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PubMed2001

Evolving concepts in the pathogenesis of multiple sclerosis and their therapeutic implications.

Recent evidence suggests that multiple sclerosis (MS) is a continuously active neuropathologic process, even during the subclinical relapsing/remitting phase of the disease. Patients commonly feel well and function without disability for many years, experiencing only occasional relapses and nondisabling symptoms. In time, many evolve into a pattern of continuously progressive neurologic disability termed secondary progressive MS (SP-MS). SP-MS is hypothesized to occur once disease severity has exceeded a threshold. Above that threshold, compensatory mechanisms are inadequate to maintain normal function, and further disease progression is accompanied by progressively worsening disability. Inflammation dominates the early stage of disease. Progressive axonal pathology may underlie clinical disease progression in later stages. These concepts have important implications related to the diagnosis, methods for patient follow-up, type and timing of disease therapy, and the testing of neuroprotective drugs in MS.

Adjuvants, Immunologic↗

PubMed2001

Modern pharmacotherapy for erectile dysfunction: evolving concepts with central and peripheral acting agents.

Pharmacotherapy for men experiencing erectile dysfunction has undergone dramatic advances over the past 5 years with the introduction of an effective oral agent. Sildenafil has increased the pool of couples seeking treatment for this important health issue as well as expanding the numbers of physicians treating it. Research into the growing field of erectile dysfunction is expanding at a rapid pace. Independent investigators worldwide now regularly contribute to our body of scientific knowledge. Novel oral therapies targeted at specific points along the erectile cascade are undergoing pre-clinical and early phase registration trials with the promise of rapid action, extended duration of responsiveness and an improved side effect profile. In this review, we have highlighted recent information on the next generation of phosphodiesterase inhibitors and summarized the evolving research into centrally acting agents, which may lead to effective combination therapy.

Erectile Dysfunction↗

PubMed2000

HIV in Vietnam: the evolving epidemic and the prevention response, 1996 through 1999.

OBJECTIVES: To describe epidemiologic patterns and trends in HIV infection in Vietnam from 1996 through 1999, and to summarize the national response to the epidemic. METHODS: We reviewed nationwide HIV case reports, and we analyzed annual seroprevalence among different sentinel populations in 21 provinces, using the chi2 test for linear trend to assess trends in HIV prevalence. HIV prevention efforts were also reviewed. RESULTS: Through 1999, 17,046 HIV infections, including 2947 AIDS cases and 1523 deaths had been reported in Vietnam. The cumulative incidence rate for the country was 22.5 per 100,000 population. Injection drug users (IDUs) represented 89.0% of all those for whom risk was reported before 1997 and 88.0% in the period 1997 to 1999. In 1999, HIV prevalence rates among IDUs ranged by province from 0% to 89.4%. Significantly increasing HIV trends among IDUs (p <.05) were found in 14 of the 21 sentinel provinces during 1996 to 1999. HIV prevalence among commercial sex workers (CSWs) ranged from 0% to 13.2%, increased significantly in 6 of 21 provinces. In 1999, prevalence among pregnant women, blood donors, and military recruits were 0.12%, 0. 20% and 0.61%, respectively. Major prevention activities include mass information; peer education and outreach among groups at increased risk; availability of low-cost syringes and condoms through pharmacies; needle exchange pilot projects; widely available treatment for sexually transmitted diseases; antibody screening of blood for transfusion; and free medical treatment at government hospitals. DISCUSSION: The HIV epidemic continues to evolve rapidly, intensifying among IDUs and increasing among CSWs. Serosurveillance indicators of HIV in the population at large continue to indicate the relatively slow extension beyond those at highest risk. Immediate, intensive preventions in high-risk groups may decelerate expansion to the broader population.

Adolescent↗

PubMed1997

The evolving health-care environment: new arguments for closer collaboration between cardiac surgical intensive-care nurses and clinical engineers.

"Not vain the weakest, if their force unite." Homer, Iliad (9th century, B.C.). In today's evolving health-care environment, the cardiac surgical intensive-care nurse is required to provide care to patients whose acuity levels are increasing. Simultaneously, these nurses are asked to use more technologically complex devices to deliver that care. In addition, practice protocols are being integrated into hospitals' clinical information systems. To meet these challenges, cardiac surgical intensive-care nurses must collaborate with clinical engineers on the evaluation and installation of new products and on the automation and refinement of clinical pathways and other outcomes measurement tools. Each discipline also must ensure that the other keeps pace with and maintains its levels of proficiency in the technology used to care for patients undergoing cardiac surgery.

Biomedical Engineering↗

PubMed2004

Drug-resistant variants that evolve during nonsuppressive therapy persist in HIV-1-infected peripheral blood mononuclear cells after long-term highly active antiretroviral therapy.

The aim of this study was to determine whether drug-resistant virus persists in peripheral blood mononuclear cells (PBMCs) after long-term suppression of virus replication. Proviral DNA was extracted from the PBMCs of 11 patients on long-term highly active antiretroviral therapy (HAART). Genotyping of the reverse transcriptase (RT) and protease gene of several proviral variants was performed using limiting dilution polymerase chain reaction and single-copy sequencing. All patients were on successful HAART for a mean period of 59 months but had a history of suboptimal therapy and genotypic drug resistance before. Comparison of the amino acid sequence of the RT and protease gene in the different proviral variants, with that of the plasma virus isolated before HAART treatment, revealed that the different drug-resistant viral variants that evolved during the process of gradually building up resistance were still detectable in the PBMCs in 10 of the 11 patients tested. The proportion of resistant variants was found to correlate with the time that the resistant variants had been able to replicate. These data clearly show that virus variants that are able to replicate for a certain period enter the latent reservoir and remain archived in the PBMCs for a very long period.

Adult↗

PubMed2005

Rheumatoid arthritis and cardiovascular disease: the role of systemic inflammation and evolving strategies of prevention.

PURPOSE OF REVIEW: The incidence and mortality of cardiovascular disease are increased in the context of rheumatoid arthritis. The purpose of this review is to examine our evolving understanding of the pathogenesis of cardiovascular disease in rheumatoid arthritis and to underscore the importance of tailored prevention of cardiovascular disease in this select population. RECENT FINDINGS: Recent reports have highlighted the shared pathobiology of cardiovascular disease and rheumatoid arthritis, both of which represent inflammatory disorders. Several reports have also provided much-needed insight into the deleterious impact that select therapies (including cyclo-oxygenase-2-specific inhibitors) may have in terms of the risk of cardiovascular disease in rheumatoid arthritis. Although further study is warranted, preliminary investigations also suggest that aggressive anti-inflammatory therapy, including the adjunctive use of statins, may play important cardioprotective roles in rheumatoid arthritis. SUMMARY: The pathogenesis of cardiovascular disease in rheumatoid arthritis is complex and involves several intermediate factors, including dyslipidemia, elevations in serum homocysteine, impaired insulin sensitivity, and endothelial dysfunction. Given the burden of cardiovascular disease in this population, it is important that health care providers caring for rheumatoid arthritis patients adopt a treatment course that is both comprehensive and individualized to address specific risk factors for cardiovascular disease.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Evolving global epidemiology, syndromic classification, general management, and prevention of unknown mushroom poisonings.

OBJECTIVE: To assess the evolving global epidemiology of mushroom poisoning and to identify new and emerging mushroom poisonings and their treatments, a descriptive analysis and review of the world's salient scientific literature on mushroom poisoning was conducted. DATA SOURCE: Data sources from observation studies conducted over the period 1959-2002 and describing 28,018 mushroom poisonings since 1951 were collected from case reports, case series, regional descriptive studies, meta-analyses, and laboratory studies of mushroom poisonings and the toxicokinetics of mycotoxins. STUDY SELECTION: Studies included in the review were selected by a MEDLINE search, 1966-2004, an Ovid OLDMEDLINE search, 1951-1965, and a medical library search for sources published before 1951. DATA EXTRACTION: To better guide clinicians in establishing diagnoses and implementing therapies, despite confusing ingestion histories, data were extracted to permit an expanded syndromic classification of mushroom poisoning based on presentation timing and target organ systemic toxicity. DATA SYNTHESIS: The final 14 major syndromes of mushroom poisoning were stratified first by presentation timing and then by target organ systemic toxicity and included early (<6 hrs), late (6-24 hrs), and delayed syndromes (> or =1 day). There were eight early syndromes (four neurotoxic, two gastrointestinal, two allergic); three late syndromes (hepatotoxic, accelerated nephrotoxic, erythromelalgia); and three delayed syndromes (delayed nephrotoxic, delayed neurotoxic, rhabdomyolysis). Four new mushroom poisoning syndromes were classified including accelerated nephrotoxicity (Amanita proxima, Amanita smithiana), rhabdomyolysis (Tricholoma equestre, Russula subnigricans), erythromelalgia (Clitocybe amoenolens, Clitocybe acromelalgia), and delayed neurotoxicity (Hapalopilus rutilans). In addition, data sources were stratified by three chronological time periods with >1,000 confirmed mushroom ingestions reported and tested for any statistically significant secular trends in case fatalities from mushroom ingestions over the entire study period, 1951-2002. CONCLUSIONS: Since the 1950s, reports of severe and fatal mushroom poisonings have increased worldwide. Clinicians must consider mushroom poisoning in the evaluation of all patients who may be intoxicated by natural substances. Since information on natural exposures is often insufficient and incorrect, a new syndromic classification of mushroom poisoning is recommended to guide clinicians in making earlier diagnoses, especially in cases where only advanced critical care, including organ transplantation, may be life saving.

Diagnosis, Differential↗

PubMed2004

Left ventricular assist devices: evolving devices and indications for use in ischemic heart disease.

PURPOSE OF REVIEW: The mortality with end-stage heart failure is extremely high, especially when patients become refractory to conventional medical therapy and require frequent hospitalization. Ischemic heart disease remains the primary cause of advanced heart failure. Mechanical pumps or devices have been developed called ventricular assist devices and are being used to support an increasing number of patients with refractory heart failure. RECENT FINDINGS: The use of ventricular assist devices has evolved from initially only support of patients unable to be weaned from a heart-lung machine after cardiac surgery to use now as a bridge to a heart transplant, including patients with acute myocardial infarction and shock and severe pulmonary hypertension. More recently, they have been proven as a definitive alternative for patients not eligible for heart transplantation. There are new devices being examined in clinical trials, including a change from pusher-plate to devices with axial flow technology that are much smaller and easier to implant. Outcomes with their use are improving rapidly as the devices become more reliable and more is learned about the importance of candidate selection. SUMMARY: This review describes current indications for the use of these devices, the types of pumps now available, criteria for initiating ventricular assist device support, complications of their use, and new applications such as a platform for stem cell therapy for treatment of end-stage heart failure.

Cardiac Surgical Procedures↗

PubMed2006

Epipolis laser in-situ keratomileusis: an evolving surface ablation procedure for refractive corrections.

PURPOSE OF REVIEW: The aim of this article is to provide an update on epipolis laser in-situ keratomileusis--an alternative surface photorefractive surgical technique for the correction of myopia. RECENT FINDINGS: In-vivo studies on animal models provide evidence that the replacement of the epithelial sheet on an ablated cornea can control corneal wound healing. Preliminary clinical data confirm that epipolis laser in-situ keratomileusis can provide excellent long-term visual and refractive results. The problems of late visual rehabilitation and postoperative pain, however, have not yet been fully addressed. SUMMARY: Being a recently introduced surgical photorefractive technique for ametropias correction, epipolis laser in-situ keratomileusis is a fast evolving area of interest for refractive surgeons.

Epithelium, Corneal↗

PubMed2003

Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site.

PURPOSE: The prevention and treatment of prostate cancer metastasis continue to provide a significant clinical challenge. Identification of the rate limiting steps of metastasis and their underlying molecular mechanisms may lead to new therapeutic targets and also allow more accurate risk stratification for clinical metastases. We review the literature supporting growth of disseminated tumor cells at the secondary site as a key rate limiting step in metastasis. We also reviewed the definition, identification and characterization of metastasis suppressor genes, and discuss their evolving role in regulating this step. MATERIALS AND METHODS: We performed MEDLINE searches and manual bibliographic reviews on the specific steps of metastasis, including growth at the secondary site. In addition, we performed a comprehensive literature review to identify genes fitting the classic definition of a metastasis suppressor gene. The literature was also searched to assess the status of each gene in clinical cancer and evaluate functional support for the potential involvement of each gene in regulating growth at the secondary site. RESULTS: Clinical studies in prostate cancer and other cancer types suggest that dissemination to the secondary site is often an early clinical event. However, not all patients with tumor cells at the secondary site have overt metastatic lesions even in the absence of therapy, suggesting that growth at the secondary site may be highly inefficient. Complimentary approaches have allowed researchers to document and quantify the inefficiency of cancer cell growth at the secondary site. Regarding the mechanism of growth control, many studies support a role for the interaction of a cancer cell and the microenvironment at the secondary site influencing whether growth into metastasis may occur. The 7 genes that suppress metastasis without affecting primary tumor growth that have been identified are KAI1, CD44, mitogen activated protein kinase (MAPK) kinase 4, nm23-H1, nm23-H2, KiSS1 and BrMS1. Three of these genes (KAI1, CD44 and MAPK kinase 4) act as metastasis suppressor genes of prostate cancer, while the remainder have yet to be tested in this cancer type. Loss of expression has been demonstrated for most of these genes during the clinical progression of prostate cancer to metastasis. MAPK kinase 4 and KiSS1 appear to suppress metastasis by inhibiting cancer cell growth at the secondary site. Interestingly many metastasis suppressor genes have common roles in growth control, adhesion and cytoskeletal reorganization, suggesting a common mechanism of metastasis suppression. Proposed candidate pathways include signaling through Src kinase and Rac GTPase. CONCLUSIONS: The findings discussed support growth at the secondary site as a clinical target for metastasis treatment and prevention. Metastasis suppressor genes may offer valuable mechanistic insight for guiding specific therapeutic strategies, which may include drug induced reactivation of metastasis suppressor genes and their signaling pathways. Clinical assessment of metastasis suppressor gene product status in disseminated cancer cells may improve the accuracy of predicting the prognosis in patients with clinically localized disease.

Animals↗

PubMed2003

The evolving role of docetaxel in the management of androgen independent prostate cancer.

PURPOSE: Androgen independent prostate cancer is an advanced disease with an extremely poor outcome. In view of this fact, a great deal of interest has recently been generated in the potential use of chemotherapeutic agents, particularly docetaxel. We reviewed the evolving role of docetaxel as a chemotherapeutic agent for the management of this disease. MATERIALS AND METHODS: The main emphasis of this review is discussion of the various clinical trials that have investigated the use of docetaxel alone or combined with other agents for androgen independent prostate cancer. RESULTS: Docetaxel, which acts primarily by inhibiting microtubular depolymerization, in combination with other agents has consistently demonstrated a palliative response, a decrease in serum prostate specific antigen levels by 50% or greater in more than 60% of patients, a decrease in measurable disease and the suggestion of improved survival. CONCLUSIONS: Docetaxel based regimens are moderately well tolerated and they have shown promising results in various phase 2 trials. The completion of ongoing phase III randomized trials are eagerly awaited since they may determine whether a definite beneficial impact on overall survival can be achieved.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: an evolving concept.

The concept of Waldenstrom macroglobulinemia has evolved from the original description of a clinical syndrome to its more recent designation as a distinct clinicopathologic entity, that is, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), in the World Health Organization (WHO) classification and by the participants of consensus meetings on WM. The diagnosis of LPL/WM, however, remains a challenge in daily practice. Distinguishing LPL/WM from other B-cell lymphomas, especially marginal zone B-cell lymphomas, which share overlapping morphologic features, is difficult. The traditional practice of separating LPL/WM from other lymphomas by an arbitrary level of serum IgM is no longer considered valid. The characteristic immunophenotype described for LPL/WM by the WHO classification, that is, CD5(-)CD10(-)CD23-, is observed in 60-80% of neoplasms, but variations from this pattern of antigen expression are common, with CD23 being detected in up to 40% of cases. Lack of a distinct molecular genetic hallmark complicates the distinction of LPL/WM from other B-cell lymphomas. Although the t(9;14) is stated to be present in 50% of cases in the WHO classification, translocations involving the Ig heavy chain including the t(9;14) are actually rare in LPL/WM. Deletion of 6q21-q23, a nonspecific finding, is the most common aberration reported in 40-70% of patients. At the molecular level, the neoplastic clone in most cases has undergone Ig variable gene mutation, but not isotype switching, and the clone retains the capability of plasmacytic differentiation. Currently, the diagnosis of LPL/WM can only be established by incorporating clinical and pathologic findings and excluding alternative diagnoses. In some cases, in our opinion, distinguishing LPL/WM from marginal zone B-cell lymphomas seems arbitrary using currently recommended criteria.

Antigens, CD↗

PubMed2004

Evolving infectious aortitis caused by Streptococcus pneumoniae.

Infections of major vessels leading to mycotic aneurysms can be a diagnostic dilemma for clinicians, and can be accompanied by a high mortality rate. Successful treatment of this condition often requires a high index of suspicion and prompt medical and surgical attention. The authors report two cases of infectious aortitis caused by pneumococcus that evolved during hospitalization, and discuss diagnostic difficulties that accompany this entity.

Aged↗

PubMed2005

The evolving role of interventional radiology in trauma care.

BACKGROUND: Although the traditional role of radiology in trauma care has been diagnostic, therapeutic interventional radiology (IR) techniques have now become essential in the management of many injuries. We hypothesized that IR has evolved at our institution over the last decade from a largely diagnostic to a more therapeutic role in the care of the injured patient. METHODS: Demographic information, computed tomographic scans of the chest and abdomen, and angiographic procedures (APs) performed within 48 hours of admission were reviewed in all patients evaluated at a Level I trauma center for the periods 1993 to 1995 and 2000 to 2002. All APs performed with the intent to embolize, stent, or insert a device into a vessel were designated as therapeutic. Analysis by means of chi provided between-group comparisons for questions of interest and the Student's t test was used for comparison of means. RESULTS: A total of 4,750 patients were reviewed, 1,677 from the time period 1993 to 1995 and 3,073 from the period 2000 to 2002. Overall injury severity as measured by the Injury Severity Score (ISS) was similar in both groups (9.6 vs. 9.9, p = not significant). The number of angiograms obtained decreased significantly from 7.1% to 4.0% of all patients (p < 0.01). Concurrently, the fraction of all angiograms that were considered therapeutic rose from 10% to 22% (p < 0.05). The overall number of aortic arch angiograms decreased over time (from 3.6% to 0.9%, p < 0.01), and the percentage of positive examinations increased from 5.0% to 21.4%. In comparison, the number of computed tomographic scans of the chest increased from 1.6% of all patients to 10.8% (p < 0.01). CONCLUSION: Axial imaging studies are being used more frequently to screen trauma patients for injury. Concurrently, diagnostic APs are less frequently performed but are more frequently positive. In addition, IR studies are increasingly focused on therapeutic intervention. IR program development and support is an integral aspect of modern trauma care. These findings have prompted our institution to equip the IR suite to function as an active resuscitation area similar to the trauma bay and intensive care unit.

Angiography↗

PubMed2004

Relationship between flow-metabolism uncoupling and evolving axonal injury after experimental traumatic brain injury.

Blood flow-metabolism uncoupling is a well-documented phenomenon after traumatic brain injury, but little is known about the direct consequences for white matter. The aim of this study was to quantitatively assess the topographic interrelationship between local cerebral blood flow (LCBF) and glucose metabolism (LCMRglc) after controlled cortical impact injury and to determine the degree of correspondence with the evolving axonal injury. LCMRglc and LCBF measurements were obtained at 3 hours in the same rat from 18F-fluorodeoxyglucose and 14C-iodoantipyrine coregistered autoradiographic images, and compared to the density of damaged axonal profiles in adjacent sections and in an additional group at 24 hours using beta-amyloid precursor protein (beta-APP) immunohistochemistry. LCBF was significantly reduced over the ipsilateral hemisphere by 48 +/- 15% compared with sham-controls, whereas LCMRglc was unaffected, apart from foci of elevated LCMRglc in the contusion margin. Flow-metabolism was uncoupled, indicated by a significant 2-fold elevation in the LCMRglc/LCBF ratio within most ipsilateral structures. There was a significant increase in beta-APP-stained axons from 3 to 24 hours, which was negatively correlated with LCBF and positively correlated with the LCMRglc/LCBF ratio at 3 hours in the cingulum and corpus callosum. Our study indicates a possible dependence of axonal outcome on flow-metabolism in the acute injury stage.

Amyloid beta-Protein Precursor↗

PubMed2006

Inflammatory transverse myelitis: evolving concepts.

PURPOSE OF REVIEW: Acute transverse myelitis is a pathogenetically heterogeneous inflammatory disorder of the spinal cord. Here we describe recent advances in inflammatory non-infectious transverse myelitis. Particular attention will be paid to the serum autoantibody marker NMO-IgG and its application to acute transverse myelitis. RECENT FINDINGS: The recent identification of neuromyelitis optica-IgG, a novel marker of neuromyelitis optica spectrum disorders (including longitudinally extensive transverse myelitis), contributes to an evolving understanding of acute transverse myelitis. Other serological markers, such as collapsin response-mediator protein-5 -IgG and amphiphysin-IgG, predict specific cancers in the setting of a paraneoplastic acute transverse myelitis. Furthermore, novel inflammatory markers such as interleukin-6 or other proteins in their signaling pathways may represent markers of disease severity and potential therapeutic targets. Additional cerebrospinal fluid biomarkers, such as protein 14-3-3 and neuron-specific enolase, may be useful prognostic indicators in transverse myelitis. Acute transverse myelitis in children, in contrast to adults, is more likely to be longitudinally extensive, and has a better prognosis and lower likelihood of recurrence. Prognostic factors in pediatric transverse myelitis are reviewed. SUMMARY: The recent identification of novel biomarkers associated with acute transverse myelitis has led to a better understanding of the spectrum of disorders associated with inflammatory transverse myelitis, as well as a greater appreciation of its diverse and complex pathogenetic basis.

Aquaporins↗

PubMed2004

Evidence that disgust evolved to protect from risk of disease.

Disgust is a powerful human emotion that has been little studied until recently. Current theories do not coherently explain the purpose of disgust, nor why a wide range of stimuli can provoke a similar emotional response. Over 40 000 individuals completed a web-based survey using photo stimuli. Images of objects holding a potential disease threat were reported as significantly more disgusting than similar images with little or no disease relevance. This pattern of response was found across all regions of the world. Females reported higher disgust sensitivity than males; there was a constant decline in disgust sensitivity over the life course; and the bodily fluids of strangers were found more disgusting than those of close relatives. These data provide evidence that the human disgust emotion may be an evolved response to objects in the environment that represent threats of infectious disease.

Age Factors↗

PubMed2005

Regressive evolution of an eye pigment gene in independently evolved eyeless subterranean diving beetles.

Regressive evolution, the reduction or total loss of non-functional characters, is a fairly common evolutionary phenomenon in subterranean taxa. However, the genetic basis of regressive evolution is not well understood. Here we investigate the molecular evolution of the eye pigment gene cinnabar in several independently evolved lineages of subterranean water beetles using maximum likelihood analyses. We found that in eyeless lineages cinnabar has an increased rate of sequence evolution, as well as mutations leading to frame shifts and stop codons, indicative of pseudogenes. These results are consistent with the hypothesis that regressive evolution of eyes proceeds by random mutations, in the absence of selection, that ultimately lead to the loss of gene function in protein-coding genes specific to the eye pathway.

Amino Acid Sequence↗