The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders.

Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for insulin-like growth factor-1 (IGF-1) in normal CNS development. Work in model systems has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of efficacy in disorders of the CNS, including autism spectrum disorder (ASD). In this review, we explore the molecular pathways and downstream effects of IGF-1 and summarize the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. This aim of this review is to provide evidence for the potential of IGF-1 as a treatment for neurodevelopmental disorders and ASD.

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual disability, accounting for between 0.5% and 2.0% of cases. The cause of PMS has been isolated to loss of function of one copy of SHANK3, which codes for a master scaffolding protein found in the postsynaptic density of excitatory synapses. Reduced expression of SH3 and multiple ankyrin repeat domains 3 (SHANK3) leads to reduced numbers of dendrites, and impaired synaptic transmission and plasticity. Recent mouse and human neuronal models of PMS have led to important opportunities to develop novel therapeutics, and at least 2 clinical trials are underway, one in the USA, and one in the Netherlands. The SHANK3 pathway may also be relevant to other forms of ASD, and many of the single-gene causes of ASD identified to date appear to converge on several common molecular pathways that underlie synaptic neurotransmission. As a result, treatments developed for PMS may also affect other forms of ASD.

Prevalence of adjunctive antipsychotic treatment for non -psychotic predominantly Latino depressed adults: a retrospective study / Prevalencia del tratamiento adjunto con antipsicóticos en pacientes adultos predominantemente Latinos con depresión no psicótica: Un estudio retrospectivo

The use of atypical antipsychotics as an adjunctive therapy to antidepressants for treating non-psychotic major depressive disorder (MDD) has been a common practice long before large-scale randomized double-blind placebo-controlled clinical trials demonstrated their efficacy. In this study, we aimed to study the frequency with whichpatients with non-psychotic major depression were prescribed antipsychotics (AP) and to examine the effect of age, race, and ethnicity on the type and dose of individual antipsychotics prescribed, in a cohort of patients before the recent Food and Drug Administration (FDA) approval of adjunctive aripiprazole. The charts of 1537 patients with unipolar depression were analyzed. 1376 had non-psychotic depression; among them 466 (33.9%) patients were prescribed antipsychotics with a significant predilection towards males (males vs. females: 41.7% vs. 27.8%. z=2.4, p<.02; odds ratio=1.97 with a standard error of 0.57) of Hispanic origin (X 2 = 35.8, df = 1, p < 0.0001).Quetiapine was the most commonly prescribed antipsychotic (n=209, 44.8%) with a mean (±SEM) 195.1±13.1 mg. Our results confirm previous reports of the common clinical practice of the use of atypical antipsychotics, specifically quetiapine, as adjunctive treatment for non-psychotic patients with unipolar depression. Further research is required to study the long term effect of this class of medications in patients without a primary psychotic disorder.

El uso de antipsicóticos atípicos como terapia adjunta a antidepresivos en el tratamiento del trastorno depresivomayor (TDM) no psicótico fue práctica común por un largo periodo antes de que los ensayos clínicos a doble-ciego,controlados (con placebo) y al azar, llevados a cabo a gran escala, demostraran su eficacia. El presente estudio se propuso evaluar la frecuencia con la cual pacientes diagnosticados con TDM recibieron tratamiento con agentes antipsicóticos (AP) y examinar los efectos de edad, raza y etnicidad sobre el tipo y dosis de los anti-psicóticos prescritos a una cohorte de pacientes antes de la reciente aprobación de aripiprazole por la Administración de Alimentos y Drogas (FDA), como medicación adjunta para el manejo de esta entidad clínica. Se analizaron lashistorias clínicas de 1537 pacientes portadores del diagnóstico de depresión unipolar. 1376 presentaron depresiónno psicótica y de ellos, 466 (33,9%) recibieron antipsicóticos con predominio de pacientes varones (hombres vs. mujeres: 41,7% vs. 27,8%. z=2,4, p<0,02; odds ratio (OR)=1,97, con error estándar (SE) de 0,57) de origen Hispánico (X2= 35,8, df = 1, p < 0,0001). Quetiapina fue el antipsicótico más comúnmente prescrito (n=209,44,8%) con una dosis promedio (±SEM) de 195,1±13,1 mg. Nuestros resultados confirman reportes previos del uso de antipsicóticos (específicamente quetiapina) en la práctica clínica habitual, como tratamiento adjunto en pacientesno psicóticos con diagnóstico de depresión unipolar. Se requiere investigación adicional que indague los efectos a largo plazo de este tipo de medicación en pacientes sin un diagnóstico de trastorno psicótico primario.

Long-term follow-up after anti-reflux surgery in patients with Barrett's esophagus.

BACKGROUND: Factors associated with the risk of progression of Barrett's esophagus remain unclear, and the impact of therapy on this risk remains uncertain. The aim of this study was to assess patients followed long-term after anti-reflux surgery for Barrett's esophagus. METHODS: A retrospective review was performed of all patients with Barrett's who underwent anti-reflux surgery from 1989 to 2009 and had ≥5 years of follow-up. RESULTS: There were 303 patients and 75 had follow-up ≥5 years. Median follow-up time for the 75 patients was 8.9 years (range 5-18). Regression was seen in 31%. Progression occurred in 8%, and these patients were significantly more likely to have a failed fundoplication (67% vs. 16%, p = 0.0129). The rate of progression from non-dysplastic Barrett's to high-grade dysplasia or cancer was 0.8% per patient year, and was seven times higher in patients with a failed fundoplication. CONCLUSION: Compared to the accepted rate of progression of non-dysplastic Barrett's to high-grade dysplasia or cancer of 1.0% per patient year, anti-reflux surgery reduces this rate during long-term follow-up. The rate of progression was significantly lower in patients with an intact compared to a disrupted fundoplication, further suggesting that anti-reflux surgery can alter the natural history of Barrett's esophagus.

Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing.

BACKGROUND: To determine the optimal follow-up strategy after esophagectomy for adenocarcinoma of the esophagus or gastroesophageal junction by evaluating the timing of recurrence and the method that first detected the recurrence. STUDY DESIGN: Between 1991 and 2007, 590 patients had an esophagectomy for adenocarcinoma. Recurrence occurred in 233 (40%) and, of those, 174 had complete follow-up at our center with a protocol that consisted of an office visit with CT scans and laboratory studies every 3 months for 3 years, every 6 months for 2 years, and then annually. A subset of patients had PET annually. RESULTS: Recurrence in the 174 patients with complete follow-up was systemic in 104 (60%), locoregional/nodal in 51 (30%), and both in 19 (10%). Recurrence was first suspected by symptoms and/or physical examination in 29 patients (17%), by CT scan in 105 (60%), PET in 32 (18%), and by elevated CEA in 8 (5%). Recurrence was detected at a median of 11 months (range 3 to 72 months) and occurred later after esophagectomy alone compared with patients who received neoadjuvant therapy (12 versus 8 months; p = 0.01), but the pattern of recurrence was similar. More than 90% of recurrences were detected within 2 years after neoadjuvant therapy, compared with 3 years after esophagectomy alone. Median survival after recurrence was 7 months and was significantly longer in patients treated for the recurrence (9 versus 3 months; p = 0.001). CONCLUSIONS: Frequent early follow-up is appropriate after esophagectomy for adenocarcinoma because >90% of recurrences will occur by 3 years after esophagectomy alone and by 2 years following neoadjuvant therapy. Beyond these time periods, 2% to 3% of recurrences were detected each year, suggesting that annual follow-up is adequate. Survival after recurrence was improved with therapy, confirming the use of careful follow-up in these patients.