Faculty Bibliography

Lithium, a drug that has long been used to treat bipolar disorder and some other human pathogenesis, has recently been shown to stimulate neural precursor growth. However, the involved mechanism is not clear. Here, we show that lithium induces proliferation but not survival of neural precursor cells. Mechanistic studies suggest that the effect of lithium mainly involved activation of the transcription factor NF-AT and specific induction of a subset of proliferation-related genes. While NF-AT inactivation by specific inhibition of its upstream activator calcineurin antagonized the effect of lithium on the proliferation of neural precursor cells, specific inhibition of the NF-AT inhibitor GSK-3beta, similar to lithium treatment, promoted neural precursor cell proliferation. One important function of lithium appeared to increase inhibitory phosphorylation of GSK-3beta, leading to GSK-3beta suppression and subsequent NF-AT activation. Moreover, lithium-induced proliferation of neural precursor cells was independent of its role in inositol depletion. These findings not only provide mechanistic insights into the clinical effects of lithium, but also suggest an alternative therapeutic strategy for bipolar disorder and other neural diseases by targeting the non-canonical GSK-3beta-NF-AT signaling

Background: In the 7 years after the WTC disaster, the annual number of FDNY retirements attributable to pulmonary disability increased nearly 4-fold. FDNY rescue workers evaluated for pulmonary disability at our subspecialty center were previously found to have an obstructed phenotype based on FEV₁/FVC, Methacholine Challenge Test (MCT) reactivity, or bronchodilator (BD) reactivity (59% of N=1720). In this pilot study, we examined the long-term efficacy of treatment and its effect on disease progression in a subgroup (N=450) of individuals with subspecialty pulmonary testing who were referred for disability evaluation before and after a course of treatment. Methods: Our study cohort includes individuals that were symptomatic, had subspecialty pulmonary testing (pre-treatment), and were referred for disability evaluation after a full course of treatment (post-treatment). Disability evaluations were performed 30 days after weaning from inhaled medication. Individuals were excluded if their post-treatment PFT was less than three months after starting treatment. Change in lung function over time and post treatment were analyzed (N=415). Values are presented as medians with IQR. We defined statistical significance as P<0.05 using the paired t-test. Analyses were performed using GraphPad and SPSS software. Results: Individuals evaluated by MCT presented for disability evaluation earlier, with a shorter interval of treatment (7.5 months (5-10)) compared to those that received spirometry with BD, (14.5 months (8-25) p<0.0001). FEV₁ %Pred and FEV₁/FVC declined significantly; p<0.0001. FEV₁ observed declined at a slower rate in the treatment group than in the entire WTC-exposed FDNY cohort, including those not referred for subspecialty evaluation: 15cc/year vs. 26cc/year. After treatment course, BD response was unchanged, but methacholine reactivity improved significantly; Fig. 1. (Figure presented) Airway Hyperreactivity Post-Treatment. (A): BD response did not improve from pre- to post-treatment, (N=135). Shading represents a positive BD response. (B): Methacholine reactivity significantly improved, from failing at a cumulative dose of 1.4 mg/mL to failing at a cumulative dose of 64 mg/mL (N=35). There was no difference between individuals receiving bronchodilator response and methacholine challenge in FEV1 or FEV1/FVC both pre- and post treatment, the decline FEV1 from pre- to post-Treatment, time to entry into treatment cohort, or demographics (years of service, exposure, age at 9/11, or BMI). Conclusion: Treatment with removal from fire fighting, inhaled steroids and beta agonists did not improve spirometric measures, or BD response, but slowed the rate of decline and decreased hyper-reactivity to the MCT. Improvement in reactivity defined by MCT but not defined by BD response suggests that the pathways leading to BD response and MCT reactivity may be different and may respond differently to treatment

Introduction: Airway dysfunction has been detected by oscillometry in obese subjects despite normal large airway function as assessed by spirometry. This has been attributed to lung/airway compression as reflected by reduced FRC; we previously demonstrated improvement of abnormalities towards normal upon voluntary inflation to predicted FRC (AJRCCM 2010; 181:A2532). However, other causes of airway dysfunction such as inflammation or concomitant intrinsic airway disease may coexist and could not be excluded. The present study re-evaluated these subjects following bariatric surgery induced weight loss to evaluate for residual abnormality. Methods: 22 morbidly obese subjects without history of smoking and/or cardiopulmonary disease, underwent evaluation pre/post bariatric surgery (20% reduction in weight). Spirometry, plethysmography and impulse oscillometry (IOS) were performed. IOS parameters included resistance at 5Hz (R5), resistance at 20Hz (R20) frequency dependence of resistance (R5-20) and reactance at 5Hz (X5).IOS was also performed at an elevated lung volume (~1 liter) targeted to restore FRC to predicted values. All IOS measurements were repeated post bronchodilator. Results: Baseline weight and BMI were 256+/-43 kg and 46+/-7 kg/m², respectively. All subjects lost >20% of body weight, but obesity persisted in all subjects (weight 182 kg, BMI 33 kg/ m2). FEV /FVC was normal at baseline and remained unchanged post weight loss 1 (81+/-3% vs 83+/-4%) indicating normal large airway function. FRC and ERV improved post weight loss but values remained abnormal (FRC from 60+/-12 to 77+/-21% predicted, ERV from 46+/-16 to 75+/-38% predicted, p<0.05). Although IOS parameters improved following weight loss, data remained above the upper limit of normal (R5 from 6.8+/-1.8 to 5.1+/-1.4 cmH₂O/l/s, R₂₀ from 4.7+/-1.1 to 3.9+/-0.9 cmH₂O/l/s, R_5-20 from 2.1+/-1.1 to 1.2+/-0.9 cmH_2O /l/s, X₅ from -3.2+/-1.7 to -1.8+/-0.9 cmH₂O /l/s, p<0.05). Since FRC remained abnormal following weight loss, IOS was repeated following voluntary lung inflation (FRC 142+/-30%). While R20 corrected to normal at the elevated FRC (R₂₀ 3.1+/-1.0 cmH₂ O/l/s), R5, R5-20 and X5 remained abnormal indicating residual distal airway dysfunction (R₅ 4.2+/-1.4 cmH₂O/l/s, , R_5-20 1.1+/-0.7 cmH₂O /l/s, X₅ -2.0+/-0.8 cmH₂O /l/s); these residual oscillometric abnormalities were present in 11/22 subjects. Residual airway dysfunction was demonstrated by low specific conductance (assessed at 5HZ) despite restoration of FRC to supranormal values. Conclusions: Distal airway dysfunction persisted following weight loss and was not attributable to persistent mass loading in a subgroup of patients without clinical evidence of airway disease. These abnormalities may represent either functional abnormalities due to persistent obesity and/or intrinsic airway disease

Introduction: Pulmonary function evaluation in patients with cystic fibrosis (CF) has demonstrated disparity between spirometric and oscillometric assessments. Most studies have indicated that oscillometry may appear normal despite significant abnormalities on spirometry. However, normal values for impulse oscillometry (IOS) in pediatric populations are limited and vary by study. The present study assessed the role for IOS by assessment of both the acute response to bronchodilator and the chronic response to treatment. Methods: Patients hospitalized with exacerbations of CF were evaluated with both spirometry and oscillometry. Data were obtained pre and post bronchodilator administration and related to published normative data. When feasible, lung volumes were assessed by plethysmography. Serial testing was performed during and following standard therapy which included vigorous chest physical therapy and intravenous antibiotics targeted to the predominate organism isolated from sputum or bronchoscopy specimens. Results: Data were available in 5 patients with CF with age ranging from 5 to 44 years. Abnormal spirometry was evident in 4 subjects. Although FEV₁/FVC was mildly reduced in these subjects (68+5%), the predominant abnormality was reduction in vital capacity (50+12%). HRCT demonstrated severe mucous plugging in multiple airways and bronchoscopy in one patient confirmed total occlusion of the bronchial lumen form respiratory secretions. Despite these spirometric and radiographic abnormalities, oscillometric assessment of resistance assessed was within published normal limits in these subjects. However, a positive response to bronchodilator was observed in 3 patients and serial testing in one subject demonstrated further improvement in airway resistance by IOS. These changes in oscillometric data occurred with minimal change in FVC and FEV₁. Conclusions: Although IOS parameters in an individual patient may be within published normal limits, reduction in resistance may be apparent either acutely post bronchodilator or chronically following treatment. These improvements in IOS parameters may not be apparent on spirometry, providing a potential role for IOS in the evaluation of patients with CF. These data suggest that improvement in post bronchodilator measurements of airway resistance may be a useful adjunct to guide the appropriate length of treatment for CF exacerbations

BACKGROUND: Models of autism spectrum disorders (ASD) as neural disconnection syndromes have been predominantly supported by examinations of abnormalities in corticocortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state functional magnetic resonance imaging has revealed detailed maps of striatal circuitry in healthy and psychiatric populations and vividly captured maturational changes in striatal circuitry during typical development. METHODS: Using resting state functional magnetic resonance imaging, we examined striatal functional connectivity (FC) in 20 children with ASD and 20 typically developing children between the ages of 7.6 and 13.5 years. Whole-brain voxelwise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds for each hemisphere. RESULTS: Children with ASD mostly exhibited prominent patterns of ectopic striatal FC (i.e., functional connectivity present in ASD but not in typically developing children), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insula cortex. CONCLUSIONS: Examination of FC of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas, such as the brainstem and insula, with a pattern of increased FC in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits

Nasal positive expiratory pressure (nEPAP) delivered with an expiratory valve (ProventVentus Medical) has recently been shown to have a beneficial effect on sleep disordered breathing (Rosenthal, JCSM 2009; 5:532). The mechanism of action is not fully understood but effects on lung volume have been invoked (Patel, JCSM in press). In the present study we evaluate the effect of nEPAP on functional residual capacity (FRC) and upper airway (UA) dimensions. Methods: Fast MRI was used to acquire 4-5 images/sec in the awake state during multiple cycles of nose breathing with and without nEPAP in 6 patients with S