The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials.

BACKGROUND: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. METHODS: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). RESULTS: Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). CONCLUSIONS: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.

Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose.

Administration of insulin-like growth factor-I to patients with diabetes enhances insulin action and reduces the degree of hyperglycemia but it is associated with a high rate of adverse events. Infusion of the combination of rhIGFBP-3 (the principal binding protein for IGF-I in plasma) with rhIGF-I to patients with type I diabetes improved insulin sensitivity and was associated with a low incidence in side effects. In this study, 52 patients with insulin-treated type 2 diabetes received recombinant human IGF-I plus rhIGFBP-3 in one of four dosage regimens for 14 days. The four groups were: (1) continuous subcutaneous infusion of 2 mg/kg/day; (2) the same 2 mg/kg dose infused subcutaneously over 6 h between 2000 and 0200 h; (3) 1 mg/kg twice a day by bolus subcutaneous injection; (4) a single bedtime subcutaneous injection of 1 mg/kg. Across these four groups rhIGF-I/rhIGFBP-3 decreased insulin requirements between 54% and 82%. Fasting glucose decreased by 32-37%. Mean daily blood glucose (4 determinations per day) declined in all 4 groups (range 9-23% decrease). Frequent sampling for total IGF-I, free IGF-I and IGFBP-3 was performed on days 0,1,7,14 and 15. The peak total IGF-I values were increased to 4.0-4.8-fold at 16-24 h. For free IGF-I the increase varied between 7.1 and 8.2-fold and peak values were attained at 16-20 h after administration. Both the time to maximum concentration (Tmax) and the maximum free IGF-I levels (Cmax) on day 1 for all groups were substantially less than previously published studies, wherein lower doses of rhIGF-I were given without IGFBP-3. The improvement in glucose values and the degree of reduction in insulin requirement were the greatest in groups 2 and 3 and the patients in those groups had the highest free IGF-I levels. The frequency of side effects such as edema, jaw pain and arthralgias was 4% which is less than that has been reported in previous studies wherein IGF-I was administered without IGFBP-3. We conclude that rhIGF-I/rhIGFBP-3 significantly lowers insulin requirements yet improves glucose values and these changes may reflect improvement in insulin sensitivity. Coadministration of IGFBP-3 with IGF-I produces lower free IGF-I (Tmax and Cmax) levels compared to administration of IGF-I alone and is associated with relatively low incidence of side effects during 2 weeks of administration.

Beyond therapy: bringing social work back to human services reform.

Based on field interviews in a Chicago community development corporation and settlement houses in New York City and St. Louis, as well as interviews with leading social services innovators and social work educators, this article explores the intersection of current social work practice and human services innovation. The article offers a rationale and a blueprint for a reorientation of social work's "helping relationship," reviews a number of promising innovations and strategies that may help the profession make this reorientation operational, and explores forces restraining as well as driving such change.

Androgen receptors in bone-forming tissue.

Androgen receptors (AR) were stained in sections of normal human growth plate of the costo sternal junction obtained at postmortem from one 4-day-old and two 5-day-old male infants, and in osteoblasts, grown in culture obtained from the femora of 3 male patients undergoing orthopaedic surgery for osteoarthritis. In the growth plate AR were found mostly in a narrow band of chondrocytes occupying an area about midway between the proximal and distal end of the epiphysis. Nearly all AR were in the cytoplasm and appeared in a granular form; there was no diffuse staining and the nuclei were either completely devoid of AR or only contained a few. Less-differentiated chondroblasts, perichondrial cells and hypertrophic chondrocytes contained few or no AR. Osteoblasts (and osteocytes) contained numerous AR and almost all were in the cytoplasm. Normal human osteoblasts, in their second or third passage, were grown on coverslips either in a medium with no added androgen or in the presence of 5alpha-dihydrotestosterone or methyltrienolone for a period of 24 h or longer. In control cultures, with vehicle and no added androgen, nearly all AR were found in the cytoplasm, with hardly any in the nucleus. In the presence of added androgen some osteoblasts from two of the specimens demonstrated a clear translocation of AR into the nucleus, whilst osteoblasts from a third specimen failed to translocate. These preliminary results indicate that AR translocation to the nucleus occurs in osteoblastic cells derived from osteoarthritic subjects. However, the ability to translocate may depend on the state of differentiation of the osteoblast and on culture conditions.

Long-term psychosocial characteristics of patients treated for idiopathic scoliosis.

Psychosocial characteristics of 95 female patients treated with Milwaukee bracing for idiopathic scoliosis were examined using a battery of five psychosocial scales. Sixty-five patients treated with bracing alone and 30 patients who also underwent arthrodesis for curve progression were compared with 49 age-matched female controls. At an average follow-up of 7 years, no differences in depression or health locus of control existed. Significant perceptions of discrimination and a lower satisfaction of overall appearance was recalled during the treatment phase. By final follow-up, there was no longer any difference between the patients and controls in these areas. Significantly, differences in body-image scores persisted at follow-up. Operative patients had a more negative body image of the axial skeleton in comparison with the braced and control groups. We conclude that transient psychological effects are often present during treatment, and a lower body image may persist for several years in surgical patients.

Effect of amiodarone on the lung shown by polarized light microscopy.

OBJECTIVE: To show lipid deposits in the lung of patients treated with amiodarone. MATERIALS AND METHODS: Formalin-fixed, unstained frozen sections were used to reveal lipid deposits by means of polarized light. Lung tissues obtained at the postmortem examination of one patient and the surgical biopsy of another were available. RESULTS: Birefringent lipid deposits were seen in the alveolar lining cells and macrophages, as well as in the walls of arterioles and venules. CONCLUSIONS: To assess the effect of amiodarone on the lung, polarized light microscopy of unstained, frozen sections is a simple and rapid method.

Use of the Milwaukee brace for progressive idiopathic scoliosis.

One hundred and two (92 per cent) of 111 immature patients in whom idiopathic scoliosis had been treated with a Milwaukee brace were followed to determine the effectiveness of the brace in preventing progression of the scoliosis. The average time from cessation of bracing until the latest radiographs were made for the patients who were managed non-operatively was six years and four months. The average progression of the curve, from the time of initial bracing until use of the brace was stopped, in the eighty-eight patients who were included in the statistical analysis was 4 degrees. The curve continued to progress an average of 5 degrees after use of the brace was stopped in the patients who did not have an arthrodesis. Forty-two patients (48 percent) had more than 5 degrees of progression at the time that use of the brace was stopped. Thirty-seven patients (42 per cent) had an operation or a curve of sufficient magnitude to warrant operative intervention. The maximum correction of the Cobb angle in the brace had prognostic importance for progression of the curve. The patients in whom the curve did not progress or who did not need operative intervention had had an average correction of 20 per cent, while the patients who had a failure had had an average correction of 8 per cent. The patients who eventually had the indications for an arthrodesis were on the average, one year younger (eleven years and none months) and had a curve of a larger magnitude at the time of bracing than the patients who did not need an arthrodesis. The findings of this study do not agree with previously reported favorable results with bracing and raise questions about whether the natural history of progressive idiopathic scoliosis is truly altered by use of the Milwaukee brace.

Localisation of androgen receptors in dermal fibroblasts, grown in vitro, from normal subjects and from patients with androgen insensitivity syndrome.

Human genital skin fibroblasts show the androgen receptor (AR) as bright red granules (0.5 micron in diameter) after treatment with one (of 3) primary polyclonal antibody and a secondary antibody linked to alkaline phosphatase. Almost all AR were cytoplasmic in 12 normal strains and in 8 strains from patients with partial (PAIS) and 6 with complete androgen insensitivity syndrome (CAIS). When 25.8 nM 5-alpha-dihydrotestosterone (DHT) or methyltrienolone was added to the medium, some AR were translocated into the nucleus in 13 experiments with 8 strains of normal fibroblasts; of 8 strains of patients with PAIS 3 failed to translocate to a detectable extent in the presence of androgen in the medium and none of the 6 strains from patients with CAIS translocated.

Surface vs. fine-wire electrode ensemble-averaged signals during gait.

Dynamic electromyography (EMG) utilizes either surface or fine-wire intramuscular electrodes. Ensemble-averaging of EMG profiles provides a convenient and commonly performed way to analyse these signals. This study was designed to evaluate the similarities of ensemble-averaged profiles of the two electrode types. We studied two muscles, the right vastus medialis (VM) and the left biceps femoris (BF), at freely-selected speeds of walking and jogging on a treadmill. Both electrodes were simultaneously attached to the subjects' legs. EMG signals were conditioned to produce linear envelopes. Pearson's correlation coefficients (r) and variance ratios (VR) were determined to assess the degree of similarity in the EMG profiles and the repeatability of the muscle activity, respectively. The ensemble-averaged signals reflect a high degree of pattern similarity as evidenced by high r values (usually greater than 0.90) for both muscles at both speeds. The low mean VRs indicate reasonable reproducibility for both electrode types; fine-wire electrodes in the BF and VM exhibit similar variability to surface electrodes. For the purpose of establishing relative profiles of activation during gait, ensemble-averaged surface and fine-wire signals are closely equivalent.

Predicting and optimizing success in an intra-uterine insemination programme.

We analysed 381 consecutive cycles of homologous intrauterine insemination (IUI) in 215 infertile couples, resulting in 48 pregnancies (12.6%/cycle, 22.3%/patient). Cycle fecundity ranged from 0.11 to 0.14 in women aged 25-39 years, falling to 0.04 beyond age 40 years. Of the 48 pregnancies, 43 occurred in the first three treatment cycles, in which fecundity was 0.14, 0.16 and 0.10 respectively. Beyond three cycles, fecundity was 0.07 (P = 0.05 versus first two cycles). The occurrence of pregnancy varied with diagnosis (P = 0.04). Fecundity was significantly greater for women with ovulatory dysfunction (0.30) than for endometriosis, male factor, tubal factor, idiopathic infertility or multifactorial (0.08-0.14). Ovulation induction using menopausal gonadotrophins offered significant advantage over natural cycles or cycles using clomiphene citrate without gonadotrophins (0.15 versus 0.03, P = 0.01). Cycles in which pre-ovulatory surges were either induced or supported with human chorionic gonadotrophin (HCG) were superior to spontaneous luteinizing hormone surges (0.13 versus 0.03, P = 0.05). Recruitment of at least two mature (> 1.6 cm) follicles was critical. Only one pregnancy occurred in 64 cycles characterized by one mature follicle, compared with a pregnancy rate of 0.15 in cycles characterized by two or more mature follicles (P = 0.006). IUI is not beneficial to women > 40 years old, and has the best chance of success within three cycles. Multiple follicle recruitment using gonadotrophin-based stimulation protocols and mid-cycle HCG are necessary to achieve an acceptable pregnancy rate.

Serum folate and chronic fatigue syndrome.

We assayed serum folate levels of 60 patients with chronic fatigue syndrome (CFS) and found that 50% had values below 3.0 micrograms/l. Some patients with CFS are deficient in folic acid.

A multicenter study on the use of pulsed low-intensity direct current for healing chronic stage II and stage III decubitus ulcers.

BACKGROUND AND DESIGN: Pulsed low-intensity direct current (300 to 600 microA) has been used in a double-blind placebo multicenter study in the treatment of stage II and stage III chronic decubitus ulcers. RESULTS: Seventy-four ulcers were treated in four centers. Forty-three patients were selected for the experimental group, and 31 control subjects used the sham instrument (placebo group). In the treated group, 25 ulcers (58%) healed in 8 weeks, whereas in the placebo group, only one ulcer (3%) healed and most ulcers increased in size. Statistical analysis, based on surface area and ulcer depth before and after treatment, showed that low-intensity direct current had a significant influence on the healing rates for these ulcers (P < .0001). Experiments with guinea pigs (n = 10) showed that pulsed low-intensity direct current caused a rapid calcium flux in the epidermis. CONCLUSIONS: Pulsed low-intensity direct current represents a useful approach for the treatment of stage II and stage III chronic decubitus ulcers by increasing the healing rate. The growth of fibroblasts and keratinocytes may be enhanced by pulsed low-intensity direct current due to changes in calcium homeostasis.

Surfactant and adult respiratory distress syndrome.

In order to determine if the Adult Respiratory Distress Syndrome (ARDS) is associated with a shortage of pulmonary surfactant, we have examined a series of 155 undiluted tracheal aspirates obtained from 23 patients with ARDS and from 30 patients without ARDS, all 53 needing ventilatory support. The unfixed and unstained specimens were examined by polarized light microscopy for the presence of pulmonary surfactant. Free surfactant particles were present in the aspirates of 50 patients (95%). Within minutes of obtaining the specimen, in addition to showing surfactant, the examination of these undiluted, unfixed tracheal aspirates by light microscopy showed the presence of bacterial and fungal infection. As fibrinogen/fibrin inactivates surfactant, the undiluted aspirates of 21 patients with ARDS and of 30 patients without ARDS were stained for the presence of these proteins by a new slide method using 0.01 ml of tracheal aspirate. Fibrinogen/fibrin was found in the aspirates from 20 of 21 patients with ARDS and in only five of 30 patients without ARDS; these five had bronchopneumonia. The method has a sensitivity of 0.95 and a specificity of 0.83. The role of plasma proteins and of neutrophil leucocytes in causing ARDS is discussed.

Rapid visualization of NMDA receptors in the brain: characterization of (+)-3-[125I]-iodo-MK-801 binding to thin sections of rat brain.

We have developed and characterized a method for the rapid autoradiographic determination of receptor sites for the non-competitive NMDA receptor antagonist, MK-801, using an iodinated form of the compound, (+)-3-[125I]-iodo-MK-801. The binding site was shown to exhibit those criteria necessary for its definition as a receptor site, i.e., the binding was saturable, of high affinity, easily reversible, and stereospecific. Saturation analysis of binding to thin brain sections revealed a Bmax of 108.1 +/- 10.5 fmol/mg protein and a Kd of 383 +/- 67 pM. The pharmacology of the interaction of the ligand with the binding site yielded good correlation between the potency of various substances to complete for the binding site and their ability to act as antagonists of NMDA. Autoradiographs of thin coronal brain sections using (+)-3-[125I]-iodo-MK-801 yielded high quality images in 24-48 h with a distribution of binding sites paralleling that reported for the tritiated form of the ligand, i.e., with high densities in the hippocampus, cerebral cortex and lateral septum. Other areas with significant binding included parts of the thalamus, the amygdala and the olfactory tubercules. Furthermore, due to its high specific activity, this ligand lends itself to the study of regions not rich in MK-801 binding sites, such as the diencephalon.

Microscopic observations on tracheal aspirates from ventilated neonates. II. The onset of bronchopulmonary dysplasia and other changes.

A total of 450 undiluted and unprocessed tracheal aspirates from 120 intubated infants were examined microscopically for evidence of bronchopulmonary dysplasia and other changes. In 19 infants desquamated sheets of dysplastic epithelium in the fresh aspirate provided an early indication of developing bronchopulmonary dysplasia. Examination of unstained tracheal aspirates can provide, within minutes, information not only about the onset and development of bronchopulmonary dysplasia, but also provide evidence for milk or formula aspiration and for gastro-oesophageal reflux.

Gonadotropin suppression with oral contraceptives before in vitro fertilization.

One hundred eighty-one stimulation cycles in which gonadotropin suppression with oral contraceptives (OCs) preceded induction of follicle stimulation (study group) and 113 stimulation cycles without pituitary suppression (control group) were compared. The mean length of ovarian suppression was 35.3 +/- 0.9 days. No spontaneous luteinizing hormone (LH) surges occurred when the use of OC preceded ovarian hyperstimulation, whereas in the control group the incidence of LH surges was 19.5%. The mean amount of human menopausal gonadotropin required was significantly lower in the study group than in the control group (8.9 +/- 0.4 and 10.9 +/- 0.4 ampules, respectively). Significantly more follicles greater than or equal to 1.5 cm in diameter were seen on the day before oocyte retrieval and significantly more oocytes were retrieved per attempt in the group with OC pretreatment. Our data clearly demonstrate that OCs are useful in vitro fertilization stimulation protocols to facilitate scheduling of cycles and to prevent spontaneous LH surges.

Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization.

The present study was undertaken to evaluate endometrial thickness and the amount of endometrial growth (delta) in patients who conceived during in vitro fertilization (IVF) (n = 36) compared with matched women who did not conceive (n = 72). Estradiol (E2) and endometrial thickness were measured daily from cycle day 10 to the day after human chorionic gonadotropin (hCG). Mean endometrial thickness and E2 levels on cycle day 10 did not differ. On the day before ovum retrieval, significantly thicker endometrium was observed in the pregnant than in the nonpregnant women (8.6 +/- 0.3 [SEM] and 7.1 +/- 0.3 mm, respectively; P less than 0.0005), whereas the mean E2 levels did not differ. The delta endometrial growth was greater in the women who conceived than in the nonpregnant group (4.3 +/- 0.2 and 2.5 +/- 0.2 mm, respectively; P less than 0.0005). The fertilization rate and serum E2 levels did not correlate with endometrial thickness nor with delta endometrial growth. Our data suggest that the amount of endometrial growth during ovarian hyperstimulation and the endometrial thickness on the day before oocyte retrieval deserve further study as possible predictive parameters for implantation.

Decreases in mediobasal hypothalamic and preoptic area opioid ([3H]naloxone) binding are associated with the progesterone-induced luteinizing hormone surge.

In view of evidence implicating hypothalamic opioid systems in the control of LH release, we have examined the binding of [3H]naloxone (NAL) to slices of mediobasal hypothalamus (MBH) and preoptic area (POA) during the induction of an afternoon LH surge (1630-1700 h) in estradiol benzoate (EB)-primed ovariectomized (OVX; day 0) rats by treatment with progesterone (P; day 2). Such a surge was invariably accompanied by a decrease from early morning (1000 h) values in the number of NAL-binding sites detectable in the MBH, while the affinity of the binding site was not affected over the course of the day. Time-course studies indicated that P injection at 1000 h on day 2 was followed by a transient midday elevation in the amount of NAL bound to slices of MBH; the binding decreased significantly before the onset of and during the LH surge. A similar diurnal change was not observed in MBH slices of either oil-treated OVX rats (controls) or EB-treated OVX rats, which displayed only a 2-fold increase in LH release in the afternoon. Further studies indicated a similar change in NAL binding to slices of the POA of EBP-treated rats. Since hypothalamic opioid systems inhibit LH release, the decrease in opioid binding to MBH as well as POA slices suggests that P may curtail the existing opioid inhibitory influence in these areas before and during the course of the afternoon LH surge.

Dynamic changes in neuropeptide y concentrations in the median eminence in association with preovulatory luteinizing hormone release in the rat.

Abstract Neuropeptide Y (NPY) stimulates luteinizing hormone (LH) release in the rat by a dual action, one in the hypothalamus to excite LH-releasing hormone (LHRH) release and the other at the level of pituitary gonadotrophs to activate and/or potentiate LH release induced by LHRH. Because NPY produces effects similar to norepinephrine with which it may comprise an excitatory hypothalamic circuit, it was hypothesized that NPY concentrations in the hypothalamus would change in a time- and site-specific manner in association with the preovulatory LH surge on proestrus. Concentrations of NPY in individual nuclei of the preoptic-tuberal pathway and serum LH levels were estimated by radioimmunoassays in rats during diestrus 2 and proestrus. On proestrus, serum LH levels were basal between 1000 and 1400 h, rose significantly at 1500 h and plateaued between 1600 and 1800 h. Of the five neural sites examined, only NPY in the median eminence displayed marked fluctuations in close association with the LH surge. NPY concentrations were low between 1000 and 1300 h, and rose abruptly at 1400 h (P<0.05) preceding the onset of LH rise at 1500 h. These elevated levels were maintained until 1600 h, during which time serum LH rose to a plateau and then fell at 1800 h to the low range seen between 1000 and 1300 h. In contrast, the pattern of changes in NPY levels in the arcuate nucleus, suprachiasmatic nucleus and medial preoptic area, three additional sites in the preoptic-tuberal pathway known to participate in the preovulatory LH surge, were markedly different from that seen in the median eminence. In each of these three sites, NPY levels rose significantly at 1800 h from the values at 1000 to 1200 h with a slightly different time-course of increment. None of these areas exhibited changes in NPY concentrations on diestrus 2; NPY concentrations also were unaltered on diestrus 2 or proestrus in the ventromedial nucleus. The present observations of site-specific, dynamic changes in NPY levels on proestrus, in a manner previously documented for LHRH, support the hypothesis that a subset of NPY neurons terminating in the median eminence may be a component of excitatory neural circuitry that either independently or in co-action with the adrenergic system is responsible for the induction of preovulatory LH release.

Tracheal aspirates from neonates during endotracheal intubation: detection of surfactant by polarized light microscopy.

A technique for detecting the presence of pulmonary surfactant in the tracheal aspirates obtained from preterm babies is described. The specimens were examined by means of polarized light microscopy. Surfactant could be simply and rapidly identified by its appearance as birefringent particles in volumes of aspirate as little as 1 microliter. Tracheal aspirate specimens from 108 babies, obtained on the first day of life, were examined without knowledge of the patient's clinical details. When the samples from each baby were subdivided into three groups on the basis of the amount of surfactant particles seen, this subgrouping corresponded well with the babies' ventilatory requirements at the time of sample collection. This method of detecting surfactant material may prove valuable in determining the degree of surfactant deficiency in individual preterm babies with respiratory illness.