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Sildenafil in the management of primary pulmonary hypertension.

Primary pulmonary hypertension is a rare disorder of unknown etiology with a poor prognosis. There is no cure, and drug therapy is effective in only a few patients. Calcium-channel antagonists and anticoagulants are the mainstay of therapy. Prostacyclin therapy leads to significant clinical improvement but its use is restricted due to high cost and complex drug delivery systems. Sildenafil is a selective vasodilator and has been shown to be effective in decreasing pulmonary vascular resistance in animal models of pulmonary hypertension. We report the use of sildenafil in two patients of primary pulmonary hypertension who were refractory to conventional drug therapy.

Adult↗

[From dysmorphology to genetics].

OBJECTIVE: Consider how the advances in molecular medicine in recent years have lead to a great improvement in understanding dysmorphogenesis and the diagnosis of different syndromes of multiple congenital anomalies and mental retardation (ACM/RM). DEVELOPMENT: Development of the human brain depends on a very precise sequence of differentiation, proliferation and maturation. Anomalous processes occurring during embryonic development tend to affect the more complex organs. Thus cerebral structure and function are often affected in ACM/RM syndromes. In fact, RM is present in almost half the children with ACM. In recent years different syndromes involving malformations have been described. Their recognition was made possible by the development of imaging techniques, which permit improved morphological analysis of the dysplasic cortex and the availability of new genetic data. Chromosome anomalies are also an important cause of RM and congenital anomalies. Molecular cytogenetic techniques, such as fluorescent hybridization (FISH), currently permit the detection of chromosome rearrangement which is undetectable using standard cytogenetic analysis. CONCLUSIONS: For a long time dysmorphology has been based on defining different syndromes using detailed clinical descriptions. These descriptions have certainly been very valuable and important for the diagnosis of many patients and genetic counselling for their families. However, advances in genetics and genomics in recent years have caused great changes in reaching the diagnosis in ACM/RM. The complexity and cost of genetic tests makes it necessary to use them only when there are sufficient clinical grounds, basically when symptoms and signs suggest a specific diagnosis.

Brain↗

Criteria for mitral valvotomy; roentgen evidence in pulmonary hypertension.

Although catheterization is the most accurate and sometimes the only adequate method of measuring pulmonary hypertension as an indication for mitral valvotomy in rheumatic heart disease, it is so costly and complex that simpler methods are desirable. Clinical evidence of pulmonary hypertension is least accurate; electrocardiography is confirmatory in half of all cases. Roentgenologic findings are more helpful; moderate or severe enlargement in the pulmonary arteries has been associated in 92 per cent of cases with resting systolic pressure of 50 to 90 mm. of mercury in the pulmonary artery. In cases in which there is little or no enlargement, hypertension may still be present and demonstrable only by catheterization. Other roentgen signs noted as helpful are abrupt narrowing of the large branches of the pulmonary artery in the middle and lower lobes, and the septal lines of Kerley.

Blood Pressure↗

[How to test at once six cytokines in samples as small as 25 microl?].

Inflammatory and regulatory or anti-inflammatory cytokines (TNFalpha, IL-1beta, -6, -8, -10 and -12) regulate both the humoral and cellular immune responses. Cytokines have diverse peripheral and central functions. They are critical mediators of protective host responses, including defense against microbial invasion and tumorigenesis. However, the production of specific proinflammatory cytokines must be tightly regulated and compartmentalized to prevent the overexpression of these molecules that can end in chronic inflammation and tissue injury. Many diseases like autoimmune disease (rheumatoid arthritis, multiple sclerosis, arteriosclerosis, Crohn's disease), neurodegenerative disease (Alzheimer's and Parkinson's disease), tumor invasion and metastasis correlate with a deregulation in cytokine action. Thus, cytokines network provides an attractive and intensely competitive area of potential targets for therapeutic intervention. To monitor such secretion patterns in presence of putative drugs obtained by high throughput screening (HTS) some new techniques recently appeared on the market. We here compared results obtained by CBA (BD Cytometric Bead Array) to IC50 values obtained by classical sandwich Elisa. The complexity and cost of this new method is largely compensated by simultaneous testing of 6 cytokines in only 25 micro L of cell supernatant.

Flow Cytometry↗

Best practices and safety issues in the ICU.

Intensive care is the most complex and costly care provided in hospitals. These case studies look at what hospitals are doing to better staff their ICUs, prevent errors, incorporate information technology, involve family members and reduce unnecessary costs.

Benchmarking↗

Preoperative lymphoscintigraphy and internal mammary sentinel lymph node biopsy do not enhance the accuracy of lymphatic mapping for breast cancer.

Lymphoscintigraphy (LS) may identify sentinel lymph nodes (SLNs) outside the axilla. Biopsy of these nodes could improve the accuracy of lymphatic mapping (LM) for breast cancer (BC) if a significant number of tumor-positive extra-axillary sentinel nodes are identified. To address this, we evaluated the impact of the use of preoperative LS and biopsy of axillary and internal mammary SLNs in women with BC. From October 1997 to July 2003, 175 women with breast cancer received technetium sulfur colloid, and images were obtained. Isosulfan blue dye was injected intraoperatively, and LM of the axillary and internal mammary lymph node basins was performed with a hand-held gamma probe. The anatomic location and histologic status of all SLNs identified with LS and LM was recorded, and the impact of the findings on LS and internal mammary LM were evaluated. LS showed SLN in 127/175 (73%) women and "hot spots" were found with the gamma probe in 142/175 (81%). At least one SLN was identified by LM in 168/175 (96%) patients, and 48/168 (29%) had metastases. One hundred sixty-two of 168 (96%) patients had SLN exclusively in the axilla. Only 10 of 175 (6%) women had internal mammary (IM) SLNs seen on LS. LM identified IM sentinel nodes in 6 of these 10 patients, but none were involved with tumor. Preoperative lymphoscintigraphy and biopsy of internal mammary sentinel nodes do not enhance the accuracy of lymphatic mapping for breast cancer. Omitting lymphoscintigraphy reduces the complexity and cost of lymphatic mapping without compromising the identification of tumor-positive sentinel nodes.

Adult↗

Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura.

Extracorporeal immunoadsorption of plasma to remove IgG and circulating immune complexes (CIC) was evaluated as a therapy for adults with treatment-resistant immune thrombocytopenic purpura (ITP). Seventy-two patients with initial platelet counts less than 50,000/microL who had failed at least two other therapies were studied. They received an average of six treatments of 0.25 to 2.0 L plasma per procedure over a 2- to 3-week period using columns of staphylococcal protein A-silica (PROSORBA immunoadsorption treatment columns; IMRE Corp, Seattle, WA). The treatments caused an acute increase in the platelet count to greater than 100,000/microL in 18 patients and to 50,000 to 100,000/microL in 15 patients. The median time to response was 2 weeks. Responses were transient (less than 1 month duration) in seven of those patients (10%), but no additional relapses were reported over a follow-up period of up to 26 months (mean of 8 months). Clinical responses were associated with significant decreases in specific serum platelet autoantibodies (including anti-glycoprotein IIb/IIIa), platelet-associated Ig, and CIC. Thirty percent of treatments were associated with transient mild to moderate side effects usually presenting as a hypersensitivity-type reaction. Continued administration of failed therapies for ITP, which always included low-dose corticosteroids (less than or equal to 30 mg/d), had no demonstrable influence on the effectiveness of immunoadsorption treatment but did depress the incidence and severity of side effects. The degree of effectiveness of protein A immunoadsorption therapy in patients with treatment-resistant ITP is promising and further controlled studies in this patient population are warranted.

Adult↗

Enhanced biotransformation of furfural and hydroxymethylfurfural by newly developed ethanologenic yeast strains.

Furfural and hydroxymethylfurfural (HMF) are representative inhibitors among many inhibitive compounds derived from biomass degradation and saccharification for bioethanol fermentation. Most yeasts, including industrial strains, are susceptible to these inhibitory compounds, especially when multiple inhibitors are present. Additional detoxification steps add cost and complexity to the process and generate additional waste products. To promote efficient bioethanol production, we studied the mechanisms of stress tolerance, particularly to fermentation inhibitors such as furfural and HMF. We recently reported a metabolite of 2,5-bis-hydroxymethylfuran as a conversion product of HMF and characterized a dose-dependent response of ethanologenic yeasts to inhibitors. In this study, we present newly adapted strains that demonstrated higher levels of tolerance to furfural and HMF. Saccharomyces cerevisiae 307-12H60 and 307-12H120 and Pichia stipitis 307 10H60 showed enhanced biotransformation ability to reduce HMF to 2,5-bis-hydroxymethylfuran at 30 and 60 mM, and S. cerevisiae 307-12-F40 converted furfural into furfuryl alcohol at significantly higher rates compared to the parental strains. Strains of S. cerevisiae converted 100% of HMF at 60 mM and S. cerevisiae 307-12-F40 converted 100% of furfural into furfuryl alcohol at 30 mM. The results of this study suggest a possible in situ detoxification of the inhibitors by using more inhibitor-tolerant yeast strains for bioethanol fermentation. The development of such tolerant strains provided a basis and useful materials for further studies on the mechanisms of stress tolerance.

Biotransformation↗

[Causes and treatment of recurrent varices of the lower limbs].

Recurrence of varicose veins following surgery is a common, complex and costly problem in vascular surgery. The aims of our study were to determine the causes of recurrent varicose vein disease, to compare the preoperative duplex ultrasound findings with surgical findings, and to evaluate the efficacy of our surgical policy. We retrospectively studied 49 limbs operated on for recurrent varicose veins. All patients were monitored 6 weeks and 6 months after surgery and then underwent clinical examination in June 2005. Preoperative duplex ultrasound showed 100% specificity and 97% sensitivity. The patients were operated on for recurrence 152.2 +/- 95.5 months after the primary operation. The incidence of postoperative minor complications was 8.1% and of re-recurrence 10.2%. In 73.5% of patients during surgical re-exploration of the groin we found one or more tributaries of the great saphenous vein/common femoral vein, producing reflux. In 90.1% of cases we also treated incontinent perforator vessels. We recommend surgical re-exploration of the sapheno-femoral venous junction and thorough preoperative study of the perforator vessels in all patients with recurrent varicose veins.

Adult↗

Optimizing malarial epidemiological studies in areas of low transmission.

Malaria risk factor studies have traditionally used microscopy readings of blood slides as the measure of malaria infection in humans, although alternatives are available. There is the need for an assessment of how the use of these alternative diagnostic approaches will influence the efficiency and significance of epidemiological studies. In an area of Sri Lanka with known risk factors for malaria, two cross-sectional surveys were done at the start and at the peak of transmission season. Microscopy was compared with enzyme-linked immunosorbent assays (ELISA) and polymerase chain reaction (PCR). The major risk factor in this area was the location of houses relative to confirmed vector breeding sites. At the peak of the transmission season, the results pointed in the same direction, irrespective of the diagnostic method used. However, the importance of distance from the breeding site was not statistically significant when microscopy was used, which can be explained by the lower prevalence of microscopy positivity in comparison to the prevalence of ELISA- and PCR-positivity. This study suggests that in low-transmission areas, such as Sri Lanka, smaller sample sizes can be used for epidemiological research studies using PCR instead of microscopy to estimate parasite prevalence. This efficiency gain has to be weighed against the higher cost and complexity of the PCR. PCR cannot replace microscopy as the standard diagnostic procedure at the field level. ELISA is not directly comparable with microscopy and PCR but it can also be a useful tool in malaria epidemiological studies. This study indicates that cross-sectional surveys are only efficient if they take place during peak transmission season. Cross sectional surveys currently implemented by the Sri Lankan government in response to local malaria outbreaks can form the basis for valid epidemiological studies and be used for the generation of malaria risk maps if samples were also analyzed using PCR.

Cross-Sectional Studies↗

In-training evaluation using hand-held computerized clinical work sampling strategies in radiology residency.

PURPOSE: The in-training evaluation and final in-training evaluation are the mainstay format for evaluation summaries in Canadian residency training programs. This study investigates the feasibility of a clinical work sampling (CWS) approach to evaluation in radiology residency, with the aid of personal hand-held computing devices METHODS: This study was conducted over a 1-year period with 14 radiology residents spanning 4 postgraduate years. Residents were provided with a hand-held device to enter evaluation data, with entries assessing 9 categories of resident performance. Results from the CWS entries were compared with standard in-training evaluations completed at the end of the residents' rotations, as well as with an established annual objective evaluation tool. RESULTS: The overall reliability of the CWS approach according to the observed 7 forms per resident was 0.62, suggesting that a minimum of 20 forms would be required to achieve a reliability of 0.80. For the in-training evaluation report (ITER), internal consistency was 0.98, reflecting very high correlations between categories and indicating that the individual categories are not discriminating. Correlation across rotations was 0.36, which is low for summative evaluation. Correlation between the 2 measures was 0.47 (P = 0.09); neither measure was correlated with the American College of Radiology evaluation. CONCLUSION: The CWS strategy is feasible for adaptation to radiology residency, although compliance with voluntary entries was less than expected. It is not clear whether this reflects the additional burden of using the hand-held device, the fact that entries were voluntary rather than mandatory, or the many demands on both residents and evaluators. The added potential of this evaluation format includes the opportunity to discuss performance at the time of data entry, rather than resorting to the usual end-of-rotation evaluation. Nevertheless, the study has shown that the ITER remains only of marginal value for summative evaluation; the addition of the CWS would require at least 20 forms for acceptable reliability and might not justify the additional cost and complexity.

Canada↗

Study design and genetic susceptibility factors in the risk assessment of chemical carcinogens.

Molecular epidemiology approaches are being employed to examine the validity and elucidate the basis for hypothesized associations of genetic susceptibility factors with common malignancies due to carcinogen exposure. This approach integrates traditional epidemiologic study designs with state-of-the-art laboratory assays. Advantages of this strategy include the possibility of gaining insight into mechanisms and better exposure assessment. Disadvantages include added complexity and cost. Three examples of pharmacogenetic risk factors are discussed: the first two are p450 enzymes whose activity has been associated with susceptibility to lung cancer (debrisoquine hydroxylase, aryl hydrocarbon hydroxylase), and the last, N-acetyltransferase, a non-p450 enzyme, has been associated with bladder cancer susceptibility. In this context, a case-control study which examined the hypothesis of an association between the debrisoquine metabolic phenotype and lung cancer is discussed. While various studies from the molecular to the population level provide evidence to support each of these associations, methodologic problems exist and a causal association remains to be decisively demonstrated. New epidemiologic studies, the application of improved DNA based tests for the genotype, and further basic investigations regarding the mechanisms of the proposed associations continue, and progress is anticipated in the resolution of these questions with important consequences for our understanding of chemical carcinogenesis in these common malignancies. While these associations remain controversial, the existence of wide interindividual variation in the population in the ability to metabolize certain chemical carcinogens is certain and this argues for a conservative approach in the regulation of chemical carcinogens.

Biotransformation↗

Cone-beam transmission computed tomography for nonuniform attenuation compensation of SPECT images.

This paper develops and tests cone-beam transmission computed tomography (CB-CT) for attenuation compensation of SPECT images. CB-CT was implemented on a rotating gamma camera with a point source (1-2 mCi) of 99mTc, and a light-weight aluminum source holder. A cone-beam collimator may be used but is not required. Since the point source is either located at the collimator focal point, or the camera is uncollimated, CB-CT has excellent sensitivity (at least 150 times that of a parallel-hole, high-resolution collimator). The predicted resolution is equal to the intrinsic gamma camera resolution (3-4 mm), which is much higher than for a high-resolution, parallel-hole collimator (10-20 mm). In the present study, CB-CT provided low noise, high-resolution attenuation maps for use in a nonuniform attenuation-weighted backprojection algorithm. The attenuation compensation accuracy was tested using basic geometries of line sources and nonuniform density models. For the appropriate scaling of the attenuation map, the attenuation compensation was accurate and removed the SPECT image distortion associated with nonuniform attenuation. Attenuation maps acquired either with cone beam collimator or without any collimator were both successful. Using CB-CT, SPECT can thus be made much more accurate without adding unduly to the imaging time, complexity, or cost.

Algorithms↗

Evaluation of obstructive sleep apnoea in Singapore using computerised polygraphic monitoring.

There is no information of the prevalence and severity of obstructive sleep apnoea (OSA) in Asian snorers. One reason is the complexity and cost of a full polysomnographic recording. We have studied 37 snorers using an ambulatory recording system (Vitalog CA). Overnight recordings for seven hours were made of: 1) Respiratory pattern using respiratory inductance plethysmography; 2) Heart rate from the electrocardiograph (ECG); 3) Body position; 4) Body movements; 5) Oxygen saturation using finger-probe oximetry. The data were stored and analysed and scored using a dedicated microcomputer. Twenty-eight patients had OSA based on polygraphic criteria. The most consistent clinical findings in these patients were daytime somnolence and short thick necks. Respiratory events, oximetry and arousals during sleep showed a graded response according to the severity of excessive daytime somnolence. We conclude that OSA may not be uncommon in Asian patients and that the clinical severity can be confirmed by simplified polygraphic recordings using microcomputer analysis.

Adult↗

[Organization of radiotherapy of patients with cancer of the mouth].

During the last 15 years, the incidence of oropharyngeal cancer in the Chelyabinsk region increased from 2.0 to 5.7 per 100,000 of population. Lethality was 2.8 per 100,000. The radiological service of the region includes 4 radiological departments with a total of 270 beds equipped with 7 and units for gamma-ray teletherapy whereas in the oncological dispensary intrathecal gamma-ray therapy can be performed. Under these conditions, it is justified to plan treatment in the regional dispensary and to carry out gamma-ray teletherapy in the radiological department located most closely to the patient's place of residence whereas interstitial therapy should be performed in the dispensary. The said approach assured higher efficacy of treatment, better psychosocial status of patients and shorter duration of therapy; it holds promise for tumors of other sites requiring complex and costly procedures of intrathecal irradiation.

Brachytherapy↗

Divergent post and tube and screw systems for the short crown preparation.

A one-step divergent sliding post incorporated through a crown casting provides effective auxiliary retention for the short crown preparation, especially when interocclusal distance is minimal. With this procedure, retention is gained from the residual walls of both the extracoronal preparation and the canal preparation even though their respective axes may be divergent. A tube and screw attachment may also be incorporated inside and understructure coping to secure a permanently cemented short crown-and-bridge retainer. Both techniques may be used separately or in combination for maximal retention and, despite the additional complexity and cost, will compensate for the short extracoronal walls of the second molar preparation.

Crowns↗

Pharmacologic approaches to the prevention and treatment of neonatal hyperbilirubinemia.

Because of the high frequency, serious sequelae, and complex and costly management, neonatal jaundice is a good candidate for preventive treatment. In this respect the clinical problem of neonatal jaundice has many similarities with the problem of hemorrhagic disease of the newborn. Both conditions are transient peculiarities of newborn metabolism. Most neonates exhibit the biochemical abnormality, but a small minority is placed in jeopardy of life or suffers serious sequelae. In both conditions a loose relationship exists between the degree of biochemical abnormality and the clinical manifestations that are poorly predicted by monitoring the abnormalities. The administration of vitamin K at birth corrected the biochemical abnormalities and eliminated clinical hemorrhagic disease. The simplicity, efficacy, and safety of vitamin K prevention of hemorrhagic disease of the newborn is the prototype in the search for the solution to the problem of neonatal jaundice. For most neonates, antenatal phenobarbital comes close to this prototype in terms of efficacy and simplicity. The combination of antenatal and postnatal therapy seems suitable for use in preterm labor in combination with tocolysis. This recommendation is conditional on the demonstration of safety by long-term follow-up. The competitive inhibition of HO by synthetic metalloporphyrins offers an even simpler solution, but the level of efficacy achieved with the doses and compounds used so far are not comparable with that of phenobarbital. For the time being, phenobarbital is recommended for population groups with high risk of severe neonatal jaundice, or scarcity of resources for the management of neonatal jaundice with phototherapy and exchange transfusion.

Bilirubin↗