The Functional Status of the ACL in Varus OA of the Knee: The Association With Varus Deformity and Coronal Tibiofemoral Subluxation

BackgroundThe present article analyzes the association of the functional anterior cruciate ligament (ACL) status and the overall varus deformity and coronal tibiofemoral subluxation (CTFS) in varus OA of the knee.MethodsOne hundred consecutive knees with varus OA in 84 patients were prospectively included. Knees were divided into two groups, in accordance with the ACL status (functionally sufficient or insufficient). All included patients were potential candidates for unicompartmental knee arthroplasty with predominantly medial compartment OA. Knees with Kellgren/Lawrence ≥ grade 3 in the lateral compartment were excluded leaving 79 knees to be included in this study. Mechanical varus deformity and CTFS were evaluated on AP radiographs and valgus stress radiographs, and compared between the two groups.ResultsKnees with a functionally insufficient ACL had significantly more varus deformity on hip-to-ankle AP standing radiographs (P = .001) and on valgus stress radiographs (P = .017). CTFS on AP standing radiographs was significantly higher (P = .045) in knees with a functionally insufficient ACL. Seventy-three percent (8/11) of the ACL-insufficient knees had a varus deformity of ≥10° and 64% (7/11) of ACL-insufficient knees had CTFS ≥ 6mm. By contrast, only one patient (2%, 1/41) with an insufficient ACL had< 10° varus deformity and a CTFS of < 6mm.ConclusionFunctional ACL insufficiency in osteoarthritic varus knees is associated with greater varus deformity and more advanced CTFS. Seventy-three percent of ACL-insufficient knees had a varus deformity of ≥10° and 64% of ACL-insufficient knees a CTFS of ≥ 6mm. In the work-up for medial unicompartmental knee arthroplasty, functional ACL insufficiency is likely in knees with varus deformity of ≥10° and CTFS of ≥ 6mm.     

Modulation of oral squamous cell carcinoma incidence in rats via diet and a novel calcium channel antagonist

An unexpected dose related increase in oral squamous cell carcinomas was observed in a standard 2-year carcinogenicity study with a novel calcium channel blocker, in which Wistar rats received daily doses of 0, 1.5, 7, 20, or 40 mg/kg of the compound mixed with a standard diet containing fibers from barley. This finding was associated with an increased incidence of severe (destructive) periodontitis and the formation of oro-nasal fistulae at the 2 highest doses. Five assays of the compound for genotoxicity were negative indicating that a genotoxic effect was highly improbable. To investigate the underlying pathogenic mechanisms a second 2-year study in the same strain of rats was initiated and the influence of the diet and/or a possible local irritancy by the drug was assessed. In this second study the compound was administered by oral gavage at daily doses of 0, 7, or 40 mg/kg (later reduced to 20 mg/kg due to systemic intolerance) to rats maintained either on the standard diet or on a low fiber diet assumed to be less aggressive in terms of inducing periodontal lesions. Dose dependent gingival overgrowth (a class-related effect) was observed in the incisor and molar teeth area of all treated groups but was independent of the diet used. No oral tumors were found in the standard diet or low fiber diet controls and all treatment groups fed the low fiber diet, whereas in the high-dose group fed the standard diet a total of 8 oral squamous cell carcinomas were detected in association with an increased incidence of severe periodontitis. These results indicate that the increased incidence of squamous cell carcinomas observed upon chronic administration of the compound is not due to a direct tumorigenic effect of the drug. Tumor formation is attributable to severe periodontal disease favored by the diet and class related gingival overgrowth.     

Flecked chorioretinopathy associated with Birt-Hogg-Dubé syndrome

Background: BirtHogg-Dubé's syndrome is a rare skin disease characterized by multiple trichofibromas of the skin and polyps of the intestine. Ophthalmologic manifestations associated with the syndrome have not been reported in detail. Case reports and methods: Two siblings suffering from Birt-Hogg-Dubé syndrome were examined clinically. Electrooculography and electroretinography were performed according to international standards. Color fundus photographs were taken as well as fluorescein angiograms. The two patients showed multiple perifollicular fibromas and trichodiscomas of the skin of the head. Funduscopy and fluorescein angiography revealed a flecked chorioretinopathy in one patient with progressive constriction of visual fields and severely reduced electroretinographic responses. Ophthalmoscopy in his sister showed peripheral pigmentary changes with only minor functional abnormalities. Conclusion: These findings suggest that Birt-Hogg-Dubé syndrome may be associated with a progressive flecked chorioretinopathy with constricted visual fields and that patients with the syndrome should undergo ophthalmological examination.     

SYMPOSIUM: Experimental Biology 1995 Role of Mesangial Cell Ion Transport in Glomerular Physiology and Disease: ANGIOTENSIN II-INDUCED TYROSINE PHOSPHORYLATION IN MESANGIAL AND VASCULAR SMOOTH MUSCLE CELLS

• 1 Angiotensin II (AngII)-induced, activation of phospholipase C (PLC) and Ca²⁺-dependent Cl^? channels is an important signal transduction pathway for the regulation of vascular smooth muscle cell (VSMC) and glomerular mesangial cell contraction and growth. While AT receptors are traditionally thought to be G-protein coupled to the β isoform of PLC, recent evidence suggests that in some tissues AT receptors may also activate the PLC-γ isoform via tyrosine phosphorylation.
• 2 By western analysis, we identified PLC-γ1 in the above cell types. We found that within 3 min of exposure to 10^?7 mol/L AngII, tyrosine phosphorylation of PLC-γ1 was observed; however, peak response (> 3-fold increase) occurred within 0.5 min. In addition, pre-incubation of these cells with the tyrosine kinase inhibitor genistein blocked the tyrosine phosphorylation of PLC-γ1 by AngII. In contrast, preincubation with the tyrosine phosphatase inhibitor sodium vanadate increased the levels of tyrosine phosphorylation of PLC-γ1. Similar results were found when intracellular levels of 1,4,5-IP₃ were measured after AngII exposure.
• 3 By using patch clamp techniques on cultured rat mesangial cells exposed to AngII, we found that the release of 1,4,5-IP₃-sensitive intracellular Ca²⁺ stores stimulated low conductance Cl^? channels. Preincubation with genistein, abolished the usual 10-fold increase in Cl^? channel activity observed with AngII.
• 4 Therefore, we conclude that in VSMC and glomerular mesangial cells (i) AngII transiently stimulates PLC activity via tyrosine phosphorylation of the γ1 isoenzyme, (ii) tyrosine phosphorylation of PLC-γ1 and production of 1,4,5-IP₃ in response to AngII is dramatically inhibited by tyrosine kinase inhibition and stimulated by tyrosine phosphatase inhibition, (iii) activation of Ca²⁺-dependent Cl^? channels by AngII-induced release of 1,4,5-IP₃-dependent intracellular Ca²⁺ stores is also abolished by tyrosine kinase inhibition. In summary, this AngII-induced signal transduction cascade provides a possible mechanism for both the contractile and growth-stimulating effects of AngII on VSMC and glomerular mesangial cells.

     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.