Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl

We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (HuCI)-transgenic mice showed elevation of plasma triglycerides (mg/dl) compared to controls in both the fasted (211 +/- 81 vs 123 +/- 52, P = 0.0001) and fed (265 +/- 105 vs 146 +/- 68, P < 0.0001) states. Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)-transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95 +/- 23 vs 73 +/- 23, P = 0.002, fasted and 90 +/- 24 vs 61 +/- 14, P < 0.0001, fed). Lipoprotein fractionation showed increased VLDL and IDL + LDL with an increased cholesterol/triglyceride ratio (0.114 vs 0.065, P = 0.02, in VLDL). The VLDL apo E/apo B ratio was decreased 3.4-fold (P = 0.05) and apo CII and apo CIII decreased in proportion to apo E. Triglyceride and apo B production rates were normal, but clearance rates of VLDL triglycerides and postlipolysis lipoprotein "remnants" were significantly slowed. Plasma apo B was significantly elevated. Unlike HuCII- and HuCIII-transgenic mice, VLDL from HuCI transgenic mice bound heparin-Sepharose, a model for cell-surface glycosaminoglycans, normally. In summary, apo CI overexpression is associated with decreased particulate uptake of apo B-containing lipoproteins, leading to increased levels of several potentially atherogenic species, including cholesterol-enriched VLDL, IDL, and LDL.     

Effect of external extra-articular ligament plasty on the results of anterior cruciate ligament reconstruction with patellar tendon, a 4 years follow-up

PURPOSE OF THE STUDY: The purpose of this study was to compare the functional results obtained when an external extra-articular plasty was added to an anterior cruciate ligament (ACL) reconstruction using an autologous bone tendon-bone patellar tendon graft. MATERIAL AND METHODS: The authors analyzed two consecutive series of 60 and 50 patients operated by the same surgeon for a chronic rupture of the anterior cruciate ligament, one by reconstruction of the cruciate ligament with a free graft of the patellar tendon supplemented by an external extra-articular plasty made with a quadriceps tendon graft and the second with an isolated free patellar tendon graft. Anterior laxity was measured before and after surgery, by dynamic X-rays and by the Medmetric KT-1000 arthrometer. Functional results were evaluated four years after operation, with the French A.R.P.E.GE score based on sport activity level and intensity. RESULTS: Anterior laxity was not different before operation in both groups and there was no difference between males and females. Medmetric KT-1000 arthrometer showed the same negative differential laxity immediately after surgery in both groups and the same evolution during the first 4 years, without any significant difference on laxity on the middle aspect of the knee. Radiological results were different. After a 4 years follow-up, anterior laxity did not show significant difference on the medial compartment of the knee (5.3 +/- 2.3 mm and 5.5 +/- 1.7 mm), but there was a significant minor laxity in the lateral compartment for the lateral extra-articular plasty group (11.0 +/- 2.3 mm against 14.8 +/- 3.8 mm)(p = 0.002). Functional results and sport activity were similar in both groups. Examination showed 4 positive pivot shift tests (2 "sliding" and 2 positive) in the group with extra-articular plasty, even though 8 positive pivot shift tests in the isolated ACL group (5 "sliding" and 3 positive) were found. DISCUSSION: This study, as well as five others studies found in literature, was not randomized. In all these series, the surgical techniques, the rehabilitation programs and the functional score evaluation were too different to allow any pertinent comparison. Extra-articular plasty helps to control the laxity of the lateral compartment of the knee which is incompletely controlled by ACL reconstruction, particularly in chronic cases. This is proved by radiological measurements and pivot shift tests. Jensen in 1983, about 205 patients with a 4 year follow-up and Noyes, which used an allograft patellar tendon, found an advantage to do extra-articular plasty. But Strum (in 1989), as O'Brien (in 1991) and Roth (in 1987), did not found any advantage with extra-articular plasty. CONCLUSION: It is therefore obvious, after a four-year follow-up, that extra-articular supplementation presents an advantage for reconstruction of the ACL. by a free graft of the patellar tendon in chronic cases. Further randomized study will confirm that isolated ACL reconstruction is possible in some well defined categories of anterior laxity.     

The role of emergency medical services in primary injury prevention. East Carolina Injury Prevention Program

Recent studies have shown a high frequency of genetic hemochromatosis in the Caucasian population. In addition, the well known organ involvement of genetic hemochromatosis was evident; more than 50% of patients develop a typical arthropathy which may result in severe physical disability. Among approximately 5000 patients referred to the rheumatology outpatient clinics of Bad Nauheim and Frankfurt with different rheumatologic diagnoses, 11 patients with typical signs of hemochromatotic arthropathy were identified. In none of those cases had the diagnosis "genetic hemochromatosis" been previously established. These patients had been treated for rheumatoid arthritis and other rheumatologic disorders over several years. All showed severe organ dysfunction due to iron overload, resulting in a reduced life expectancy. This investigation shows that knowledge of the typical signs of hemochromatotic arthropathy could lead to an earlier diagnosis of genetic hemochromatosis which is necessary to prevent the complications of iron overload in those patients.     

Word recognition performance in various background competitors

BACKGROUND: Inhaled nitric oxide (NO) has been shown to selectively lower pulmonary vascular resistance and is applied in patients with pulmonary hypertension (PHT). However, application and monitoring is complex and not always successful ("non-responders"). We evaluated the effect of aerolized prostacyclin (aePGI2) as a therapeutic alternate to NO. PATIENTS AND METHODS: aePGI2 and NO were applied to patients with different causes of pulmonary hypertension (Group 1a: preoperative patients with intracardiac shunting defects and Eisenmenger's disease, n = 30; Group 1b: patients with primary or postoperative PHT, n = 13; Group 2: PHT immediately following surgery for congenital heart disease, n = 6). RESULTS: Pulmonary vascular resistance could be lowered significantly (Group 1a: from 91% of systemic vascular resistance to 58% with NO and 53% with aePGI2; Group 1b: from 20.2 Wood Units*m2 to 13.4 and 11.3; Group 2: from 24.9 Wood Units*m2 to 9.5 and 10.5); cardiac index increased (Group 1b: from 2.96 to 3.55 and 3.96 l/min*m2, Group 2: from 1.57 to 1.89 and 2.00 l/min*m2). CONCLUSIONS: The short-term application of aePGI2 shows a selective pulmonary vasodilation similar to NO. Given adequate monitoring, aePGI2 appears to be useful for the acute treatment of PHT.     

HtrI is a dimer whose interface is sensitive to receptor photoactivation and His-166 replacements in sensory rhodopsin I

Single cysteine substitutions were introduced into three positions of otherwise cysteineless HtrI, a phototaxis transducer found in Halobacterium salinarum that transmits signals from the photoreceptor sensory rhodopsin I (SRI) to a cytoplasmic pathway controlling the cell's motility. Oxidative cross-linking of the monocysteine HtrI mutants in membrane suspensions resulted in dimer forms evident in SDS-polyacrylamide gels. The rate of cross-linking of I64C on the cytoplasmic side of HtrI was accelerated by SRI binding in the dark and further increased by SRI photoactivation. Several residue replacements of His-166 in SRI accelerated the cross-linking rate of I64C in the dark and His-166 mutants that exhibit "inverted signaling" (mediating repellent instead of the normally attractant response to orange light) inverted the light effect on the cross-linking rate of I64C. Secondary structure prediction of HtrI indicates a coiled coil structure in the cytoplasmic region following TM2, a dimerization domain found in a diverse group of proteins. We conclude that 1) HtrI exists as a dimer both in the absence of SRI and in the SRI-HtrI complex, 2) binding of SRI in the dark increases reactivity of the two cysteines at position 64 in the dimer by increasing their proximity or mobility, 3) light activation of wild-type SRI further increases their reactivity, 4) His-166 replacements in the SRI receptor have conformational effects on the structure of HtrI at position 64, and 5) inverted signaling by His-166 mutants likely results from an inverted conformational change at this region induced by SRI photoactivation.     

Biosynthesis of progesterone derived neurosteroids by developing avian CNS: in vitro effects on the GABAA receptor complex

Although enthusiasm for measuring health-related quality of life (HRQL) in clinical trials exists, information is limited on the meaning of scores. We examined the relation between scores from the 34-item Medical Outcomes Study HIV Health Survey (MOS-HIV) and the more detailed HIV Overview of Problems-Evaluation System (HOPES) using the responses of 318 HIV-infected outpatients being treated in Los Angeles and Baltimore. With the HOPES problem statements as independent variables, statistically significant predictors of the variation in MOS-HIV scores for the Physical Function, Mental Health, and Energy/Fatigue scales were identified using stepwise regression. Approximately 60% to 70% of the variation in each of the scores was explained by five to seven different HOPES problem statements, with a single item explaining 47% to 59% of the variation. We created illustrative profiles for each of the three MOS-HIV scales using the HOPES items identified in the regressions. Independent of the scale, persons scoring in the top MOS-HIV quartile tended to report few if any problems, whereas a decline in score to the next quartile was characterized by functional difficulties (e.g., "HIV interferes with work"). The onset of specific problems might trigger further evaluation and potential intervention from health care providers to help maintain patient functioning.     

Search for the optimal schedule for the oxaliplatin/5-fluorouracil association modulated or not by folinic acid: preclinical data

The combination of oxaliplatin (LOHP)-5-fluorouracil (FU)-folinic acid (FA) has provided high response rates in pretreated patients with advanced colorectal cancer that is resistant to FU-FA. However, the choice of the optimal schedule between LOHP, FU, and FA remains open. The purpose of the present study was to compare, at equivalent drug area under the curve, different schedules for the LOHP-FU +/- FA combinations on four human colorectal cancer cell lines. FU +/- FA was tested as a 2-h short exposure ("bolus"), a 118-h continuous exposure ("infusion"), or a 22-h mixed exposure ("De Gramont protocol"). LOHP was administered for 2 h before, during, or after FU +/- FA exposure. Isobologram analyses revealed that LOHP associated with FU +/- FA resulted in synergistic cytotoxic effects whatever the tested schedules (in > or = 75% of cases). For the FU-LOHP combination, cytotoxicity was significantly different according to the FU exposure type (short > mixed > continuous) and was independent of the LOHP position. In contrast, for the FU-FA-LOHP combination, neither the FU exposure type nor the LOHP position significantly influenced cytotoxicity. The presence of FA significantly enhanced the cytotoxicity of FU-LOHP (P < 0.001); this potentiation was independent of the FU exposure type and was significantly influenced by the LOHP position (LOHP after FU-FA > LOHP during FU-FA > LOHP before FU-FA). In conclusion, in contrast with the recognized superiority of continuous FU exposure over short exposure when the drug is given alone, the FU-LOHP combination is more cytotoxic when FU is given as a short exposure. This suggests the potential interest of such a schedule in the clinical setting.     

Standards, Options, and Recommendations for the management of patients with malignant mesothelioma of the pleura. Fédération Nationale des Centres de Lutte Contre le Cancer

The "Standards, Options and Recommandations" (SOR), started in 1993, are a collaborative project between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcomes for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary experts group, with feedback from specialists in cancer care delivery. The objectives are to develop a clinical practice guideline with definitions of Standards. Options and Recommendations for the clinical care of malignant pleural mesothelioma. Data have been identified by literature search using Medline (1966-June 1997) and personal references lists. The main criteria considered were incidence, risk factors, pronostic factors and efficacy of cancer treatment. Once the guideline was defined, the document was submitted to 40 independent reviewers for peer review, and to the medical committees of the 20 French Cancer Centres for review and agreement. The results are: 1) systematic assessment of (professional) exposure to asbestos is based on a standardized interrogatory, completed by specific consultation for professional disease; 2) diagnostic and clinical staging is based on multiple biopsies under thoracoscopy and thoracic scanner; 3) there is no indication for extemporaneous examination, immunocytochemistry should use cytokeratine, EMA, vimentine, ACE, Leu-M1; 4) clinical care: the recommended staging classification is the IMIG (International Mesothelioma Interest Group) classification; 5) validated, independent pronostic factors are stage of disease patient's functional status and histologic type (i.e. epithelial lesions are of better prognosis); 6) treatment is based on symptomatic and palliative treatment options. Anticancer treatments (surgery, chemotherapy, immunotherapy, radiotherapy) did not show significant improvement of survival. The inclusion of patients in clinical trials is recommended.     

Isaacs syndrome: long-term improvement with intravenous polyvalent immunoglobulins

A 35 year-old man developed a syndrome with muscle cramp, myokimia, generalized, fasciculations, excessive sweating, sleep disorders and severe impairment. It was a syndrome of continuous muscle fiber activity--or Isaacs syndrome--with central disorders (this may be called "Maladie de Morvan"). Previous reports have suggested that Isaac's syndrome might be an autoimmune disorder. Moreover, high doses intravenous immunoglobulins were given resulting in a substantial improvement six months after the onset of this treatment.