The effect of treatment intensification in HIV-infection: a study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine. Prometheus Study Group.

OBJECTIVE: To evaluate the effect of treatment with ritonavir (RTV)/saquinavir (SQV)/6 stavudine (D4T) or RTV/SQV alone, with treatment intensification if needed, in protease inhibitor- and D4T-naïve HIV-1-infected individuals. DESIGN: Multicentre, open-label, randomized controlled trial. Two-hundred and eight patients were randomized to receive treatment with RTV 400 mg/SQV 400 mg twice daily or RTV 400 mg/SQV 400 mg/D4T 40 mg twice daily. Intensification of study medication with reverse transcriptase inhibitors was permitted if serum HIV-RNA remained > 400 copies/ml after 12 weeks of treatment. Follow-up of this study was 48 weeks. RESULTS: In a strict intention-to-treat analysis, counting all dropouts as virological failures, 63% [95% confidence interval (CI), 54-73%] of subjects in the RTV/SQV group (n = 104) reached a serum HIV-RNA < 400 copies/ml at week 48, as compared with 69% (95% CI, 60-78%) in the RTV/SQV/D4T group (n = 104; P = 0.379). In the on-treatment analysis these percentages were 88 and 91% respectively. Thirty-one patients intensified their study medication according to the protocol (28 in the RTV/SQV group, three in the RTV/SQV/D4T group). Thirty out of 31 (97%) patients had a serum HIV-RNA < 400 copies/ml at their last follow-up visit. Ten per cent of patients discontinued study medication due to adverse events. CONCLUSION: The concept of starting with a simple, potent regimen, that could be intensified if necessary, showed good virological results after 48 weeks in this study, comparable to starting with more drugs from the beginning. Longer follow-up is needed to determine the long-term efficacy of this treatment strategy.

Detection of RET mutations in multiple endocrine neoplasia type 2a and familial medullary thyroid carcinoma by denaturing gradient gel electrophoresis.

Germline missense mutations within the coding region of the RET proto-oncogene have recently been described in patients with the dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). To date, the sequence variations occur in RET exons 10 and 11 and alter highly conserved cysteine residues in the proposed extracellular domain at codons 609, 611, 618, 620, and 634. To expedite rapid screening of populations at risk of MEN 2a or FMTC, we developed a PCR-based denaturing gradient gel electrophoresis (DGGE) strategy that detects polymorphisms occurring at all five Cys codons in both RET exons using identical gel conditions. In this report, the screening results from DGGE analysis of 15 distinct MEN 2a and FMTC mutations are shown. Each mutation generated a clearly distinguishable and unique homo- and heteroduplex band pattern. Given the highly efficient, reproducible, and sensitive nature of this approach, DGGE is particularly appropriate for rapid, large-scale screening of patients. Since prior knowledge of the RET mutation is unnecessary for analysis, DGGE is potentially valuable for distinguishing germline from seemingly sporadic medullary thyroid cancer as well as identifying novel sequence changes.

Mechanical loading on the low back in three methods of refuse collecting.

The mechanical loading on the low back was studied in three different current methods of refuse collecting: in polythene bags, two-wheeled mini-containers and large four-wheeled containers. To this end the most prominent activities of each collecting method were performed in a laboratory. On the basis of movement analysis, force measurements and biomechanical modelling, spinal compressive and shear forces were estimated. From these forces and from the frequency of activities during the working day (assessed in a preliminary field study) the low-back stress in each collecting method was evaluated. In the bag-method, peak forces when throwing the bags ranged from 3341 to 5179 N (average compression) and from 284 to 673 N (shear) among the different conditions studied. The act of picking up bags also showed rather high forces (exceeding the NIOSH limit for disc compression in most cases). The frequency of exposure to these forces in the field is rather high (workers pick up and throw on average 807 times each day). The mini-container method compares favourably to the bags method. Peak compressive and shear force in tilting/pushing and pulling mini-containers ranged from 1657 to 2654 N and from 123 to 248 N respectively. Also, the frequency of stressful events in the field is lower in this method. In the large container method extremely high peak forces (e.g. compression ranged from 4991 to 5810 N) were observed in the task of putting the empty container back from street level to sidewalk level (surmounting the kerb). The frequency of activities like pushing, pulling and lifting the large container in the field is much lower compared with activities in the other methods. On the basis of the frequency and magnitude of spinal forces it was concluded that the mini-containers should be preferred to the bags. If kerbs are removed at container places and tasks are performed by two instead of a single person, the large container method would form another good alternative to the stressful task of collecting refuse in bags.

Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete?

BACKGROUND: Recent identification of RET mutations in multiple endocrine neoplasia type 2A (MEN 2A) allows a DNA-based approach to diagnosis in lieu of calcitonin sampling. To prospectively evaluate the efficacy of mutational analysis, genetic screening was performed in 124 patients (53 male, 71 female; age, 1 month to 80 years) at risk for MEN 2A referred over 3 months. METHODS: Analysis used genomic DNA and a polymerase chain reaction-based denaturing gradient gel electrophoresis strategy for mutation detection at RET codons 609, 611, 618, 620, and 634. Ninety-three of 124 patients were from established MEN 2A kindreds (group A), and screening replaced calcitonin testing. Twenty-one of 124 patients (group B) represented index cases of medullary thyroid carcinoma (MTC), and DNA analysis was performed to distinguish sporadic from hereditary disease. Ten patients (group C) had modest calcitonin elevations or had undergone thyroidectomy without confirming pathologic results, and testing was undertaken to clarify status. RESULTS: Group A: RET mutations occurred in 29 (median age, 10 years) of 93 patients, 14 of whom underwent thyroidectomy. No false-positive results were observed. Group B: five (24%) of 21 patients with seemingly sporadic MTC had RET mutations at codons 618 (one), 620 (one), or 634 (three). Group C: Nine of 10 patients with alleged MEN 2A had genetically negative results. CONCLUSIONS: Denaturing gradient gel electrophoresis reliably detects MEN 2A. Modest calcitonin elevations may lead to a false-positive diagnosis of MTC. DNA testing is the optimal approach to evaluating MEN 2A. Index cases of sporadic MTC should also undergo DNA analysis.

Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease.

BACKGROUND: The clinical association of multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprung's disease (HD), although rare, has been previously observed. Recently, germline mutations in the RET proto-oncogene, a transmembrane receptor with tyrosine kinase activity, have been detected in patients with familial HD. RET is also the predisposition gene for the inherited cancer syndrome MEN 2A. METHODS: We describe a DNA sequence variation within the coding region of RET in two large unrelated kindreds with MEN 2A (with 83 and 42 persons affected) in which HD cosegregated with MEN 2A in seven patients. Mutational analysis was performed with a highly sensitive polymerase chain reaction-based denaturing gradient gel electrophoresis technique followed by direct sequencing of mutants. RESULTS: Genetic analysis by denaturing gradient gel electrophoresis detected mutant bands in RET exon 10 in patients with MEN 2A from both kindreds. Direct DNA sequencing of mutants revealed a thymine-to-adenine base change in codon 618, resulting in a cysteine-to-serine substitution. The identical mutation was present in all seven children with HD. Of these children five underwent thyroidectomy for C-cell abnormalities; one 3-year-old child is awaiting thyroid surgery, and the remaining patient died at age of 12 weeks. CONCLUSIONS: The RET codon 618 Ser mutation could predispose patients with MEN 2A to HD. RET may assume a critical role in embryologic enteric nerve migration and tumorigenesis of cells from neural crest lineage.

Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast.

BACKGROUND: Many studies have analyzed the metastatic patterns of breast carcinoma. However, very few studies have analyzed the differences in metastatic patterns of lobular versus ductal carcinoma. METHODS: By use of our tumor registry, the metastatic sites of all invasive lobular and invasive ductal breast carcinoma cases during an 18-year period (January 1973 to December 1990) were analyzed. RESULTS: There were 2605 cases of invasive lobular and invasive ductal breast carcinoma. Lobular carcinoma accounted for 359 (14%) and ductal carcinoma for 2246 (86%) of the cases. The percentage of patients with regional lymph node metastasis at diagnosis was not significantly different between the two groups. The rates of metastasis to all lymph nodes, liver, and central nervous system were not significantly different. However, the rates of metastasis to the gastrointestinal system (4.5% vs 0.2%), gynecologic organs (4.5% vs 0.8%), peritoneum-retroperitoneum (3.1% vs 0.6%), adrenal glands (0.6% vs 0%), bone-marrow (21.2% vs 14.4%), and lung-pleura (2.5% vs 10.2%) were significantly different (p < 0.05). CONCLUSIONS: The metastatic patterns of lobular and ductal carcinoma of the breast are different, with gastrointestinal system, gynecologic organ, and peritoneum-retroperitoneum metastases markedly more prevalent in lobular carcinoma. Physicians should be aware of these different metastatic patterns of lobular and ductal carcinoma of the breast.

Use of uniform terminology by occupational therapists.

Uniform Terminology for Occupational Therapy-Second Edition (American Occupational Therapy Association, 1989b) was published to foster consistency in terminology among occupational therapists. In this study, agreement between occupational therapists and Uniform Terminology about the definition and categorization of 15 terms was examined. Agreement was measured on 113 responses from a randomly selected sample of 180 occupational therapists. Low levels of agreement were found on both definition of terms (71.9 mean percentage of agreement, SD = 12.4) and categorization of terms into larger conceptual categories (34.9 mean percentage of agreement, SD = 11.7). Therapists selected an alternative definition more often than the one given by Uniform Terminology on 2 of 15 terms and selected an alternative categorization more often than the one given in Uniform Terminology on 8 of 15 terms. These results indicate that therapists do not agree with many Uniform Terminology definitions and categorizations.