Mesenchymal stromal cells: inhibiting PDGF receptors or depleting fibronectin induces mesodermal progenitors with endothelial potential.

Realizing the full therapeutic potential of mesenchymal stromal/stem cells (MSCs) awaits improved understanding of mechanisms controlling their fate. Using MSCs cultured as spheroids to recapitulate a three-dimensional cellular environment, we show that perturbing the mesenchymal regulators, platelet-derived growth factor (PDGF) receptors or fibronectin, reverts MSCs toward mesodermal progenitors with endothelial potential that can potently induce neovascularization in vivo. MSCs within untreated spheroids retain their mesenchymal spindle shape with abundant smooth muscle α-actin filaments and fibronectin-rich matrix. Inhibiting PDGF receptors or depleting fibronectin induces rounding and depletes smooth muscle α-actin expression; these cells have characteristics of mesenchymoangioblasts, with enhanced expression of mesendoderm and endoderm transcription factors, prominent upregulation of E-cadherin, and Janus kinase signaling-dependent expression of Oct4A and Nanog. PDGF receptor-inhibited spheroids also upregulate endothelial markers platelet endothelial cell adhesion molecule 1 and vascular endothelial-cadherin and secrete many angiogenic factors, and in vivo they potently stimulate neovascularization, and their MSCs integrate within functional blood vessels that are perfused by the circulation. Thus, MSC potency and vascular induction are regulated by perturbing mesenchymal fate.

Trichinella spiralis antigens prime mixed Th1/Th2 response but do not induce de novo generation of Foxp3+ T cells in vitro.

Many parasitic helminth infections induce Th2-type immune responses and engage the regulatory network. In this study, we specifically investigated the influence of antigens derived from different life stages of the helminth Trichinella spiralis on the polarization of naive CD4(+) T cells by dendritic cells. Results obtained from C57BL/6 mice showed that T. spiralis derived antigens have the capacity to induce bone marrow-derived dendritic cells to acquire an incompletely mature phenotype that promotes a significant proliferation of naive CD4(+) T cells and a mixed Th1/Th2 cytokine profile with the predominance of Th2 cytokines. Increased production of IL-4, IL-9, IL-10 and IL-13 accompanied increased IFN-γ. Furthermore, dendritic cells pulsed with T. spiralis antigens did not induce an increase in the population of Foxp3(+) T regulatory cells. Although other helminth antigens have demonstrated the capacity to induce de novo generation of Foxp3(+) T regulatory cells, here our in vitro studies provide no evidence that T. spiralis antigens have this capacity.

Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity.

The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies' largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity.

Inflammatory cues enhance TGFß activation by distinct subsets of human intestinal dendritic cells via integrin αvß8.

Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-ß (TGFß), which is secreted by cells as a latent complex that requires activation to function. However, how TGFß activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFß, integrin αvß8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c+ but not the CD141+ intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGFß-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin αvß8 expression and TGFß activation by human DC. We also show that DC expression of integrin αvß8 enhanced induction of FOXP3 in CD4+ T cells, suggesting functional importance of integrin αvß8 expression by human DC. These results show that microbial signals enhance the TGFß-activating ability of human DC via regulation of integrin αvß8 expression, and that intestinal inflammation may drive this pathway in patients with IBD.

Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial.

BACKGROUND: The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder. We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder. METHODS: One hundred seventy-six nondepressed outpatients with panic disorder, with or without agoraphobia, from 10 sites followed identical protocols that used a flexible-dose design. After 2 weeks of single-blind placebo, patients were randomly assigned to 10 weeks of double-blind, flexible-dose treatment with either sertraline hydrochloride (50-200 mg/d) or placebo. RESULTS: Sertraline-treated patients exhibited significantly greater improvement (P=.01) at end point than did patients treated with placebo for the primary outcome variable, panic attack frequency. Significant differences between groups were also evident for clinician and patient assessments of improvement as measured by the Clinical Global Impression Improvement (P=.01) and Severity (P=.009) Scales, Panic Disorder Severity Scale ratings (P=.03), high end-state function assessment (P=.03), Patient Global Evaluation rating (P=.01), and quality of life scores (P=.003). Adverse events, generally characterized as either mild or moderate, were not significantly different in overall incidence between the sertraline and placebo groups. CONCLUSION: Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder.

Patterns of axis I comorbidity in early-onset versus late-onset major depressive disorder.

BACKGROUND: This study of a large clinical sample of depressed patients examined whether childhood onset as compared with adult onset Major Depressive Disorder (MDD) would confer a greater risk for Axis I comorbidity and whether childhood onset MDD would also differ from adult onset MDD in the pattern of comorbid disorders. METHODS: We examined lifetime co-occurrence of Axis I disorders among 381 adult outpatients with MDD by Structured Clinical Interview for DSM-III-R-Patient Edition (SCID-P). Subjects were divided into childhood onset (n = 47), adolescent onset (n = 101) and adult onset (n = 233) MDD groups. RESULTS: We found that the two early-onset groups exhibited significantly increased rates of Axis I comorbidity. The childhood onset group accounted for a disproportionately high percentage of depressed adults with two or more comorbid Axis I disorders. Social and simple phobias and alcohol abuse/dependence were significantly more prevalent among individuals with childhood onset MDD than among individuals with adult onset MDD. Alcohol abuse/dependence, but not anxiety disorders, was significantly more prevalent among adolescent onset than adult onset MDD groups. Panic, generalized anxiety, obsessive-compulsive and somatoform disorders were equally distributed across MDD onset groups. Comorbid disorders were much more likely to have followed onset of MDD among individuals with childhood compared with adult onset, except for social phobia which more frequently preceded the depression. The relative ordering among the comorbid conditions with respect to whether they followed or preceded MDD did not vary notably across the three age of onset groups. CONCLUSIONS: We conclude that early-onset MDD is associated with an increased density of Axis I comorbidity that seems to be limited to specific disorders.

Early nonresponse to fluoxetine as a predictor of poor 8-week outcome.

OBJECTIVE: The purpose of this study was to quantify the proportion of patients who show no response to a fixed dose of fluoxetine after 2, 4, and 6 weeks of treatment and then respond by week 8. METHOD: In an open trial, 143 outpatients who met DSM-III-R criteria for major depressive disorder were treated with a regimen of fluoxetine, 20 mg/day. The authors analyzed the proportion of patients who had less than a 20% decrease from baseline in their scores on the Hamilton Rating Scale for Depression after 2, 4, and 6 weeks and who went on to have a 50% or greater reduction by week 8. A last-observation-carried-forward strategy was used to calculate conditional probabilities of 8-week response. Kaplan-Meier survival analysis was used to estimate probabilities of response at week 8 given degrees of response at week 2. RESULTS: Eighty-two subjects (57.3%) who started the trial responded by week 8. Of those subjects who showed no improvement at weeks 2, 4, and 6, the proportions of responders at week 8 were 36.4%, 18.9%, and 6.5%, respectively. The Kaplan-Meier estimate of 8-week response given nonresponse at week 2 was 0.45. CONCLUSIONS: The proportion of patients with no response to antidepressant treatment by 4 or 6 weeks who responded by week 8 was substantially less than that for subjects who had at least a partial response. Nonresponse as early as week 2 predicted 8-week outcome.

Timing of onset of antidepressant response with fluoxetine treatment.

OBJECTIVE: The purpose of this study was to assess the time until onset of antidepressant response with fluoxetine treatment. METHOD: The authors evaluated 182 outpatients with major depression who had a sustained acute response to fluoxetine treatment. The outpatients received 8 weeks of treatment with 20 mg/day of fluoxetine and were assessed biweekly with the 17-item Hamilton Depression Rating Scale. The onset of response was defined as a 30% decrease in score on the Hamilton depression scale that persisted and led to a 50% decrease by week 8. The Kaplan-Meier product limit and Cox regression analysis were used to model the relationship between relevant variables and time until onset of response. RESULTS: The authors found that at weeks 2, 4, and 6, the probabilities of having an onset of response (for responders) were 55.5%, 24.7%, and 9.3%, respectively. The cumulative probabilities of onset of response at each time point were 55.5%, 80.2%, and 89.5%. Neither demographics nor clinical characteristics of depression predicted time until initial response. CONCLUSIONS: These data suggest that more than half of eventual responders to fluoxetine treatment at 8 weeks start to respond by week 2; over 75% start to respond by week 4. Conversely, the lack of onset of response at 4-6 weeks was associated with about a 73%-88% chance that patients would not have an onset of response by 8 weeks.

Relationship of childhood anxiety to adult panic disorder: correlates and influence on course.

OBJECTIVE: This study investigated the correlates of a childhood history of anxiety disorders in adult patients participating in a longitudinal study of panic disorder. The authors hypothesized that a history of anxiety during childhood would be associated with higher rates of comorbid anxiety and depressive disorders, greater likelihood of anxiety disorders in family members, and greater chronicity, as reflected by decreased time spent in remission. METHOD: The presence of a childhood history of anxiety disorders was assessed by structured interview, and its association with comorbid anxiety and depressive disorders, family history, and select anxiety severity variables was examined in a replication sample of 94 patients. The influence of childhood anxiety on the prospectively ascertained course of disorder was assessed in a full group of 194 patients. RESULTS: Over half (54%) of the patients experienced anxiety disorders during childhood. These patients experienced higher rates of comorbid anxiety and depression, family history of anxiety, and increased levels of agoraphobia, panic frequency, and global severity of illness at baseline evaluation. Childhood anxiety disorders were not independently associated with the number of months in remission or the severity of illness over time, although a modest effect for this variable was evident when degree of avoidance and anxiety sensitivity at baseline were statistically controlled. CONCLUSIONS: Adult panic patients with a history of anxiety disorders in childhood have elevated rates of comorbid anxiety and depressive disorders and a tendency toward increased avoidance, but there was not strong evidence that these patients respond differently to treatment over time.

Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone.

BACKGROUND: The development of effective and well-tolerated anxiolytic agents is an area of critical clinical importance. Abecarnil, a beta carboline, is a partial benzodiazepine-receptor agonist that has demonstrated promise as an anxiolytic agent. In this study, we examine the efficacy, safety, and discontinuation-related effects of abecarnil, buspirone, and placebo in the acute and long-term treatment of patients who have generalized anxiety disorder. METHOD: This is a double-blind, placebo-controlled study of two dosages of abecarnil and buspirone. In total, 464 patients were randomized. After a placebo run-in week, patients entered a 6-week double-blind treatment period, followed by an optional 18-week maintenance period for treatment responders. After abrupt discontinuation of the acute or maintenance treatment, patients entered a 3-week placebo-substitution follow-up period. Treatment response was assessed with the Hamilton Rating Scale for Anxiety and the Clinical Global Impressions (CGI) Scale. RESULTS: Compared with placebo, abecarnil showed significant anxiolytic activity early in the treatment period, particularly in the high-dosage group, though these differences did not maintain statistical significance at the end of the trial. Buspirone was associated with a slower onset of action and better symptom relief than placebo after 6 weeks of therapy. Withdrawal symptoms emerged in patients who abruptly discontinued abecarnil (particularly at the higher dosage) only in those receiving a longer duration of treatment. CONCLUSION: The results of this study need to be understood in the context of a high placebo-response rate, which hampers the ability to demonstrate significant drug-placebo differences. This study suggests that abecarnil may be an effective anxiolytic agent; further attention is warranted to assess its spectrum of clinical effectiveness.

Residual symptoms in depressed patients who respond acutely to fluoxetine.

BACKGROUND: Antidepressants have unequivocal efficacy as compared with placebo, but many patients have residual symptoms despite a robust response to antidepressant therapy. The purpose of this study is to assess residual symptoms in outpatients who respond acutely to fluoxetine. METHOD: Two hundred and fifteen outpatients with major depressive disorder as assessed with the Structured Clinical Interview for DSM-III-R (SCID-P) were treated openly with fluoxetine 20 mg/day for 8 weeks. One hundred and eight (50.2%) were considered full responders (final 17-item Hamilton Rating Scale for Depression [HAM-D] score < or =7). Percentages of full responders who continued to have subthreshold or full major depressive disorder symptoms were calculated. The relationship between residual symptoms and Axis I and Axis II (assessed with SCID-II for personality disorders) comorbidity was assessed. RESULTS: Of the 108 responders, 19 (17.6%) had no subthreshold or threshold SCID-P major depressive disorder symptoms, while 28 (25.9%) had 1 symptom, and 61 (56.5%) had 2 or more symptoms. No statistically significant relationships were found between number of residual symptoms and selected Axis I comorbid conditions or total number of Axis II disorders. CONCLUSION: Less than 20% of full responders to fluoxetine by HAM-D criteria were free of all SCID-P subthreshold and threshold major depressive disorder symptoms after 8 weeks of treatment. While depressed patients benefit from antidepressants, most continue to have some symptoms of depression. The high prevalence of residual symptoms among antidepressant responders suggests the need for further study including whether residual symptoms abate with longer treatment or increased dose of fluoxetine. Other strategies, such as cognitive behavioral therapy, may be needed to address residual symptoms.

Citalopram for social phobia: a clinical case series.

Social anxiety disorder is a common illness with significant associated disability. Serotonin selective reuptake inhibitors (SSRIs) have become first-line treatment given their improved tolerability; however, there are few reports on the use of citalopram. Nine consecutive patients with a primary diagnosis of DSM-IV generalized social phobia were prospectively treated with citalopram. Citalopram was generally well-tolerated, and seven patients achieved responder status. This series of patients improved significantly on all measures. Results suggest that citalopram may be a safe and effective treatment for social anxiety disorder.

Relationship of antecedent stressful life events to childhood and family history of anxiety and the course of panic disorder.

The authors examined the incidence of significant life events during the year prior to the onset of panic disorder and its relationship to childhood and family history of anxiety difficulties, comorbidity, and the course of illness in 223 panic patients followed in a naturalistic study of panic disorder. Similar to previous reports, antecedent negative life events occurred in the majority (80%) of patients. Patients with a childhood history of anxiety and comorbid adulthood major depression were more likely to report an antecedent, stressful life event. Antecedent events were not linked with comorbid, adulthood anxiety disorders or a family history of anxiety difficulties. Despite its associations with childhood anxiety pathology and adulthood major depression, the presence of an identifiable antecedent at the onset of panic disorder was not associated with the subsequent severity or course of the disorder.

Ropinirole for antidepressant-induced sexual dysfunction.

Sexual dysfunction is a relatively common side-effect of antidepressants, occurring in approximately one-half of patients, and is associated with significant distress and treatment non-compliance. Dopaminergic agents have been reported to be helpful for the treatment of antidepressant-induced sexual dysfunction and, in this report, we examined the efficacy of the dopamine agonist ropinirole for this indication. Thirteen patients (three women, 10 men), aged 42.6 +/- 7.7 years, who reported sexual dysfunction on a stable dose of antidepressant, were treated openly with ropinirole initiated at 0.25 mg/day and titrated up to 2-4 mg/day over 4 weeks, as tolerated. Ten of the 13 took ropinirole for at least 4 weeks, one discontinued due to an adverse event and two because of lack of response. Sexual dysfunction, as assessed by the Arizona Sexual Experience Scale scores, was reduced from 18.8 +/- 3.6 to 13.8 +/- 4.3 after 4 weeks on ropinirole at a mean dose of 2.1 mg/day. Overall, seven of 13 patients (54%) were rated as responders on the Clinical Global Impression of Improvement Scale. The addition of ropinirole may represent a potentially useful treatment strategy for antidepressant-induced sexual dysfunction.

Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression.

BACKGROUND: Folate and B12 deficiencies may result in macrocytic anemia, and are common in major depression; hypofolatemia may result in poorer antidepressant response. We wished to determine whether anemia or macrocytosis predict hypofolatemia, low B12, or refractoriness to antidepressants. METHODS: After obtaining serum folate, B12, and hematological indices, 213 depressed adults were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was measured. RESULTS: Neither macrocytosis nor anemia predicted low serum folate/B12, or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12, none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders, 3% had macrocytosis; 24% had low HCT; 25% had low RBC. CONCLUSION: Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants. Measurement of folate and B12 should be considered when evaluating treatment refractoriness.

Attention deficit hyperactivity disorder in childhood among adults with major depression.

The prevalence of attention deficit hyperactivity disorder (ADHD) with childhood onset and its relationship to course and treatment outcome of major depressive disorder (MDD) in adults was studied in 116 patients (ages 18-65) consecutively enrolled for treatment of MDD. Sixteen percent of the patient were found to meet full or subthreshold criteria for the DSM-III-R diagnosis of childhood ADHD. Twelve percent endorsed persistence of ADHD symptoms into adulthood. Depressed adults meeting criteria for childhood ADHD did not differ significantly from other depressed adults on any measures related to the chronicity or severity of the mood disorder, Axis I comorbidity, or response to acute antidepressant treatment. Our results are clinically important as they suggest that clinicians need to be aware of the possibility that a substantial proportion of patients with MDD may suffer from comorbid ADHD and that treatments need to include the targeting of possible residual ADHD symptoms in addition to those of depression.

A comparison of the efficacy of clonazepam and cognitive-behavioral group therapy for the treatment of social phobia.

There is a growing body of evidence that social phobia may be treated effectively by either pharmacologic or cognitive-behavioral interventions. but few studies have examined the relative benefits of these treatments. In this study, we examined the relative efficacy of pharmacotherapy with clonazepam and cognitive-behavioral group therapy (CBGT) for treating social phobia. In addition, we examined potential predictors of differential treatment response. Outpatients meeting Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria for social phobia were randomly assigned to treatment. Clinician-rated and patient-rated symptom severity was examined at baseline and after 4, 8, and 12 weeks of treatment. All clinician-rated assessments were completed by individuals blind to treatment condition. Patients in both conditions improved significantly, and differences between treatment conditions were absent, except for greater improvement on clonazepam on several measures at the 12-week assessment. Symptom severity was negatively associated with treatment success for both methods of treatment, and additional predictors-sex, comorbidity with other anxiety or mood disorders, fear of anxiety symptoms, and dysfunctional attitudes-failed to predict treatment outcome above and beyond severity measures. In summary, we found that patients randomized to clinical care with clonazepam or CBGT were equally likely to respond to acute treatment, and pretreatment measures of symptom severity provided no guidance for the selection of one treatment over another.

The role of anxiety sensitivity in sleep disturbance in panic disorder.

Previous research has demonstrated that individuals with panic disorder (PD) report significant sleep disturbances, although the mechanism of this disturbance is not clear. Patients with PD tend to report abnormally high levels of anxiety sensitivity (AS). Because higher AS involves increases in attention and fearfulness about anxiety and associated physical sensations, which in turn may cause excessive psychological and physiologic arousal, we hypothesized that amongst individuals with PD, higher AS would be associated with sleep disruption, particularly in the form of increased sleep latency. As expected, PD was associated with poorer sleep as measured by the Global Pittsburgh Sleep Quality Index (PSQI) compared to controls and AS was significantly associated with longer sleep latency. Our data suggest that sleep disturbance, and in particular sleep latency, in PD may be partly due to high levels of AS, which can be targeted with cognitive-behavioral therapeutic strategies.

An open trial of oral sildenafilin antidepressant-induced sexual dysfunction.

BACKGROUND: Sildenafil is a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5 that has been associated with greater improvement of erectile function compared to placebo among men with erectile dysfunction. The goal of our study was to evaluate its efficacy in a small sample of outpatients with antidepressant-induced sexual dysfunction. METHODS: We studied the first 14 depressed outpatients (9 men and 5 women; mean age: 46.4 +/- 8.4) who were consecutively treated with oral sildenafil. Twelve of the 14 patients were treated with an SSRI and 2 with mirtazapine. All patients were prescribed oral sildenafil tablets at the initial dose of 50 mg q.d. p.r.n., with the possibility of increasing the dose to 100 mg q.d. p.r.n., if clinically indicated. We administered a sexual functioning questionnaire derived from the Guided Interview Questionnaire for females and males and from the Arizona Sexual Experience Scale to all patients before and after at least 4 weeks of treatment with oral sildenafil. The mean sildenafil dose in our 14 patients was 57 +/- 18 mg/day. RESULTS: All 14 subjects completed the follow-up assessments and no subjects discontinued the drug prematurely. We observed statistically significant improvements in all domains of sexual functioning, including libido, arousal, orgasm, sexual satisfaction, and (in males only) erectile function, with a 69% rate of patients reporting themselves as much or very much improved. Oral sildenafil treatment appeared to be very well tolerated, with only 1 out of 14 (7%) patients reporting an adverse event (hot flashes). CONCLUSIONS: Our findings of statistically significant improvements in all domains of sexual functioning in a sample of 14 men and women with antidepressant-induced sexual dysfunction suggest that this agent may represent an efficacious approach to this population.