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Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy.

Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations. The latter mutation has not been associated with famciclovir resistance. Thus, the addition of famciclovir to lamivudine therapy in persons with group 2 lamivudine resistance may lead to virus suppression. The effect of lamivudine/famciclovir combination therapy on HBV infection was monitored in 5 lamivudine-resistant patients by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus. No patients treated with combination therapy had a decline in HBV load >1 log10. Continual evolution of the viral polymerase was detected in association with virologic resistance to both drugs. Cloning experiments identified the preexistence of these multidrug-resistant virus variants as minority species prior to addition of famciclovir therapy. HBV resistance to lamivudine monotherapy is associated with a complex mixture of variants that limit the efficacy of second-line nucleoside-analogue therapy. First-line potent combination therapy may reduce the emergence of HBV drug resistance.

2-Aminopurine↗

Transitional-cell carcinoma of the renal pelvis: ureteroscopic and percutaneous approach.

There are a variety of publications advocating the ureteroscopic or the percutaneous approach for the treatment of transitional cell carcinoma of the renal pelvis. The diagnostic tool of choice for the upper urinary tract and collecting system is the flexible ureteroscope. One of the major concerns about ureteroscopic management of renal disease initially was the lack of flexibility of the instruments and therefore the inability to deal with demanding sites. The advent of new ureteroscopic techniques, as well as the continuous evolution of the technology, have paved the way for safe and effective access to the upper urinary tract. In the hands of an experienced urologist, such procedures can provide reliable treatment options for small upper urinary tract lesions. Coupling minimal morbidity with ever-improving optics and flexibility, the ureteroscope of today leaves no area of the urinary tract unseen. In patients with bulky tumors or in whom easy access and resection is not possible ureteroscopically, the percutaneous approach to the renal pelvis, although more invasive, provides a better working environment. Clearly, the most difficult aspect of ureteroscopic access to the lower pole is not just visibility but the loss of deflection caused by passage of various instruments through the working channel. Direct access via percutaneous approach with a large resectoscope avoids these problems.

Carcinoma, Transitional Cell↗

Laparoscopically implantable nerve-stimulating electrode (LINSE): application to the cavernous nerve in acute and chronic canine models.

Using a new laparoscopic procedure, we investigated stimulation of the cavernous nerves to achieve erection in a canine model. The technique was developed during acute experiments in four dogs, following which, chronic studies (4- to 6-weeks survival after surgery) were undertaken in three dogs. A monopolar cuff electrode was inserted laparoscopically by a transperitoneal approach and placed around the cavernous nerve. The leads were brought out to the subcutaneous space, where they were attached to stimulation receivers that could be activated by an external radiofrequency transmitter. An intracavernous pressure elevation indicative of successful stimulation was obtained acutely in five of eight cavernous nerves in the four acute-study dogs and in four of six nerves in the three chronic-study dogs. The implanted equipment associated with four of six cavernous nerves failed mechanically in the chronic-study animals, such that only two receiver-electrode sites were intact at the time of sacrifice 4 to 6 weeks later. Transmitter-driven stimulation of one of these two sets produced an intracavernous pressure rise above 100 cm H2O. We present this technique as part of the continuing evolution of laparoscopy as both a research and a clinical tool. The present use of the laparoscopically implantable nerve-stimulating electrode is a new animal research tool and a potential first step in the human application of the technology.

Animals↗

Laparoscopic common bile duct exploration: a review.

The use of laparoscopic methods to explore the common bile duct is now well-established, although they continue to undergo continuous evolution and improvement. In experienced hands laparoscopic management of choledocholithiasis may be undertaken with morbidity and mortality at least as good as that of open surgery. The use of diagnostic endoscopic retrograde cholangiopancreatography (ERCP) with or without sphincterotomy before or after laparoscopic intervention must be evaluated. The degree of acceptance that laparoscopic techniques for common bile duct exploration (CBDE) will achieve within the surgical community remains to be determined, but will likely increase as more practicing surgeons familiarize themselves with them.

Cholangiography↗

Prevalence of the type I and type II DHFR genes in trimethoprim-resistant urinary isolates of Escherichia coli from Greece.

Trimethoprim resistance in 64 Escherichia coli urinary isolates from five hospitals in Greece was studied. Of the 40 isolates exhibiting transferable high-level resistance (MIC > 1024 mg/L), 21 hybridized with a specific probe for dihydrofolate reductase (DHFR) I, 13 with a probe for DHFR II, and one with a probe for DHFR V. Eleven isolates hybridized with a probe for transposon Tn7. Among the 17 isolates with non-transferable high-level resistance, seven hybridized with the probe for DHFR I, three with the probe for DHFR II, and eight were Tn7-positive. None of the seven isolates with low-level resistance (MIC 4-1024 mg/L) reacted with the probes used. Of the 28 isolates positive for DHFR I, 12 (43%) failed to hybridize with the Tn7 probe. Conversely, three isolates hybridized with the Tn7 probe, but not with the probe for DHFR I. Colony hybridization experiments showed that all but three transconjugants reacted similarly to their respective parent strains. The plasmids coding for trimethoprim-resistant DHFRs were found to differ on the basis of restriction enzyme analysis. These findings suggest that trimethoprim resistance among E. coli urinary isolates in Greece is mediated predominantly by heterogeneous transferable plasmids encoding either DHFR I or DHFR II. The dissociation between DHFR I and Tn7, together with the high incidence of trimethoprim-resistant isolates which did not hybridize with the probes for the common DHFR I or II types, indicates the continued evolution of trimethoprim resistance determinants.

Bacteriuria↗

The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents.

OBJECTIVES: The Alexander Project is a continuing surveillance study, begun in 1992, examining the susceptibility of pathogens involved in adult community-acquired respiratory tract infections (CARTI) to a range of antimicrobial agents. MATERIALS AND METHODS: This study tested the susceptibility of isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected between 1998 and 2000 to 23 antimicrobials. Minimum inhibitory concentrations of agents were determined using the broth microdilution method and interpreted according to NCCLS and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. RESULTS: In total, 8882 isolates of S. pneumoniae, 8523 isolates of H. influenzae and 874 isolates of M. catarrhalis were collected during 1998-2000 from centres in 26 countries. The world-wide prevalence of penicillin resistance (penicillin MICs > or = 2 mg/l) in isolates of S. pneumoniae was 18.2% over the study period, and the prevalence of macrolide resistance (erythromycin MICs > or = 1 mg/l) in this pathogen was 24.6%. Over the study period, macrolide resistance exceeded penicillin resistance in 19 of the 26 countries included in the study. Of the non-fluoroquinolone agents, the only oral agents to which over 90% of S. pneumoniae isolates were susceptible at both NCCLS and PK/PD breakpoints were amoxicillin (95.1%) and co-amoxiclav (95.5-97.9%). The prevalence of fluoroquinolone-resistant S. pneumoniae (ofloxacin MICs > or = 8 mg/l) was 1.1%. Gemifloxacin was the most potent fluoroquinolone tested against S. pneumoniae (99.9% susceptible). In isolates of H. influenzae, beta-lactamase production was 16.9%, whereas the prevalence of beta-lactamase-negative, ampicillin-resistant strains was low (0.2%). beta-Lactamase production in M. catarrhalis world-wide remained high over the period studied (92.1%). Using PK/PD breakpoints, the most active non-fluoroquinolone agents against H. influenzae were ceftriaxone (100% susceptible), cefixime (99.8%) and co-amoxiclav (98.1-99.6%). Co-amoxiclav, cefdinir and cefixime (100%) were the most active beta-lactams against M. catarrhalis. Both H. influenzae and M. catarrhalis were highly susceptible to the fluoroquinolones. CONCLUSIONS: These data demonstrate the continued evolution of and geographical variation in bacterial resistance and highlight the need for appropriate prescribing of antimicrobials in CARTI, using agents with adequate activity, based on local susceptibility profiles and PK/PD parameters.

Anti-Bacterial Agents↗

The epidemiology of end-stage renal disease in the Baltic countries: an evolving picture.

INTRODUCTION: The epidemiology of end-stage renal disease (ESRD) and renal replacement therapy (RRT) is under continuous evolution all over the world. Of particular interest is the development of RRT in the countries of the former Soviet bloc which underwent great political and socio-economical changes in the last decade. We report here the epidemiological analysis of ESRD and RRT in the three Baltic countries: Lithuania, Estonia, Latvia. Subjects and methods. This epidemiological report is based on data from centre questionnaires which were collected from 1996 onwards, with a response rate of 98-99%. RESULTS: The prevalence/incidence of RRT patients in 1999 were 213/99.5 p.m.p. in Lithuania, 186/45.5 p.m.p. in Estonia and 172/55.8 p.m.p. in Latvia. Haemodialysis (HD) was the most common RRT modality in Lithuania (60% of prevalent patients), but not in Estonia (29%), while in Latvia it was nearly as common as renal transplantation (45 and 46%, respectively). Home HD was not performed. The proportion treated by peritoneal dialysis (PD) was very low in Lithuania (4% of RRT patients), while the percentage was higher in Latvia (9%) and Estonia (20.4%). The percentage of patients on RRT treated by renal transplantation was high throughout, representing the main modality of treatment in Estonia (50.5% of RRT prevalent patients, 94 p.m.p.) and in Latvia (46%, 79 p.m.p.) and being high in Lithuania (36%, 77 p.m.p.). The main renal diseases leading to ESRD were glomerulonephritis, pyelonephritis and diabetes. CONCLUSION: The epidemiology of RRT in the Baltic countries is undergoing rapid changes. Transplantation has reached an impressive level. A high percentage of RRT patients live with a functioning graft.

Estonia↗

The epidemiology of end-stage renal disease in Iran in an international perspective.

INTRODUCTION: The epidemiology of end-stage renal disease (ESRD) and renal replacement therapy (RRT) is under continuous evolution all over the world. We report here the epidemiological analysis of ESRD and RRT in Iran and discuss it against the background of the international situation. METHODS: This epidemiological report is based on data from centre questionnaires which were collected in Iran from 1997 onwards, with a response rate of 100%. RESULTS: The prevalence/incidence of RRT patients were 238/49.9 p.m.p. in the year 2000. Haemodialysis and kidney transplantation were the most common RRT modalities, accounting for 53.7% and 45.5% of prevalent RRT patients, respectively. The proportion treated by peritoneal dialysis was very low (<1%). Home haemodialysis was not performed. The majority of haemodialysis centres used synthetic membranes (70%) and 100% of the sessions were performed using acetate as a buffer; 42.5% of haemodialysis patients were treated with a twice-weekly regimen, whilst 49.6% were on the standard thrice-weekly regimen. The majority of RRT patients in Iran were young to middle aged. The great majority of renal allografts came from living donors (mainly unrelated to recipients). The main renal diseases leading to ESRD were diabetes and hypertension. The third most common category was "cause unknown". CONCLUSION: The epidemiology of RRT in Iran is characterized by: (i) young patient age (younger than the international average); (ii) high proportion of patients receiving renal allograft; (iii) use of living-unrelated donors as the major source of renal allografts.

Adolescent↗

Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer. II. Results, complications, and dosimetric and surgical considerations.

We have introduced a therapeutic alternative to exenteration for locally advanced vulvovaginal cancer using surgery for the vulvar (external genital) phase of this disease presentation, combined with radiotherapy for the internal genital phase (with adequate overlap of fields to protect surgical margins). The rationale is that this approach treats the cancer and its dual regional spread patterns, while at the same time preserving the bladder and/or rectum, and should be associated with less morbidity and mortality than exenterative surgery. This report updates our experience with a total of 48 treated cases (37 primary cases and 11 cases of recurrent disease). Of the 37 primary cases, 20 were FIGO stage III, 4 were FIGO stage IV, and 3 other cases represented "field" cancers involving vulva and/or cervix and/or vagina. Utilizing a Life Table analysis, the 5-year survival for the primary cases was 75.6%. Published FIGO survival for stage III is 32% and for stage IV 10.5%. Life Table analysis projects a 62.6% survival for recurrent cases and an overall 72% 5-year survival for all 48 cases treated. With 48 patients treated, 48 bladders and 48 rectums were at risk for surgical removal had exenteration been employed. One patient had a total pelvic exenteration for local failure, and one had a posterior exenteration for local failure. One bladder and one rectum were lost to permanent diversion because of radiation injury. Thus, 5 of these major viscera were lost of the 96 total, and 91 (94.8%) were retained. Radiation therapy and surgical details have been reviewed relevant to local control and local failure and complications. The continuing evolution of treatment modifications of all modalities will be discussed. The apparent advantages of this combined therapeutic approach over exenterative surgery include high probability of bladder and/or rectal preservation, low primary mortality, low treatment morbidity, and very good results in cancer control.

Brachytherapy↗

Medical technology and academic medicine: the doctor-producers' dilemma.

Diagnostic technologies differ from therapeutic technologies in several ways. Use of a diagnostic technologies is increasing faster than overall medical care. New diagnostic technologies tend to be additive and often have multiple uses. In evaluating their benefits, one should assess marginal, not absolute, utilities and measure clinical as well as financial costs. Although the use of therapeutic technologies is more circumscribed, these technologies tend to be in continuous evolution, especially when new. Comparative evaluations of therapeutic technologies are expensive and time-consuming. Pro-technology reimbursement biases may be the most important of the many factors promoting technology use. Academic medical centers, which have become increasingly clinically specialized, must now compete with their own graduates for specialty patients. At the same time they are urged to respond to contradictory national health policies that favor production of more generalists under a pro-specialty reimbursement system. Suggestions for more appropriate technology use should cover multiple approaches, including the changing of current financial incentives and the use of technology assessment to improve quality of care and education.

Academic Medical Centers↗

"A world of knowledge at your fingertips": the promise, reality, and future directions of on-line information retrieval.

Medical knowledge resources are increasingly available in electronic form, particularly on the World Wide Web. The promise of this medium is that it offers a vast "world of knowledge at your fingertips." The reality, however, is somewhat different, as information systems are not well integrated into clinical practice, prove difficult to find specific information in, and contain content of varying quality. The continued evolution of the medium in the future should, however, be beneficial, as synthesized evidence-based resources become available and these resources are integrated into electronic medical record systems.

Education, Medical↗

Molecular evidence for drug-induced compartmentalization of HIV-1 quasispecies in a patient with periodic changes to HAART.

OBJECTIVE: To perform molecular analysis of the predominant viral populations and drug-resistance mutations from plasma and peripheral blood mononuclear cell (PBMC) compartments over time from an HIV infected patient, who experienced virological failure while on different HAART regimens. MATERIALS AND METHODS: In a longitudinal study proviral and plasma HIV-1 sequences were amplified in the pol, protease and env genes and were sequenced directly and analysed phylogenetically. Virus was recovered from time points corresponding to viral load peaks using co-culturing techniques. The periodic failure of different highly active antiretroviral therapy (HAART) regimens was analysed sequencing. RESULTS: Longitudinal follow-up studies revealed four inflection peaks of plasma viraemia associated with the recovery of culturable virus in vitro, which indicated failure of the concurrent HAART regimen. Molecular analysis of viral strains revealed evidence of continual evolution and compartmentalization of drug-resistance mutants/quasispecies between plasma and PBMC, with the widest spectrum of mutations isolated from plasma. Importantly, these data show the periodic appearance and clearance of drug-resistance mutants concomitant with the introduction and withdrawal of zidovudine over time. CONCLUSION: This report is unique in showing drug-induced compartmentalization of viral quasispecies under the control of different HAART regimens in both plasma and PBMC. Introduction and withdrawal of zidovudine from the HAART regimen had direct bearing on the appearance and disappearance of specific zidovudine drug-resistance mutations in plasma-derived virus. This data has important implications for the management of HIV-infected patients with poor compliance with certain HAART regimens, and also in predicting the late emergence of drug-resistance mutations via the latent integrated provirus.

Adult↗

Characterization of middle cerebral artery occlusion infarct development in the rat using fast nuclear magnetic resonance proton spectroscopic imaging and diffusion-weighted imaging.

A nuclear magnetic resonance study of the middle cerebral artery occlusion in the rat is presented. Experiments were performed on seven animals before and after occlusion, which occurred in situ. The emphasis in this study was on evaluating rapid proton spectroscopic imaging. Data were acquired with experimental durations of between 4 and 15 minutes for a 32 by 32 spatial matrix, with 64 spectroscopic data points per spatial element. The spectroscopic data were interleaved with diffusion-weighted nuclear magnetic resonance water images of the same slice. The study was terminated at about 6 hours after occlusion. The brains were then frozen in liquid nitrogen for biochemical imaging. The results showed that the signal from N-acetyl aspartate decreased and that of lactate increased within the infarcted region. The temporal course of these intensity changes varied between animals. Nineteen cortical spreading depressions (CSD) were observed by electrophysiologic monitoring during the experiments. Of these, 11 could be unambiguously detected in the lactate images, and a further 3 were on the threshold of detectability. As only a single slice could be examined, it is possible that the centers of depression for the remaining 6 CSD were outside the slice. To the authors' knowledge, this is the first report of the measurement of CSD using proton spectroscopic imaging. Thus, it is shown that this method is valuable not only in following the continuous evolution of proton metabolites with a good spatial and temporal resolution, but also in observing transient phenomena which are believed to play an important role in the expansion of the infarcted territory.

Animals↗

The future of gastroenterology in the era of managed care.

Specialty practice in general, and gastroenterology in particular, is undergoing significant transformation as we head into the new millennium. Gastroenterologists will need to adapt to the continued evolution and consolidation of managed care. Among other issues, gastroenterologists will need strategies for dealing with pricing pressures, changing technology, increased consumerism, a perceived specialist oversupply, and a rapidly aging population. These and other developments will drive a myriad of physician responses in an effort to confront changing practice realities.

Delivery of Health Care, Integrated↗

Computer-assisted three-dimensional reconstruction of head and neck tumors.

OBJECTIVE: Because head and neck tumors reside in a complex area, having a three-dimensional (3-D) model of the patient's unique anatomical features may assist in the delineation of pathology. The authors describe a new computer technique of 3-D anatomical reconstruction from two-dimensional computed tomography (CT) and magnetic resonance (MR) data and discuss how it represents a step forward in the continuing evolution of 3-D imaging. STUDY DESIGN: The authors selected three patients with solitary head and neck tumors and reconstructed their anatomy in a 3-D format for study. The tumors represented locations in the nose and central skull base (patient 1), temporal bone (patient 2), and neck (patient 3). MATERIALS AND METHODS: MR and CT images from the individual patients were electronically transferred to workstations in the Surgical Planning Laboratory of the authors' institution. Registration (or fusion) was carried out between the MR and CT images. The desired anatomic components underwent segmentation (identification and isolation). Assembly of the segmented images was performed and the resulting structures were integrated to produce a 3-D model. RESULTS: 3-D models of the following were constructed and displayed in an interactive format on high-capacity computer workstations: 1) a skull base sarcoma with extension into the nasopharynx and nose; 2) an acoustic neuroma with internal auditory canal involvement; and 3) a metastatic recurrence of a tongue base squamous cell carcinoma in the posterior triangle of the right side of the neck with extension to the skull base. CONCLUSION: The authors' Surgical Planning Laboratory has developed a 3-D reconstruction technique that has several new features. The models provided a very good 3-D interactive representation of the tumors and patient anatomy. The need now exists to develop this method of 3-D reconstruction of head and neck tumors for potential applications in treatment, research, and medical education.

Adult↗

Percutaneous nephrolithotomy: an update.

PURPOSE OF REVIEW: Percutaneous nephrolithotomy has undergone an evolution in technique and in equipment since its introduction in the late 1970s. This evolution continues today and is evidenced by the numerous publications about the technique. This review summarizes some of the important articles over the past year. RECENT FINDINGS: Although ureteroscopy and shock wave lithotripsy predominate in the treatment of urolithiasis, percutaneous nephrolithotomy continues to play an important role. Percutaneous nephrolithotomy is advantageous as it causes minimal renal injury and maximizes stone clearance, especially in patients with complex stone disease. Although nephrostomy drainage tubes have always been placed after percutaneous nephrolithotomy, there may be specific indications for tubeless percutaneous nephrolithotomy. SUMMARY: Percutaneous nephrolithotomy continues to be an important part of the urologist's armamentarium. Recent studies have redefined the role of percutaneous nephrolithotomy and future studies will further delineate the importance of this procedure in the treatment of urolithiasis.

Clinical Trials as Topic↗

Red cell size heterogeneity during ontogeny.

To determine the manner in which erythrocyte changes occur during ontogeny, several red cell parameters were analyzed in fetuses, newborn infants, children, and adults. Although mean cell volume (MCV) and hemoglobin F (HbF) levels decreased as expected during in utero development, the coefficient of variation of red cell size (%CV), or red cell distribution width (RDW), increased from fetuses to newborn infants. In normal adults, the %CV was 15 (RDW was 13). The %CV in fetuses at 18-24 weeks gestation was 18, and it was 21 at term birth. High values for %CV or RDW indicate significant anisocytosis. Erythropoiesis at the time of birth is not a steady-state condition. Erythrocytes of a wide variety of sizes are present, with the appearance of new small cells on a background of older, larger red cells. This increased anisocytosis suggests that these new erythrocytes do not appear to be due to a smooth, continuous evolution of red cell size, but rather to discrete, perhaps clonal, changes.

Adolescent↗