Tuberculosis: a global overview of the situation today.

The overall tuberculosis situation in the world in 1990 and its recent trends are reviewed by an analysis of the case notifications to WHO and tuberculosis mortality reports. Estimates of the prevalence of tuberculosis infection and the incidence of tuberculosis disease and deaths predicted in 1990 were carried out with simple epidemiological models. Approximately one third of the world's population is infected with Mycobacterium tuberculosis. In the past decade, an average of 2.5 to 3.2 million cases were notified every year globally, the small decrease in notification rates in recent years being offset by population growth. In 1990, an estimated 8 million people developed tuberculosis worldwide and 2.6 to 2.9 million died. The majority of these cases and deaths occurred in Asia, with an increasing number among HIV-infected individuals, especially in Africa where an upward trend is clearly detectable. Data on tuberculosis cases notified by WHO Member States demonstrate the magnitude of the problem but must be interpreted with caution. Being less than the expected incidence, they reflect the inadequacies of tuberculosis control programmes. This review confirms the very high global magnitude of the tuberculosis problem and calls for an urgent revitalization of tuberculosis control programmes throughout the world.     

Characterization of P-glycoprotein and multidrug resistance proteins in rat kidney and intestinal cell lines.

The activity of P-glycoprotein (Pgp/MDR1/ABCB1) and multidrug resistance proteins (MRP/ABCC) influence the pharmacokinetics and bioavailability of many drugs. Few suitable cell lines for the study of drug transport exist. Additional non-human cell lines may help clarify species differences and contribute to the current knowledge of drug transport. The aim of the present study was to characterize three rat epithelial cell lines for transporter expression and activity. Transporter expression was assessed in intestinal IEC-6 and renal GERP and NRK-52E cells using RT-PCR and Western blot analysis. Pgp and Mrp transport activity were analyzed by measuring calcein accumulation and glutathione-S-bimane efflux, respectively. The three cell lines showed Pgp expression and Pgp-dependent transport, both decreasing with culture time after reaching confluency. Besides Pgp, cells expressed Mrp1, Mrp3, Mrp4, and Mrp5, while Mrp2 and Mrp6 were absent. In addition, they showed temperature- and Mrp-dependent efflux of glutathione-S-bimane. Exposure to a panel of different inhibitors showed that this efflux was probably mediated by Mrp4. In conclusion, the three rat epithelial cell lines investigated showed Pgp and Mrp expression and transport. Mrp dependent transport was most likely mediated by Mrp4. In future, these cell lines may be used as in vitro models to study drug transport.     

Early complications of stenting in patients with congenital heart disease: a multicentre study.

AIMS: Stenting has become an established interventional cardiology procedure for congenital heart disease. Although most stent procedures are completed successfully, complications may occur. This multicentre study evaluated early complications after stenting in patients with congenital heart disease, including potential risk factors. METHODS AND RESULTS: In this combined Dutch-Belgian retrospective study, 309 consecutive patients had undergone 366 catheterizations and received 464 stents in 13 different anatomical positions (418 sites). Seventy-two stenting-related complications (19%) occurred, of which 24 (5.7%) were major. Seven procedure-related deaths were documented (2.3%). Stent malpositioning and embolization were most common (7.7%). The use of non-premounted stents tended to be associated with higher complication rates. Centre inexperience with stenting and stenting of native vs. post-surgical stenosis tended to be associated with increased major complication rates. CONCLUSION: After stenting, complications are common for congenital heart disease. The vast diversity of stenotic sites combined with relatively small patient populations makes these procedures sensitive to complications. Combining operator experience may reduce the risks of stenting in congenital heart disease. The availability of premounted stents for greater vessel diameters will likely reduce incidences of stent migration and embolization.     

Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid.

A specific and sensitive radioimmunoassay for the determination of levels of zalcitabine in human plasma, urine, and cerebrospinal fluid has been developed. Commercially available radiolabel and antiserum (Sigma Chemicals) were used after dilution in assay buffer. Prior to the immunoassay, standard and patient samples were subjected to solid-phase extraction on silica columns in order to obtain purified samples. The lower limit of quantitation was determined to be 1 ng/ml. Intra- and interassay variations were less than 11% for a number of quality control samples of drug in plasma and urine. Results from parallelism studies with plasma and urine demonstrated that samples outside the standard range (1 to 30 ng/ml) could be diluted by blank plasma or assay buffer, respectively. A large number of related compounds and potentially coadministered drugs were tested for cross-reactivity. Stability tests showed that heat treatment for 30 min at 60 degrees C or storage for 1 month at -30 degrees C did not affect zalcitabine concentrations in plasma or urine. The radioimmunoassay with solid-phase extraction for sample cleanup discussed here has been successfully applied in a pharmacokinetic study of a single patient, demonstrating its applicability for clinical pharmacokinetic research with zalcitabine.     

Evaluation of collateral blood flow by myocardial contrast enhanced echocardiography.

Contrast enhanced cross sectional echocardiography is a new method for the real-time evaluation of regional myocardial perfusion. Two patients with a history of anteroseptal myocardial infarction and echocardiographically detected septal dyskinesia were examined by this new method. The first patient had two severe stenoses of the left anterior descending coronary artery and normal echocontrast opacification of the interventricular septum caused by collaterals from the right coronary artery. The second patient had good patency of left anterior descending coronary artery and no septal opacification. Thus contrast enhanced cross sectional echocardiography can be used to assess the importance of collateral blood flow in the myocardium.     

Metabolic alkalosis after pediatric cardiac surgery.

OBJECTIVE: To determine occurrence, causes and associated mortality of postoperative metabolic alkalosis in pediatric cardiac surgery. METHODS: We retrospectively analyzed clinical and biochemical variables of 186 consecutive cardiac operations other than ductal ligations on children less than 2 years old during the years 1999 and 2000. Metabolic alkalosis was defined as a pH>7.48 corrected for PCO2, with a base excess > or =5 on two or more consecutive measurements during an 8h period. RESULTS: Median age was 15 weeks [range 2 days-95 weeks] and median weight 4.5 kg [range 2.1-15.7 kg]. In 157 cases, cardiopulmonary bypass was used. In 92 [49%] procedures, metabolic alkalosis occurred with the highest corrected pH 24.3h after operation. Multivariate regression analysis associated age [P<0.001], cardiopulmonary bypass [P<0.001] and preoperative ductal dependency [P=0.04] with postoperative metabolic alkalosis. Of the surgical procedures the arterial switch for transposition of the great arteries [n=19] was strongly associated with metabolic alkalosis [100%, P<0.001]. Hemodilution appeared to enhance the development of alkalosis: those who experienced alkalosis had been hemodiluted to a greater extent [P=0.007]. Nearly 95% of patients experienced some increase in bicarbonate, but patients with metabolic alkalosis experienced more than those without [5.9 versus 3.5 mmol/l, P<0.001]. There were four postoperative deaths, only one coincidental with metabolic alkalosis. CONCLUSIONS: Metabolic alkalosis has a high incidence after pediatric cardiac surgery, strongly associated with younger age, cardiopulmonary bypass, preoperative ductal dependency and perioperative hemodilution. Early recognition allows for timely therapeutic intervention.     

An approach to protein restriction in children with renal insufficiency

Children with mild to moderate renal insufficiency may be at an increased risk for developing glomerulosclerosis and subsequent renal failure. Low protein diets (LPD) have been shown to delay the progression of renal insufficiency in laboratory animals and may be of benefit in adult humans. The nutritional costs of a LPD in adults are reportedly minimal. We review the protein and caloric requirements of growing children and discuss the potential harmful effects and benefits of an LPD in this population. We also discuss dietary adherence and the difficulty of designing an LPD for children. We conclude that the protein content of a typical American diet can safely be reduced to, but not below, the recommended daily allowance for protein if diets are carefully planned, patients and their parents extensively counseled, and if dietary supplements are given to help meet the caloric and vitamin-mineral nutrient needs of growing children. In addition, ongoing nutritional assessment, counseling, and frequent monitoring of growth, diet and biochemical indicators of protein status are essential for maintaining the health of these children.     

Variation of prostate-specific antigen expression in different tumour growth patterns present in prostatectomy specimens

Summary A series of 55 randomly chosen radical prostatectomy specimens was analyzed for expression of prostate-specific antigen (PSA) by immunohistochemical techniques. Tissue sections were selected in such a manner that in addition to glandular benign prostatic hyperplasia (BPH), one or more different prostatic tumour growth patterns were present. Four monoclonal antibodies, directed against three different PSA epitopes, and one polyclonal anti-PSA antiserum were used. Expression of PSA was compared with that of prostate-specific acid phosphatase (PAP), recognized by two different polyclonal antisera. A critical dilution aimed at a maximum of staining intensity on BPH tissue sections was chosen for all antibodies. Anti-PSA and anti-PAP antisera stained essentially all BPH samples (over 90%). Irrespective of the nature of the antibodies used, PSA expression was found to be decreased in prostatic carcinoma. A clear cut relationship was found between immunoreactivity for PSA and the degree of differentiation of the tumour area. Under the experimental conditions used the PSA monoclonal antibodies stained only 1 out of 10 undifferentiated carcinomas, whereas 50% to 70% of the well- and moderately-differentiated carcinomas showed immunoreactivity. This correlation was less pronounced with the PAP staining pattern. If the PSA antibody titer was raised the percentage of clearly staining undifferentiated carcinomas could be considerably increased (up to 60%–100%), indicating that PSA expression is not absent, but lowered in most (if not all) undifferentiated carcinomas.     

The use of the D-dimer test in combination with non-invasive testing versus serial non-invasive testing alone for the diagnosis of deep-vein thrombosis.

We studied the usefulness of the determination of plasma D-dimer levels (using an ELISA) in combination with non-invasive testing with impedance plethysmography (IPG) or real-time ultrasonography (US) for the diagnosis of deep-vein thrombosis (DVT), in outpatients with clinically suspected DVT. This combined approach was compared to serial non-invasive testing alone in these patients. The sensitivity of a positive D-dimer test (greater than 300 micrograms/l) for the presence of DVT was 100% (70/70 patients; 95% C.I.: 95-100%), whereas the specificity was 29% (69/239 patients; 95% C.I.: 23-34%). The proportion of patients in which a definitive decision about the presence or absence of DVT could be made on the day of referral, was calculated for both approaches. When applying the combined approach, in 42% of all referred patients the diagnosis of DVT could either be established or refuted on entry, as opposed to only 19% of patients using serial non-invasive testing alone. Also, the costs per DVT diagnosed were calculated for the two diagnostic approaches. For the diagnosis of DVT the costs using serial IPG were comparable to the costs using the combination of IPG and the D-dimer test. The same conclusion holds for the comparison of serial US with the combination of US and D-dimer testing. We conclude that for the diagnosis of DVT in symptomatic outpatients the combination of non-invasive testing with the D-dimer test might be preferred over serial non-invasive testing alone, although the safety of such an approach remains to be established in future management studies.