Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling

Insulin-like growth factor-1 (IGF-I) is a growth and survival factor in human multiple myeloma (MM) cells. Here we examine the effect of IGF-I on MM cell adhesion and migration, and define the role of beta1 integrin in these processes. IGF-I increases adhesion of MM.1S and OPM6 MM cells to fibronectin (FN) in a time- and dose-dependent manner, as a consequence of IGF-IR activation. Conversely, blocking anti-beta1 integrin monoclonal antibody, RGD peptide, and cytochalasin D inhibit IGF-I-induced cell adhesion to FN. IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85(PI3-K). IGF-I also triggers phosphorylation of AKT and ERK significantly. Both IGF-IR and beta1 integrin colocalize to lipid rafts on the plasma membrane after IGF-I stimulation. In addition, IGF-I triggers polymerization of F-actin, induces phosphorylation of p125(FAK) and paxillin, and enhances beta1 integrin interaction with these focal adhesion proteins. Importantly, using pharmacological inhibitors of phosphatidylinositol 3'-kinase (PI3-K) (LY294002 and wortmannin) and extracellular signal-regulated kinase (PD98059), we demonstrate that IGF-I-induced MM cell adhesion to FN is achieved only when PI3-K/AKT is activated. IGF-I induces a 1.7-2.2 (MM.1S) and 2-2.5-fold (OPM6) increase in migration, whereas blocking anti-IGF-I and anti-beta1 integrin monoclonal antibodies, PI3-K inhibitors, as well as cytochalasin D abrogate IGF-I-induced MM cell transmigration. Finally, IGF-I induces adhesion of CD138+ patient MM cells. Therefore, these studies suggest a role for IGF-I in trafficking and localization of MM cells in the bone marrow microenvironment. Moreover, they define the functional association of IGF-IR and beta1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM.     

Maternal morbidity and mortality associated with intrauterine fetal demise: five-year experience in a tertiary referral hospital

BACKGROUND: Risk factors for and management of intrauterine fetal demise (IUFD) have been investigated, but the maternal morbidity has not been evaluated. METHODS: Over a 60-month interval, all cases of IUFD after 20 weeks' gestation were reviewed for maternal trauma and maternal postpartum complications. RESULTS: In this retrospective analysis, 498 singleton and 24 twin pregnancies with an IUFD were identified. A cervical or perineal laceration requiring surgical repair complicated 9.4% of pregnancies. One uterine dehiscence and one uterine rupture occurred. Endometritis, the most common postpartum complication, occurred in 63 of 522 patients (12%). One maternal death occurred. Total mean hospital stay was 4.9 +/- 5.7 days. CONCLUSION: Maternal morbidity and rarely mortality can follow IUFD, but this morbidity is similar to that observed without IUFD.     

Correlates of adjudicative competence among psychiatrically impaired juveniles

This study examines the competence-related abilities of 120 psychiatrically hospitalized male juveniles age 10 to 17 years, using the MacArthur Competence Assessment Tool-Criminal Adjudication (MacCAT-CA), the Brief Psychiatric Rating Scale-Anchored (BPRS-A), the Massachusetts Youth Screening Instrument (MAYSI), the Kaufman Brief Intelligence Test (K-BIT), and discharge diagnoses derived from file review. The findings indicate significant age-related differences across adolescence with a relatively strong performance for most of the youths on the competence measure. While intellectual and psychiatric factors were found to contribute substantially to deficits in legal decisional ability, they were modulated by age and the developmental factors associated with it. These findings, replete with caveats concerning both the dimensional structure of competence as measured by the MacCAT-CA and the interplay with the mental status and developmental factors affecting it, underscore the multifarious nature of legal decisional capacity in youths of varying ages. The relevance of these findings to the structuring of restoration services and the application of legal theory to the competence standard in juvenile court are discussed.     

Phacoemulsification cataract extraction and posterior chamber lens implantation in patients with uveitis

PURPOSE: This study reports outcomes of phacoemulsification cataract extraction and posterior chamber intraocular lens implantation within the capsular bag in patients with uveitis. METHODS: We retrospectively reviewed the charts of 32 patients (39 eyes) with uveitis who underwent phacoemulsification cataract extraction and posterior chamber intraocular lens implantation by two surgeons at The Cleveland Clinic Foundation from January 1990 to June 1998. Patients with less than 3 months of follow-up were excluded. RESULTS: Diagnoses of uveitis included idiopathic (15 eyes), sarcoidosis (10 eyes), pars planitis (four eyes), CMV retinitis (two eyes), Fuchs heterochromic iridocyclitis (two eyes), syphilis (two eyes), and one eye each of tuberculosis, Crohn's disease, HLA-B27 associated, and acute retinal necrosis. Average follow-up was 20 months (range, 3 to 63 months). Best-corrected visual acuity improved in 37 eyes (95%). Average improvement was 4 +/- 3 Snellen acuity lines (range, 1 to 10 lines). Thirty-four eyes (87%) attained final visual acuity better than or equal to 20/40. Visual loss occurred in one eye (3%) with CMV retinitis. No improvement in visual acuity was seen in one eye (3%) that developed a retinal pigment epithelial detachment. Posterior capsule opacification occurred in 24 eyes (62%), 12 of which required Nd:YAG capsulotomy (31%). Other postoperative complications included recurrence of uveitis (41%), cystoid macular edema (33%), epiretinal membrane formation (15%), and posterior synechiae (8%). CONCLUSIONS: Phacoemulsification cataract extraction with posterior chamber intraocular lens implantation is safe in patients with uveitis. The incidences of recurrence of uveitis, cystoid macular edema, epiretinal membrane, and posterior synechiae were lower than those reported previously for extracapsular cataract extraction.     

Modeling the vertical motion of a soft contact lens

PURPOSE: The motion of a soft contact lens in the up-down or vertical (inferior-superior) and in-out (anterior-posterior) directions drives mixing in the post lens tear film. Thus, it is important to obtain an accurate assessment of lens motion. The commonly used experimental technique to measure the vertical motion, video microscopy, only gauges motion during the interblink period. Since most of the eyelid force, which drives the motion, is exerted during the blink, it is reasonable to assume that the majority of the lens motion in the up-down direction takes place during the blink and is, therefore, hidden from view. Thus, experimentally measured values of vertical lens travel are currently underpredicted. METHODS: In this paper, we use a simple mechanical force balance on the lens to predict its motion in the vertical direction. The forces included in our model are due to the upper and the lower eyelids, gravity, elasticity, and viscous stresses. We input the lens physical parameters, the various tear film thicknesses, and the upper eyelid velocity. Then we integrate a macroscopic force balance to obtain the lens vertical position as a function of time. RESULTS: The proposed model predicts that the downward lens motion during a blink is about 2--3 times the downward motion during the interblink (centration). CONCLUSIONS: The up-down motion observable during the interblink period is only a small fraction of the total lens vertical travel.     

The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells

Human multiple myeloma (MM) is a presently incurable hematological malignancy, and novel biologically based therapies are urgently needed. Proteasome inhibitors represent a novel potential anticancer therapy. In this study, we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis of human MM cell lines and freshly isolated patient MM cells; inhibits mitogen-activated protein kinase growth signaling in MM cells; induces apoptosis despite induction of p21 and p27 in both p53 wild-type and p53 mutant MM cells; overcomes drug resistance; adds to the anti-MM activity of dexamethasone; and overcomes the resistance to apoptosis in MM cells conferred by interleukin-6. PS-341 also inhibits the paracrine growth of human MM cells by decreasing their adherence to bone marrow stromal cells (BMSCs) and related nuclear factor kappaB-dependent induction of interleukin-6 secretion in BMSCs, as well as inhibiting proliferation and growth signaling of residual adherent MM cells. These data, therefore, demonstrate that PS-341 both acts directly on MM cells and alters cellular interactions and cytokine secretion in the BM millieu to inhibit tumor cell growth, induce apoptosis, and overcome drug resistance. Given the acceptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical evaluation of PS-341 to improve outcome for patients with this universally fatal hematological malignancy.     

Determination of amniotic fluid volume in twin pregnancies: ultrasonographic evaluation versus operator estimation

OBJECTIVE: We sought to determine the accuracy of amniotic fluid volume estimation (visually) in diamniotic twin pregnancy versus ultrasonography techniques. STUDY DESIGN: In this prospective study the volume of each sac in 23 sets of diamniotic twin pregnancies was subjectively and objectively estimated by a second-year obstetric resident, nurse sonographer, maternal-fetal medicine fellow, and maternal-fetal medicine staff. The actual volume was confirmed by amniocentesis and a dye-dilution technique. RESULTS: There was no difference in the total number of correct estimates of volume by level of operator experience (P =.98), ultrasonography technique (P =.87), or combined subjective versus objective correct estimates (P =.87). Identification of low volume was not different among the four evaluators (P =.48), but the percentage of correct estimates was poor (7%-29%). The 2-diameter pocket was a better predictor of oligohydramnios (57%) than the amniotic fluid index or the largest vertical pocket (12.5%; P =.002). CONCLUSION: The extremes of volume (low or high) are poorly identified by the subjective or objective assessment of volume.     

Antepartum detection of macrosomic fetus: clinical versus sonographic, including soft-tissue measurements

OBJECTIVE: To compare clinical and sonographic estimates of birth weights with five new estimation techniques that involve measurements of soft tissue, for identifying newborns with birth weights of at least 4000 g. METHODS: Over 1 year, each woman at or after 36 weeks' gestation and suspected of having a macrosomic fetus had clinical and sonographic estimates of fetal weight (EFW) based on femur length (FL) and head and abdominal circumference, followed by five additional ways to identify excessive growth: cheek-to-cheek diameter, thigh soft tissue, ratio of thigh soft tissue to FL, upper arm subcutaneous tissue, and EFW derived from it. Areas (+/- standard error) of receiver operating characteristic (ROC) curves were calculated and compared with the area under the nondiagnostic line. P <.05 was considered statistically significant. RESULTS: Among 100 women recruited, 28 newborns weighed 4000 g or more. The areas under the ROC curves with clinical (0.72 +/- 0.06) and sonographic predictions using biometric characteristics (0.73 +/- 0.06) had the highest but similar accuracies (P.05). Three of the five newer methods (upper arm or thigh subcutaneous tissue and ratio of thigh subcutaneous tissue to FL) were poor diagnostic tests (range of areas under ROC 0.52 +/- 0.06 to 0.58 +/- 0.07). Estimated fetal weight based on upper arm soft tissue thickness and cheek-to-cheek diameter (areas 0.70 +/- 0.06 and 0.67 +/- 0.06, respectively) were not significantly better than clinical predictions (P.05) for detecting macrosomic fetuses. About 110 macrosomic and nonmacrosomic infants combined would be needed to have 80% power to detect a difference between ROC curves with areas of 0.58 (thigh subcutaneous tissue) and 0.72 (clinical estimate). CONCLUSION: ROC curves indicated that measurements of soft tissue are not superior to clinical or sonographic predictions in identifying fetuses with weights of at least 4000 g.