different path from efforts to prevent the physical abuse of children. Currently, child sexual abuse prevention is virtually synonymous with group-based instruction for children on personal safety, and it appears that most schools and many after-school programs provide some form of group-based sexual abuse prevention education. Many evaluations have assessed the impact of these efforts. Seventeen studies employing random assignment to treatment and control groups are summarized in Table 1 on page 206, and 21 additional studies using quasi-experimental designs are briefly reviewed in the article text. Most studies conclude that children do learn from the experience, although such learning is neither universal nor comprehensive. Most evaluations measure the child's knowledge but are unable to assess whether a gain in knowledge will lead to a sustained beneficial change in the child's behavior. In an effort to focus on behavior change, child safety programs increasingly utilize role playing and participant modeling. A major benefit of personal safety education programs may be an increased rate of disclosures by children of past or present abuse. A major area of concern may be the potential for safety education programs to engender fear and anxiety in children Research on negative impacts is limited, and results have been mixed. The author concludes that prevention programs overall have beneficial impacts, which are strongest for children 7 to 12 years old. Characteristics of promising programs are summarized. The article concludes with suggestions for expanding prevention efforts to include public and parent education, life skills training for young adults, support groups for vulnerable children and adults, and intervention for identified victims and perpetrators.

Child↗

PubMed2006

Critical care delivery in the United States: distribution of services and compliance with Leapfrog recommendations.

OBJECTIVES: To describe the organization and distribution of intensive care unit (ICU) patients and services in the United States and to determine ICU physician staffing before the publication and dissemination of the Leapfrog Group ICU physician staffing recommendations. DESIGN AND SETTING: Stratified, weighted survey of ICU directors in the United States, performed as part of the Committee on Manpower for the Pulmonary and Critical Care Societies (COMPACCS) study. Using lenient definitions, we defined an ICU as "high intensity" if > or =80% of patients were cared for by a critical care physician (intensivist) and defined an ICU as compliant with Leapfrog if it was both high-intensity and providing some form of in-house physician coverage during all hours. SUBJECTS: Three hundred ninety-three ICU directors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We obtained a 33.5% response rate (393/1,173). We estimated there were 5,980 ICUs in the United States, caring for approximately 55,000 patients per day, with at least one ICU in all acute care hospitals. The predominant reasons for admission were respiratory insufficiency, postoperative care, and heart failure. Most ICUs were combined medical-surgical ICUs (n = 3,865; 65%), were located in nonteaching, community hospitals (n = 4,245; 71%), and were in hospitals of <300 beds (n = 3,710; 62%). One in four ICUs were high-intensity (n = 1,578; 26%), half had no intensivist coverage (n = 3,183; 53%), and the remainder had at least some intensivist presence (n = 1,219; 20%). High-intensity units were more common in larger hospitals (p = .001) and in teaching hospitals (p < .001) and more likely to be surgical (p < .001) or trauma ICUs (p < .001). Few ICUs had any in-house physician coverage outside weekday daylight hours (20% during weekend days, 12% during weeknights, and 10% during weekend nights). Only 4% (n = 255) of all adult ICUs in the United States appeared to meet the full Leapfrog standards (a high-intensity ICU staffing pattern plus dedicated attending coverage during daytime plus dedicated coverage by any physician during nighttime). CONCLUSIONS: ICU services are widely distributed but heterogeneously organized in the United States. Although high-intensity ICUs have been associated previously with improved outcomes, they were infrequent in our study, especially in smaller hospitals, and virtually no ICU met the Leapfrog standards before their dissemination. These findings highlight the considerable challenge to any efforts designed to promote either 24-hr physician coverage or high-intensity model organization.

Adult↗

PubMed1994

Nucleic acid related compounds. 84. Synthesis of 6'-(E and Z)-halohomovinyl derivatives of adenosine, inactivation of S-adenosyl-L-homocysteine hydrolase, and correlation of anticancer and antiviral potencies with enzyme inhibition.

Treatment of 9-[6-(E)-(tributylstannyl)-5,6-dideoxy-2,3-O-isopropylidene- beta-D-ribo-hex-5-enofuranosyl]adenine [2b(E)] or the 6-N-benzoyl derivative 2a(E) with iodine (or N-iodosuccinimide) or bromine (or N-bromosuccinimide) gave virtually quantitative and stereospecific conversions to the 6'-(E)-(halohomovinyl)nucleoside analogues. Analogous treatment of the 6'-(Z)-vinyl-stannanes gave the 6'-(Z)-halo compounds. Treatment of 2a or 2b with chlorine or xenon difluoride/silver triflate gave E and Z mixtures of the respective 6'-chloro- or 6'-fluorohomovinyl products. Deprotection gave the 9-[6-(E and Z)-halo-5,6-dideoxy-beta-D-ribo- hex-5-enofuranosyl]-adenines [(E and Z)-5',6'-didehydro-6'-deoxy-6'-halohomoadenosines, EDDHHAs and ZDDHHAs, 4c-7c(E and Z)]. The acetylenic 5',5',6',6'-tetradehydro-6'- deoxyhomoadenosine (3c) and the 5'-bromo-5'-deoxy-5'-methyleneadenosine (10c) regioisomer of EDDBHA [5c(E)] also were obtained from 2. Concentration- and time-dependent inactivations of S-adenosyl-L-homocysteine (AdoHcy) hydrolase were observed with 3c and the 6'-(halohomovinyl)adenosine analogues. The order of inhibitory potency was I > Br > Cl > F and E > Z for the geometric isomers. AdoHcy hydrolase effected "hydrolysis" of the 6'-halogen from the (halohomovinyl)Ado compounds (to give the putative 6'-carboxaldehyde which underwent spontaneous decomposition) independently of its oxidative activity. Partition ratios for these hydrolytic turnovers/lethal inhibitory events were in the order F > Cl > Br > I. Biological activities were evaluated with several viruses and cancer cell lines, and potencies were generally in the order I > Br > Cl > F and E > Z isomers. This represents the first observation of a direct correlation of cytostatic activity with inhibition of AdoHcy hydrolase and highlights the potential of this enzyme as a viable target for chemotherapeutic intervention in anticancer as well as antiviral drug design.

Adenosine↗

PubMed2004

Analysis of costs, length of stay, and utilization of emergency department services by frequent users: implications for health policy.

UNLABELLED: In efforts to decrease emergency department (ED) crowding and health care costs, frequent users of ED services have been targeted for interventions to decrease their utilization. Previous studies have had different definitions for "frequent users" and have considered all frequent users as a homogeneous group. To the authors' knowledge, no study has examined visit characteristics and resource utilization of different levels of frequent use. OBJECTIVES: 1) to determine the rates of ED utilization by five user groups defined by number of annual visits, 2) to examine variations in visit characteristics by frequency of ED use, and 3) to compare levels of resource utilization among frequent user groups. METHODS: This was a retrospective, cross-sectional study of clinical and financial records for all ED visits to an urban, academic hospital in 2001. Multinomial logistic and linear regression models were used for analyses. Estimates were corrected for multiple comparisons (with Bonferroni corrections), where applicable, and adjusted for clustering within individuals (with Huber-White estimators). Outcome measures were triage acuity, diagnosis-related group (DRG) severity, disposition status, primary complaint, medical diagnosis, hospital inpatient length of stay, payment method, costs, and demographics. RESULTS: Patients with three to 20 visits were more likely to be admitted to the hospital than patients visiting once or twice. Patients visiting more than 20 times were less likely to require hospital admission and more likely to present with "nonurgent" conditions, have lower severity scores, and elope or leave the ED without medical attention than patients visiting the ED once. The group had fewer inpatient days and lower average costs than patients visiting once. Patients with six to 20 visits had traditional Medicaid coverage more often than those with one or two visits. Virtually no patients visiting more than 20 times had Medicare or Medicaid managed care, a health maintenance organization, or a preferred provider organization. CONCLUSIONS: Frequent ED users are a heterogeneous group. Many patients previously thought to overutilize the ED for socioeconomic or insignificant medical problems are as sick as less-frequent ED users. There is a small subgroup with more than 20 visits who are less ill or injured but also incurred lower-than-average costs per visit.

Adult↗

PubMed2005

Three-dimensional echo-guided beating heart surgery without cardiopulmonary bypass: atrial septal defect closure in a swine model.

OBJECTIVE: In this study, we tested 3 techniques of atrial septal defect closure under real-time 3-dimensional echocardiography guidance in a swine model. METHODS: The operations were conducted under the sole guidance of a modified real-time 3-dimensional echocardiography guidance system with a x4 matrix transducer (Sonos 7500, Philips Medical Systems, Andover, Mass). Eighteen swine were anesthetized, and after median sternotomy, the echo probe was applied directly to the surface of the right atrium. To create an atrial septal defect, balloon atrial septostomy and atrial septal defect enlargement were performed. Subsequently, 3 different techniques of atrial septal defect closure were attempted: group I, direct suture closure; group II, closure of the atrial septal defect using the Amplatzer device (AGA Medical Corp, Golden Valley, Minn); and group III, patch closure of the atrial septal defect (n = 6 each). RESULTS: Real-time 3-dimensional echocardiography guidance provided sufficient spatial resolution and a satisfactory frame rate to provide a "virtual surgeon's view" of the relevant anatomy during the entire procedure. All atrial septal defects were enlarged, and the mean final size was 8.5 +/- 1.8 mm. Atrial septal defect closure was successfully accomplished with all the 3 surgical techniques examined. In groups I and III, the needles (1-3 sutures) and staples (6-12 staples) penetrated the tissue and patch material consistently, whereas in group III, the Amplatzer atrial septal defect device was easily deployed. There was no incident device/staple embolization or air introduction. Neither intraoperative 2-dimensional color Doppler echocardiography nor postmortem macro-evaluation revealed any residual shunts. CONCLUSIONS: Beating heart atrial septal defect closure under real-time 3-dimensional echocardiographic guidance is feasible and, unlike catheter-based devices, applicable for any type of secundum atrial septal defect.

Animals↗

PubMed2000

How many women lose bone mineral density while taking hormone replacement therapy? Results from the Postmenopausal Estrogen/Progestin Interventions Trial.

BACKGROUND: The frequency of bone loss among women using postmenopausal hormone therapy is unknown. METHODS: We used data from the Postmenopausal Estrogen/Progestin Interventions Trial to address the frequency of bone loss among women using postmenopausal hormone replacement therapy. Of 701 women randomized to active treatment (conjugated equine estrogens alone or in combination with 1 of 3 progestins), 538 (76.7%) were adherent and had replicate bone mineral density (BMD) measures at baseline, 12 months, and 36 months. Of 174 placebo-assigned women, 132 (75.9%) were similarly eligible. Replicate BMD measures were used to calculate within-person measurement errors, which were then used to delineate cut points that defined bone losers with 97.5%, 95.0%, 90.0%, or 75.0% confidence. RESULTS: At the lumbar spine, during the first 12 months, 1.5% of hormone users lost BMD with 97.5% confidence, corresponding to a decline of -3% per year; during months 12 to 36, only 0.6% of treated women lost spinal BMD to this degree. An annual loss of -1% or more was the criterion for spinal bone loss at the 75.0% confidence level; 5.1% and 8.0% of hormone users met this criterion in the first year and in months 12 to 36, respectively. For the total hip, during the first 12 months, 2.3% of hormone-adherent women lost -3.0% per year or more, the 97.5% confidence definition of loss; 0.4% were so classified during months 12 to 36. To be 75.0% confident of hip BMD loss, a -1.0% per year decline in BMD was required; using this criterion, 14.5% and 11.8% of hormone users lost total hip BMD between 0 to 12 and 12 to 36 months, respectively. Among hormone-adherent women, at the spine and hip, there was virtually no overlap between women classified as bone losers in the first 12 months and those classified as such in the last 24 months. With 95.0% certainty, corresponding to an approximate loss of -2.5% at the spine and hip, 31.3% and 11.7% of placebo-adherent women lost spinal BMD in the first 12 and last 24 months, respectively. Parallel figures for the hip were 32.3% and 7.9%, respectively. CONCLUSION: Bone loss while taking postmenopausal hormones is rare, and bone loss among untreated women is far from universal.

Bone Density↗

PubMed1999

Intracardiac echocardiographic guidance during microwave catheter ablation.

The purpose of this study was to explore the potential of intracardiac echocardiography in monitoring lesion formation and assisting with the assessment of ablative lesions using microwave energy. Microwave energy is a promising modality for catheter ablation. Because microwave lesions may have considerable variability in dimension, the ability to assess them may be particularly useful. One hundred twenty-five microwave lesions were created in vitro in ovine left ventricles. Correct assessment of catheter-endocardial contact was possible in virtually all cases. Intracardiac imaging always identified correctly whether or not an ablation was performed. During ablation, gas formation was observed in all instances. Sensitivity, specificity, and predictive values for identification of ablation lesions were 88% to 92%. Although the correlations with pathology for lesion dimensions were relatively poor, intracardiac imaging had a predictive accuracy of 80% to 85% to discriminate small from large lesions. Intracardiac guidance for microwave ablation is useful for verifying tissue-electrode contact, monitoring lesion formation, and localizing lesions. It is also a useful tool for the assessment of lesion size. These attributes, combined with the ability to facilitate transseptal catheterization and to identify complications such as hemopericardium, make intracardiac echocardiography a potentially useful method for guiding microwave ablation of arrhythmic foci.

Animals↗

PubMed2001

Biochemical profile and survival in nonagenarians.

OBJECTIVES: Old age is associated with an increase in frequency of disorders involving virtually all organ systems, resulting in a rise of mortality. The aim of the project was to study the relationship between biochemical markers and all-cause mortality in a defined age group. DESIGN AND METHODS: Thirty-eight nonagenarians, aged 92 +/- 2 (range 90-100) years entered the study. At the start of the study, a sample of peripheral blood and urine were obtained for analysis of 50 basic biochemical, hematologic and biologic parameters. The assessment was then repeated in 6 to 12 months intervals. The significance of difference between surviving subjects and those who died was examined by Mann-Whitney U test and the correlation between the variables was studied by Spearman rank correlation coefficient. RESULTS: During the observation period, 21 of the studied subjects died leaving 17 persons still alive at the end of the study. The mean time from the first measurement to the death was 12 +/- 10 (range 0-33) months. The mean follow-up time in surviving subjects was 31 +/- 12 (range 4-45) months. Serum vitamin E and calcium were significantly higher, and serum alanine aminotransferase (ALT) and urinary neopterin were significantly lower in survivors compared to the subjects who died. No other parameters were significantly different in survivors and in persons who died. Urinary neopterin exhibited a significant negative correlation with serum sodium concentration (RS = -0.50, p < 0.01), but the other parameters did not correlate significantly. CONCLUSION: In conclusion, among the parameters studied, differences between survivors and nonsurvivors were observed only for serum vitamin E, calcium, ALT and urinary neopterin. These findings may form a basis for prospective interventional trials in this group of patients.

Aged↗

PubMed2004

Sirolimus-eluting stents inhibit neointimal hyperplasia in diabetic patients. Insights from the RAVEL Trial.

Patients with diabetes mellitus have less favourable outcomes after percutaneous coronary intervention (PCI) than non-diabetics. We performed a subgroup analysis of the multicentre RAVEL trial to examine the impact of the sirolimus-eluting stent (SES) on outcomes in diabetic patients. The RAVEL study randomized 238 patients to treatment with either sirolimus-eluting or bare metal stents. Forty-four patients were diabetic; 19 received sirolimus-eluting stents and 25 were treated with bare metal stents. The differences in outcomes between diabetic and non-diabetic patients treated with SES (n=101) were also assessed. Follow-up angiography was performed at 6 months. Major adverse cardiac events (MACE) defined as death, myocardial infarction (MI), or target lesion revascularization (TLR) were analysed at 12-month follow-up. Six-month in-stent late lumen loss was significantly lower for the diabetic SES than the bare stent group (0.07+/-0.2 vs 0.82+/-0.5mm; P<0.001) and similar to that in non-diabetics treated with SES (-0.03+/-0.27mm). There was zero restenosis in the SES groups (diabetic and non-diabetic) compared to a 42% rate in the diabetic population assigned to bare metal stents (P=0.001). After 12 months, there was one non-Q-wave MI and one non-cardiac death in the diabetic SES group, while 12 patients in the bare metal stent group had MACE (one death, two MI, nine TLR) (P=0.01)-an event-free survival rate of 90% vs 52%, respectively (P<0.01). There were no TLRs in both SES groups compared to 36% rate in the diabetic bare metal stent group (P=0.007). Conclusion Diabetics treated with SES were associated with a virtual abolition of neointimal proliferation and low event rates at long-term follow-up.

Coronary Restenosis↗

PubMed2006

Age-related functional and histopathological changes of the ear in the MPS I mouse.

OBJECTIVE: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme alpha-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I. METHODS: Auditory brainstem responses (ABR) were obtained to clicks and tone bursts at 1-32kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in 53 mice that included: (1) wild type (+/+)-five at 2 months, five at 4-6 months, and five at 13-19 months; (2) heterozygotes (+/-)-four at 2 months, five at 4-6 months, and eight at 13-19 months; and (3) homozygotes (-/-)-five at 2 months, six at 4-6 months, and five at 13-19 months. Histopathology was also done on five newborn -/- mice. RESULTS: In newborns, no lysosomal storage was observed and the ear appeared age appropriately normal. In all other -/- mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner's membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of -/- mice was significantly decreased at all ages compared to +/+ and +/-. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by 1 year of age. CONCLUSIONS: Progressive age-related changes suggest early therapeutic intervention to prevent sensory cell damage and hearing loss.

Aging↗

PubMed2005

A non-sequence-specific requirement for SMN protein activity: the role of aminoglycosides in inducing elevated SMN protein levels.

Spinal muscular atrophy (SMA) is caused by homozygous loss of the survival motor neuron (SMN1) gene. In virtually all SMA patients, a nearly identical copy gene is present, SMN2. SMN2 cannot fully compensate for the loss of SMN1 because the majority of transcripts derived from SMN2 lack a critical exon (exon 7), resulting in a dysfunctional SMN protein. Therefore, the critical distinction between a functional and a dysfunctional SMN protein is the inclusion or the exclusion of the exon 7 encoded peptide. To determine the role of the 16 amino acids encoded by SMN exon 7, a panel of synthetic mutations were transiently expressed in SMA patient fibroblasts and HeLa cells. Consistent with previous reports, the protein encoded by SMN exons 1-6 was primarily restricted to the nucleus. However, a variety of heterologous sequences fused to the C-terminus of SMN exons 1-6 allowed mutant SMN proteins to properly distribute to the cytoplasm and to the nuclear gems. These data demonstrate that the SMN exon 7 sequence is not specifically required, rather this region functions as a non-specific 'tail' that facilitates proper localization. Therefore, a possible means to restore additional activity to the SMNDelta7 protein could be to induce a longer C-terminus by suppressing recognition of the native stop codon. To address this possibility, aminoglycosides were examined for their ability to restore detectable levels of SMN protein in SMA patient fibroblasts. Aminoglycosides can suppress the accurate identification of translation termination codons in eukaryotic cells. Consistent with this, treatment of SMA patient fibroblasts with tobramycin and amikacin resulted in a quantitative increase in SMN-positive gems and an overall increase in detectable SMN protein. Taken together, this work describes the role of the critical exon 7 region and identifies a possible alternative approach for therapeutic intervention.

Alanine↗

PubMed2001

Diltiazem to treat sinus tachycardia in critically ill patients: a four-year experience.

OBJECTIVES: To determine whether an intravenous infusion of the calcium channel blocker diltiazem was effective and safe in treating sinus tachycardia in critically ill adult patients with contraindications to beta-blockers or in whom beta-blockers were ineffective. DESIGN: Retrospective chart review. SETTING: University medical center. PATIENTS: The records of 171 surgical intensive care unit patients with sinus tachycardia treated with intravenous diltiazem were evaluated. INTERVENTIONS: In all patients with sinus tachycardia (heart rate >100 beats/min), heart rate control with intravenous diltiazem was attempted after adequate intravascular volume expansion, pain, and anxiety control. In all patients, beta-blockade either was contraindicated or (in 7%) had failed. Intravenous diltiazem was administered as a slow 10-mg bolus dose (0.1-0.2 mg/kg ideal body weight), and then an infusion was started at 5 or 10 mg/hr and increased up to 30 mg/hr, as needed, to decrease heart rate to <100 beats/min. Variables retrospectively collected included demographic data, preinfusion blood pressure, mean arterial pressure, heart rate, and preinfusion pressure-rate quotients (pressure-rate quotient = mean arterial pressure / heart rate). Intravenous bolus dose, when given, and diltiazem infusion rate and time necessary to achieve the target heart rate also were recorded. The lowest heart rate recorded within 24 hrs from the initiation of the infusion and the time necessary to achieve the lowest heart rate after beginning the infusion were recorded. MEASUREMENTS AND RESULTS: Of 171 patients studied, 97 (56%) were classified as responders. Multiple linear regression suggested that response could be predicted by age, pressure-rate quotients, baseline mean arterial pressure, and central nervous system failure. In the responders, a heart rate <100 beats/min was achieved in an average of 2 hrs, at a mean diltiazem infusion of 13.3 mg/hr. The lowest rate reached by the responders in a 24-hr period averaged 86 beats/min and was achieved in 4.8 hrs with a mean infusion rate of 14.8 mg/hr. Both target and lowest rate values were statistically different from baseline heart rate. CONCLUSION: Diltiazem was effective in achieving short-term control of heart rate in 56% of the patients, virtually without adverse effects, where beta-blockade was contraindicated or ineffective.

Academic Medical Centers↗

PubMedDate not supplied

A proposed universal medical and public health definition of terrorism.

The lack of a universally applicable definition of terrorism has confounded the understanding of terrorism since the term was first coined in 18th Century France. Although a myriad of definitions of terrorism have been advanced over the years, virtually all of these definitions have been crisis-centered, frequently reflecting the political perspectives of those who seek to define it. In this article, we deconstruct these previously used definitions of terrorism in order to reconstruct a definition of terrorism that is consequence-centered, medically relevant, and universally harmonized. A universal medical and public health definition of terrorism will facilitate clinical and scientific research, education, and communication about terrorism-related events or disasters. We propose the following universal medical and public definition of terrorism: The intentional use of violence--real or threatened--against one or more non-combatants and/or those services essential for or protective of their health, resulting in adverse health effects in those immediately affected and their community, ranging from a loss of well-being or security to injury, illness, or death.

Crisis Intervention↗

PubMed2004

Neonatal lupus: clinical features and management.

Neonatal lupus is an uncommon autoimmune disease manifested primarily by cutaneous lupus lesions and/or congenital heart block. Maternal autoantibodies of the Ro/La family are present in virtually every case, although only approximately 1% of women who have these autoantibodies will have a baby with neonatal lupus. The cutaneous lesions of neonatal lupus may be present at birth, but more often develop within the first few weeks of life. Lesions are most common on the face and scalp, often in a distinctive periorbital distribution. Lesions tend to resolve in a few weeks or months without scarring. The most common cardiac manifestation of neonatal lupus is complete heart block. Heart block typically begins in utero during the second or third trimester. In some cases, heart block begins as first- or second-degree block and then progresses to third-degree block. Complete heart block, once established, appears to be irreversible. In some cases, cardiomyopathy occurs together with complete heart block. Most cases have been noted at birth, but delayed dilated cardiomyopathy has been reported. There have been a few cases of endocardial fibroelastosis occurring in the absence of congenital heart block. Hepatobiliary disease occurs in about 10% of cases. Three types of hepatobiliary disease have been observed: liver failure occurring at birth or in utero, transient conjugated hyperbilirubinemia occurring in infants, or transient transaminase elevations occurring in infants. Hematologic disease, consisting of thrombocytopenia, neutropenia, or anemia, occurs in about 10% of cases. It is common for children with neonatal lupus not to have the full expression of disease, but rather to have only one or two organ systems involved. The diagnosis rests largely on the finding of compatible clinical manifestations plus maternal autoantibodies to Ro and/or La, or, in a few cases, to U1 ribonuclear protein. Although the pathogenesis has not been conclusively established, accumulating evidence, including evidence from animal models, implicates autoantibodies in the pathogenesis of the disease. Therapeutic interventions include attempts at prevention, early intervention, and treatment of well established disease, mainly through the use of systemic corticosteroids. Optimal therapy has yet to be determined. The long-term prognosis for children who have had neonatal lupus is still under investigation, but some children who had neonatal lupus have developed other autoimmune diseases later in childhood. About half of the mothers are asymptomatic at the time of presentation of the child, but some of these women eventually develop symptoms of autoimmune disease.

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