Predictive accuracy of second-trimester uterine artery Doppler indices for stillbirth: a systematic review and meta-analysis.

OBJECTIVE: To assess the predictive accuracy for stillbirth of second-trimester uterine artery Doppler. METHODS: We searched MEDLINE, EMBASE and The Cochrane Library databases from inception until March 2015 without language restrictions. The included studies were those that assessed the association of abnormal uterine artery Doppler parameters and stillbirth. Two independent reviewers selected the studies, extracted data and assessed quality. Results for studies that were performed in the second trimester were pooled and summary estimates of sensitivity, specificity, likelihood ratios and their 95% confidence intervals were obtained. An overall summary of test accuracy was provided by the diagnostic odds ratio. Subgroup analysis was performed according to whether the study population was high risk or unselected. RESULTS: Literature searches returned 338 relevant citations with 32 considered in full. Thirteen studies met our search criteria (85 845 women, 508 stillbirths) and were included in the review. Bivariate pooled estimate for sensitivity was 65% (95% CI, 38-85%) and for specificity 82% (95% CI, 72-88%). The positive likelihood ratio was 3.5 (95% CI, 2.3-5.5) and negative likelihood ratio 0.43 (95% CI, 0.22-0.85). The diagnostic odds ratio was 8.3 (95% CI, 3.0-22.4). Heterogeneity was high in the studies of high-risk women. CONCLUSIONS: Abnormal uterine artery Doppler indices are associated with a three- to four-fold increase in the risk of stillbirth. The heterogeneity was particularly high in the high-risk group rendering it impossible to draw firm conclusions. In view of this, there is a role for individual patient data meta-analysis to define which Doppler parameter and threshold value should be measured.

Hypoxia simultaneously alters satellite cell-mediated angiogenesis and hepatocyte growth factor expression.

Skeletal muscle regeneration is a multifaceted process requiring the spatial and temporal coordination of myogenesis as well as angiogenesis. Hepatocyte growth factor (HGF) plays a pivotal role in myogenesis by activating satellite cells (SC) in regenerating muscle and likely plays a role as a contributor to revascularization. Moreover, repair of a functional blood supply is critical to ameliorate tissue ischemia and restore skeletal muscle function, however effects of hypoxia on satellite cell-mediated angiogenesis remain unclear. The objective of this study was to examine the role of HGF and effect of hypoxia on the capacity of satellite cells to promote angiogenesis. To characterize the role of HGF, a microvascular fragment (MVF) culture model coupled with satellite cell conditioned media (CM) was employed. The activity of HGF was specifically blocked in SC CM reducing sprout length compared to control CM. In contrast, MVF sprout number did not differ between control or HGF-deficient SC CM media. Next, we cultured MVF in the presence of CM from satellite cells exposed to normoxic (20% O2 ) or hypoxic (1% O2 ) conditions. Hypoxic CM recapitulated a MVF angiogenic response identical to HGF deficient satellite cell CM. Hypoxic conditions increased satellite cell HIF-1α protein abundance and VEGF mRNA abundance but decreased HGF mRNA abundance compared to normoxic satellite cells. Consistent with reduced HGF gene expression, HGF promoter activity decreased during hypoxia. Taken together, this data indicates that hypoxic modulation of satellite cell-mediated angiogenesis involves a reduction in satellite cell HGF expression.

Transplantation and perfusion of microvascular fragments in a rodent model of volumetric muscle loss injury.

Few clinical options are available for the treatment of volumetric muscle loss (VML). An important consideration that needs to be addressed for the development of treatments for these injuries is the establishment of a vascular supply sufficient to support skeletal muscle regeneration. The objective of the current study was to evaluate the potential for microvascular fragments (MVFs) harvested from adipose tissue to support tissue perfusion for VML. Tibialis anterior muscle defects in rats were replaced with constructs that were created on the day of surgery containing either (1) collagen only (COL), (2) freshly isolated microvascular fragments in collagen (MVF), or (3) adipose tissue derived stem cells (ASCs) in collagen. Muscles were harvested 7 and 14 days after surgery. Defects treated with MVFs had a vessel density higher than the other groups at both 7 and 14 days, and those treated with ASCs had a higher vessel density than COL by day 14 (p < 0.05). Perfused vessels were observed in both the ASC and MVF treated defects at day 14, as well as at day 7 in the MVF. This study supports the use of MVFs as a platform to improve tissue perfusion to treat large VML defects. The use of freshly isolated MVFs on the day of surgery supports their clinical use and application.

Satellite cells isolated from aged or dystrophic muscle exhibit a reduced capacity to promote angiogenesis in vitro.

Deficits in skeletal muscle function exist during aging and muscular dystrophy, and suboptimal function has been related to factors such as atrophy, excessive inflammation and fibrosis. Ineffective muscle regeneration underlies each condition and has been attributed to a deficit in myogenic potential of resident stem cells or satellite cells. In addition to reduced myogenic activity, satellite cells may also lose the ability to communicate with vascular cells for coordination of myogenesis and angiogenesis and restoration of proper muscle function. Objectives of the current study were to determine the angiogenic-promoting capacity of satellite cells from two states characterized by dysfunctional skeletal muscle repair, aging and Duchenne muscular dystrophy. An in vitro culture model composed of satellite cells or their conditioned media and rat adipose tissue microvascular fragments (MVF) was used to examine this relationship. Microvascular fragments cultured in the presence of rat satellite cells from adult muscle donors (9-12 month of age) exhibited greater indices of angiogenesis (endothelial cell sprouting, tubule formation and extensive branching) than MVF co-cultured with satellite cells from aged muscle donors (24 month of age). We sought to determine if the differential degree of angiogenesis we observed in the co-culture setting was due to soluble factors produced by each satellite cell age group. Similar to the co-culture experiment, conditioned media produced by adult satellite cells promoted greater angiogenesis than that of aged satellite cells. Next, we examined differences in angiogenesis-stimulating ability of satellite cells from 12 mo old MDX mice or age-matched wild-type mice. A reduction in angiogenesis activity of media conditioned by satellite cells from dystrophic muscle was observed as compared to healthy muscle. Finally, we found reduced gene expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in both aged and dystrophic satellite cells compared to their adult and normal counterparts, respectively. These results indicate that functional deficits in satellite cell activities during aging and diseased muscle may extend to their ability to communicate with other cells in their environment, in this case cells involved in angiogenesis.

Sythesis of tropomyosin in cultures of differentiating muscle cells.

The accumulation of tropomyosin in cultures of differentiating muscle cells was quantitatively measured. Tropomyosin was isolated from cultured cells during and after myoblast fusion; both alpha- and beta-subunits were present in myotube cultures. During fusion small amounts of tropomyosin were detectable, but, as fusion approached a maximum, tropomyosin accumulation began to increase. The increased synthesis of tropomyosin after the initiation of muscle cell fusion is consistent with the increased synthesis of other proteins characteristic of muscle, including myosin.

INVITED REVIEW: Evolution of meat animal growth research during the past 50 years: Adipose and muscle stem cells.

If one were to compare today's animal growth research to research from a mere 50 yr ago, one would see programs with few similarities. The evolution of this research from whole-animal through cell-based and finally molecular and genomic studies has been enhanced by the identification, isolation, and in vitro evaluation of adipose- and muscle-derived stem cells. This paper will highlight the struggles and the milestones that make this evolving area of research what it is today. The contribution of adipose and muscle stem cell research to development and growth, tissue regeneration, and final carcass composition are reviewed.

Disproportionate accumulation of myosin and tropomyosin in cultured muscle cells.

Accumulation of two major myofibrillar proteins, myosin and tropomyosin, was monitored in differentiating skeletal muscle cultures. The tropomyosin subunit to myosin heavy chain accumulation rate ratio was more than twice the stoichiometric ratio of tropomyosin subunit to myosin heavy chain in mature skeletal muscle myofibrils and crude myofibrils from cultured muscle cells. Electron microscopy revealed normal patterns of myofibril assembly in these muscle cultures. Therefore, the observed disproportionate accumulation of tropomyosin and myosin heavy chain may be reflecting normal cellular conditions for de novo myofbril assembly.

Ovine somatomedin, multiplication-stimulating activity, and insulin promote skeletal muscle satellite cell proliferation in vitro.

Primary cultures of skeletal muscle satellite cells, the postnatal myogenic precursor cells, were induced to proliferate by exposure to physiological levels of somatomedins (Sms)/insulin-like growth factors (IGFs) and pharmacological levels of insulin. These polypeptides were included in medium containing horse serum as well as serum-free defined medium. Dexamethasone inclusion in the serum-containing medium facilitated the ovine Sm (oSm; P less than 0.05) and the multiplication-stimulating activity/rat IGF-II (MSA/rIGF-II; P less than 0.25) responses, but not the insulin proliferative response. In addition, data from defined medium studies indicate that satellite cells are more sensitive to both IGF moieties than insulin and that the proliferations induced by half-maximal concentrations of oSm and insulin were similar (P less than 0.05), but both were different from the proliferation induced by MSA/rIGF-II (P less than 0.05). In the presence of insulin concentrations that promote maximum proliferation, the addition of oSm did not produce an additive effect, whereas the addition of MSA/rIGF-II did produce a significant increase in satellite cell proliferation above that induced by insulin. MSA/rIGF-II may, therefore, be stimulating proliferation of satellite cells through a receptor system different from that serving insulin and oSm. Collectively, these data support the hypothesis that Sms/IGFs play an important role in the control of postnatal muscle growth by providing a link between these hormones and one of the significant target cells involved in this process.

Trenbolone alters the responsiveness of skeletal muscle satellite cells to fibroblast growth factor and insulin-like growth factor I.

The potential role of satellite cells in mediating the effect of trenbolone [17 beta-hydroxyestra-4,9-11-trien-3-one (TBOH)] on skeletal muscle hypertrophy was examined. Young female Sprague-Dawley rats received TBOH injections daily for 2 weeks; growth, body composition, and the composition of selected muscles were assessed. Treated rats grew more rapidly and deposited less body lipid and more protein. The semimembranosus muscle from treated rats was larger and had approximately 60% more DNA per muscle than muscles from control rats. The addition of trenbolone directly to the medium of cultured satellite cells did not stimulate cell proliferation, nor did it augment the stimulatory response of these cells to fibroblast growth factor (FGF) or insulin-like growth factor I (IGF-I). In contrast, satellite cells cultured from TBOH-treated rats exhibited greater proliferative responses to FGF and IGF-I than satellite cells from control rats. In addition, serum from TBOH-treated rats stimulated greater cell proliferation in satellite cell cultures than serum from control rats. These experiments suggest that one possible mechanism responsible for the ability of TBOH to stimulate skeletal muscle hypertrophy may be through enhanced proliferation and differentiation of satellite cells as a result of the increased sensitivity of these cells to IGF-I and FGF.

Drug modification of ECT: methohexital and diazepam. II.

A systematic comparison of methohexital and diazepam as anesthetics in the drug modification of ECT was done by holding atropinizaton, succinylcholine-depolarizing neuromuscular blockade, and resuscitation constant while monitoring four ECT in each of 24 patients. Each patient served as his own control, and two dosages of each drug (0.25 and 0.35 mg/kg diazepam, 0.9 and 1.1 mg/kg methohexital) were given each patient in all possible orderings (4! = 24) in a scheduled experimental design in which methohexital was given by very rapid (5 sec) and diazepam was given by the recommended slower (60 sec) infusion. The data revealed significant differences and methohexital was superior. Eight of 48 (17%) EKGs were abnormal post-ECT with methohexital, 18 of 48 (38%, phi = 5.3, p < 0.025) with diazepam. Five of 24 (21%) patients had an abnormal post-ECT EKG with methohexital, 15 of 24 (60%, phi 8.6, p < 0.005) with diazepam. Significantly more ventricular premature contractions (VPCs) occurred after diazepam. Diazepam records contained both more numerous and more extensive EKG abnormalities. Methohexital induction was clinically superior as well; there was little of the induction restlessness seen in seven treatments with diazepam (phi2 7.6, p < 0.01). The differences were less marked than in a previous study in which diazepam was given as rapidly as methohexital. Methohexital has been demonstrated to be the anexthesia of safety and choice for ECT when compared to diazepam.

Interaction of multiplication stimulating activity/rat insulin-like growth factor II with skeletal muscle satellite cells during aging.

Satellite cells were isolated from the skeletal muscle of 3-, 12- and 24-month-old Fischer 344 rats. In vitro growth of these cells was evaluated in serum-containing medium and in serum-free medium in response to multiplication stimulating activity/rat insulin-like growth factor II (MSA). Cells from 3-month-old rats exhibited a shorter lag phase of growth than cells from 12- or 24-month-old animals. Dose-response curves for MSA with each of the three age groups did not differ in the concentrations of MSA required for a half-maximal response or in the magnitudes of the response. Hormone-binding data using [125I]MSA, however, revealed the highest numbers of MSA-binding sites with lowest affinities in the 3-month-old rat muscle cells; cells from the 24-month-old rats were intermediate and cells from the 12-month-old rats had the highest affinity and lowest number of binding sites. The lower affinity and increased number of binding sites in the young rat cells may be due to greater numbers of IGF type I receptors in muscle from young growing rats.

Myogenic potential of satellite cells in skeletal muscle of old rats. A brief note.

Muscle satellite cells from old (> 30 months) female Long-Evans rats were isolated and grown in cell culture. Satellite cells differentiated in culture to form multinucleated myotubes that had the ability to accumulate muscle-specific proteins. Therefore, satellite cells exist in muscle through senescence and retain their myogenic potential.

Influence of age on accumulation of alpha-actin in satellite-cell-derived myotubes in vitro.

Because muscle satellite cells have been implicated in the process of muscle growth and mass regulation, as well as regeneration, alterations in the capacity of satellite cells to differentiate and accumulate muscle specific proteins during aging could play a role in the process of senile muscle atrophy. Skeletal muscle satellite cells were cultured from male rats from the following four age groups: neonatal rats (less than 5 days of age), growing rats (1--3 months of age, adult rats (9--12 months of age) and old rats (more than 24 months of age). A series of experiments was conducted in which cultures were harvested at daily intervals following fusion, and the amount of alpha-actin per myotube nucleus was determined. Analysis of maximum actin accumulation in myotubes from each experiment within each age group revealed no significant differences among cells derived from growing, adult or old rats; however, myotubes differentiating from neonatal muscle cells were able to accumulate more than three times as much alpha-actin per myotube nuclei as cells from the other three age groups. This result may reflect fundamental differences between authentic satellite cells and myogenic cells of prenatal origin. Aside from differences between neonatal cells and satellite cells, satellite cells from old muscle do not appear to have a diminished capacity to accumulate muscle-specific proteins following differentiation into muscle fibers.

Inhibition of growth of human leukaemia 60 cells by S-2-hydroxyacylglutathiones and monoethyl ester derivatives.

S-2-Hydroxyacylglutathione derivatives were found to induce growth arrest and toxicity in human leukaemia 60 cells in culture. S-D-Lactoylglutathione was the most effective with a median inhibitory concentration IC50 of 82 microM (95% C.I. 65-105 microM). No similar toxicity was induced by reduced glutathione and/or the corresponding aldonic acid (500 microM) in human leukaemia 60 cells, nor by S-D-lactoylglutathione (500 microM) in mature human neutrophils under the same culture conditions. Monoethyl ester derivatives of the S-2-hydroxyacylglutathiones were prepared and also induced growth arrest and toxicity but were less effective than the corresponding unesterified compounds. S-2-Hydroxyacylglutathione derivatives also inhibited the incorporation of [3H]thymidine into DNA early in the development of toxicity: for S-D-lactoylglutathione, the median inhibitory concentration was 74 microM (95% C.I. 47-116 microM). The mechanism of the inhibition of human leukaemia cell growth by S-D-lactoylglutathione and other S-2-hydroxyacylglutathione derivatives is unknown but appears to be mediated by the inhibition of DNA synthesis.

Inhibition of proliferation of human leukaemia 60 cells by methylglyoxal in vitro.

Methylglyoxal (2-oxopropanal) is the physiological substrate of the glyoxalase system. When exogenous methylglyoxal (50 microM-1 mM) was added to human leukaemia 60 (HL60) cells in culture (5 x 10(4) cells/ml), inhibition of growth and toxicity was induced. The median growth inhibitory concentration IC50 value was 238 +/- 2 microM. There was little differentiation of HL60 cells induced by methylglyoxal (a maximum of 2% differentiation with 500 microM methylglyoxal). There was no similar toxicity induced by methylglyoxal in corresponding differentiated cells, neutrophils, under the same culture conditions. Cell growth and toxicity induced by methylglyoxal (250 microM) in HL60 cells occurred in the initial 24 h of culture, after which residual surviving cells exhibited normal growth kinetics. It could also be prevented by replacing the culture medium in the initial 6 h of culture; thereafter, irreversible toxicity developed, reaching the maximum value after 24 h of culture. Growth arrest and toxicity induced by methylglyoxal increased with increasing serum composition of the medium. The mechanism of toxicity is unknown.

Cognitive disabilities: measuring the social consequences of mental disorders.

The disabilities associated with psychiatric illnesses can be separated into six cognitive levels that can be identified by functions the patient is able to perform, by the types of assistance required to compensate for dysfunctions, and by the social dysfunction observed in home and work environments. These cognitive levels can be used to measure the severity of mental disorders; changes in these levels reflect temporal changes in severity that are consequent to treatment and/or natural history of the condition. These cognitive levels can also be used to assess need for hospitalization and/or community placement, readiness for discharge from hospital, and effectiveness of treatment. A collaborative relationship between occupational therapists and psychiatrists is needed for the most effective use of these reliable and objective assessments of cognitive function levels in patients with psychiatric illness.

Dexamethasone suppression in depressed elderly outpatients.

The dexamethasone suppression test (DST) was performed as part of the preliminary workup in 85 previously untreated outpatients with major affective disorder, unipolar depressive type, who were over age 60. All patients were given a systematic structured interview (NIMH-DIS), and all had scores over 20 on the 21-item Hamilton Depression Rating Scale (HAM-D). Only 12 patients (14%) had positive DSTs; more of the non-melancholic (6 of 25; 24%) than melancholic (6 of 60; 10%) patients failed to suppress serum cortisol following standard dexamethasone challenge (p less than .10). DST results did not correlate with patients' HAM-D or Zung depression scores, gender, response to treatment, or any other variable studied. These findings suggest that, in comparison to previous reports, a positive DST may be 1) less common in major depressive disorders, 2) no more common in more severely depressed patients, and 3) less relevant to indications for specific treatment.

Atropine and glycopyrrolate as ECT preanesthesia.

Twenty-four patients receiving ECT were systematically studied to compare the effects of two dosages of atropine and two dosages of glycopyrrolate as preanesthetic agents. Glycopyrrolate resulted in more cardiac arrhythmias, nausea and vomiting, and episodes of bradycardia than atropine (p = .4). More patients receiving atropine showed post-ECT confusion, but the clinical impact of this was minimal. Atropine appears to be preferable to glycopyrrolate for use in ECT preanesthesia.

Incidental intoxication with phencyclidine.

Utilizing a sensitive and specific gas chromatography nitrogen detector (GC2-N) method we have demonstrated phencyclidine (PCP) in the blood of a 65-year-old widowed Mexican-American woman who lived in a second floor apartment directly over an illegal laboratory utilizing open-vat methods of PCP synthesis. This is the first proof of such incidental PCP intoxication, although police officers regularly complain of developing symptoms of intoxication after raiding such clandestine laboratories and handling the confiscated products. The presumed mechanism of incidental intoxication with PCP and the psychiatric manifestations of this patient are described and discussed.

Management of acute lower extremity arterial ischemia due to embolism and thrombosis.

Despite a general impression to the contrary, a recent survey showed that the current mortality rate for acute arterial ischemia approximates 25%. Much of this apparently relates to toxins and procoagulants released from the dying limb, a tendency which may be enhanced further by attempts at revascularization. Based on these observations, we have utilized selective management of acute arterial ischemia in an attempt to minimize deaths and to salvage the maximum number of limbs. If the patient presents within 6 to 8 hours of the onset of acute arterial occlusion and if paralysis or anesthesia is present, then ultimate limb loss is likely. The therapeutic choices are high-dose heparin therapy, operative removal of the clot, or amputation of the limb--the ultimate choice being dependent upon the particular status of the patient. But if sensation and motor function are present, viability of the limb is not threatened, and good results can be obtained by utilizing anticoagulation and delayed elective revascularization, if the latter is indicated. But revascularization attempts after 10 to 12 hours of severe ischemia often are unsuccessful, and ischemia is followed by either recurrent thrombosis and ultimate limb loss, or by death from the systemic effects of reperfusion of ischemic tissue. This type of limb is managed best by using high-dose heparin therapy if viable, or by amputation if it is not. Employing the above criteria, 54 patients with acute arterial ischemia averaging 59 years of age, were treated. Seventeen had immediate thrombectomy, yielding two deaths and four subsequent amputations. Twenty-nine received anticoagulation treatment, resulting in one death and five amputations, and six had immediate amputation, yielding one death. Three had no specific treatment, with one poor result. There were four deaths in the entire series--a mortality rate of 7.5%--and two thirds of the limbs were salvaged. We have concluded that selective management, as prescribed above, was responsible for a significant decrease in mortality rate with no corresponding increase in limb loss, and that high-dose heparin therapy ultimately may prove the initial treatment of choice in all cases of acute arterial ischemia.