Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9.

Amphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP's ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can "knock in" this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences

Transcranial Doppler Ultrasound Criteria for Recanalization After Thrombolysis for Middle Cerebral Artery Stroke

Background and Purpose—Transcranial Doppler (TCD) can demonstrate arterial occlusion and subsequent recanalization in acute ischemic stroke patients treated with intravenous tissue plasminogen activator (tPA). Limited data exist to assess the accuracy of recanalization by TCD criteria. Methods—In patients with acute middle cerebral artery (MCA) occlusion treated with intravenous tPA, we compared posttreatment TCD with angiography (digital subtraction or magnetic resonance). On TCD, complete occlusion was defined by absent or minimal signals, partial occlusion by blunted or dampened signals, and recanalization by normal or stenotic signals. Angiography was evaluated with the Thrombolysis In Myocardial Ischemia (TIMI) grading scale. Results—Twenty-five patients were studied (age 61±18 years, 16 men and 9 women). TCD was performed at 12±16 hours and angiography at 41±57 hours after stroke onset, with 52% of studies performed within 3 hours of each other. Recanalization on TCD had the following accuracy parameters compared with angiography: sensitivity 91%, specificity 93%, positive predictive value (PPV) 91%, and negative predictive value (NPV) 93%. To predict partial occlusion (TIMI grade II), TCD had sensitivity of 100%, specificity of 76%, PPV of 44%, and NPV of 100%. TCD predicted the presence of complete occlusion on angiography (TIMI grade 0 or I) with sensitivity of 50%, specificity of 100%, PPV of 100%, and NPV of 75%. TCD flow signals correlated with angiographic patency (χ2=24.2, P\u3c0.001). Conclusions—Complete MCA recanalization on TCD accurately predicts angiographic findings. Although a return to normal flow dynamics on TCD was associated with complete angiographic resumption of flow, partial signal improvement on TCD corresponded with persistent occlusion on angiography

A Broad Diagnostic Battery for Bedside Transcranial Doppler to Detect Flow Changes With Internal Carotid Artery Stenosis or Occlusion

Background and Purpose. The authors establish accuracy parameters of a broad diagnostic battery for bedside transcranial Doppler (TCD) to detect flow changes due to internal carotid artery (ICA) stenosis or occlusion. Methods. The authors prospectively studied consecutive patients with stroke or transient ischemic attack referred for TCD. TCD was performed and interpreted at bedside using a standard insonation protocol. A broad diagnostic battery included major criteria: collateral flow signals, abnormal siphon or terminal carotid signals, and delayed systolic flow acceleration in the middle cerebral artery. Minor criteria included a unilateral decrease in pulsatility index (≤ 0.6 or ≤ 70% of contralateral side), flow diversion signs, and compensatory velocity increase. Angiography or carotid duplex ultrasound (CDU) was used to grade the degree of carotid stenosis using North American criteria. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TCD findings were determined. Results. Seven hundred and twenty patients underwent TCD, of whom 517 (256 men and 261 women) had angiography and/or CDU within 8.8 ± 0.9 days. Age was 63.1 ± 15.7 years. For a 70% to 99% carotid stenosis or occlusion, TCD had sensitivity of 79.4%, specificity of 86.2%, PPV of 57.0%, NPV of 94.8%, and accuracy of 84.7%. For a 50% to 99% carotid stenosis or occlusion, TCD had sensitivity of 67.5%, specificity of 83.9%, PPV of 54.5%, NPV of 90.0%, and accuracy of 81.6%. TCD detected intracranial carotid lesions with 84.9% accuracy and extracranial carotid lesions with 84.4% accuracy (sensitivity of 88% and 79%, specificity of 85% and 86%, PPV of 24% and 54%, and NPV of 99% and 95%, respectively). The prevalence of the ophthalmic artery flow reversal was 36.4% in patients with ≥ 70% stenosis or occlusion. If present, this finding indicated a proximal ICA lesion location in 97% of these patients. Conclusions. In symptomatic patients, bedside TCD can accurately detect flow changes consistent with hemodynamically significant ICA obstruction; however, TCD should not be a substitute for direct carotid evaluation. Because TCD is sensitive and specific for ≥ 70% carotid stenosis or occlusion in both extracranial and intracranial carotid segments, it can be used as a complementary test to refine other imaging findings and detect tandem lesions

Intravenous Tissue Plasminogen Activator and Flow Improvement in Acute Ischemic Stroke Patients with Internal Carotid Artery Occlusion

Background and Purpose. It has been suggested that intravenous tissue plasminogen activator (TPA) would not lyse the large thrombus associated with internal carotid artery (ICA) occlusion and, therefore, would be ineffective in this setting. Vascular imaging, safety, and outcome of TPA therapy for ICA occlusion is not well described. Our goal was to determine the site of occlusion, early recanalization after TPA infusion, and its relationship to outcome. Methods. We reviewed our database of all stroke patients treated with IV TPA between July 1997 and July 1999. We identified all cases with carotid occlusion suggested by transcranial Doppler (TCD) and angiography. Occlusion and recanalization were assessed by site including proximal ICA (prICA), terminal ICA (tICA), and middle cerebral artery (MCA). Baseline National Institutes of Health Stroke Scale (NIHSS) scores and follow-up Rankin scores were obtained. Results. We treated 20 patients with carotid occlusion (age 63.9 ± 10.8 years, 11 males, 9 females). Time to TPA infusion after stroke onset was 128 ± 66 minutes. Baseline NIHSS scores were 16.4 ± 5.4. Time to follow-up was 3.5 ± 4.9 months (2 patients were lost to follow-up). Occlusion sites were prICA 40%, tICA 70%, and concurrent MCA 45%. Multiple sites were involved in 10/20 patients (50%). Among patients with pretreatment and posttreatment vascular imaging studies (n= 18), recanalization in the prICA and tICA was complete in 10%, partial in 16%, and none in 74%. MCA recanalization was complete in 35%, partial in 24%, and none in 41%. At follow-up, Rankin 0–1 was found in 8 patients (44%), Rankin 2–3 in 3 (17%), and Rankin 4–5 in 3 (17%). Mortality was 22% (n= 4) including 1 fatal intracerebral hemorrhage. Improvement was closely related to resumption of MCA flow (P \u3c .01). Conclusions. Most patients did not recanalize their ICA occlusion after intravenous TPA therapy. However, recanalization of associated proximal MCA clot, found in 45% of our patients, or improved MCA collateral flow was strongly associated with good outcome

Deterioration Following Spontaneous Improvement

Background and Purpose—Some stroke patients will deteriorate following improvement (DFI), but the cause of such fluctuation is often unclear. While resolution of neurological deficits is usually related to spontaneous recanalization or restoration of collateral flow, vascular imaging in patients with DFI has not been well characterized. Methods—We prospectively studied patients who presented with a focal neurological deficit that resolved spontaneously within 6 hours of symptom onset. Patients were evaluated with bedside transcranial Doppler (TCD). Digital subtraction angiography (DSA), computed tomographic angiography (CTA), or magnetic resonance angiography (MRA) were performed when feasible. DFI was defined as subsequent worsening of the neurological deficit by ≥4 National Institutes of Health Stroke Scale points within 24 hours of the initial symptom onset. Results—We studied 50 consecutive patients presenting at 165±96 minutes from symptom onset. Mean age was 61±14 years; 50% were females. All patients had TCD at the time of presentation, and 68% had subsequent angiographic examinations (DSA 10%, CTA 4%, and MRA 44%). Overall, large-vessel occlusion on TCD was found in 16% of patients (n=8); stenosis was found in 18% (n=9); 54% (n=27) had normal studies; and 6 patients (12%) had no temporal windows. DFI occurred in 16% (n=8) of the 50 patients: in 62% of patients with TCD and angiographic evidence of occlusion, in 22% with stenosis, and in 4% with normal vascular studies (P Conclusions—DFI is strongly associated with the presence of large-vessel occlusion or stenosis of either atherosclerotic or embolic origin. Normal vascular studies and lacunar events were associated with stable spontaneous resolution without subsequent fluctuation. Urgent vascular evaluation may help identify patients with resolving deficits and vascular lesions who may be candidates for new therapies to prevent subsequent deterioration

Predictors for Tracheostomy with External Validation of the Stroke-Related Early Tracheostomy Score (SETscore)

Background and Purpose: Ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) patients often require endotracheal intubation (EI) and mechanical ventilation (MV). Predicting the need for prolonged EI and timing of tracheostomy (TR) is challenging. While TR is performed for about 10–15% of patients in the general intensive care unit (ICU), the rate in the neurological ICU and for stroke patients ranges between 15 and 35%. Thus, we performed an external validation of the recently published SETscore. Methods: This is a retrospective review for all patients with IS, non-traumatic ICH, and SAH who required intubation within 48 h of admission to the neurological ICU. We compared the SETscore between tracheostomized versus successfully extubated patients, and early TR (within 7 days) versus late TR (after 7 days). Results: Out of 511 intubated patients, 140 tracheostomized and 105 extubated were included. The sensitivity for a SETscore > 10 to predict the need for TR was 81% (95% CI 74–87%) with a specificity of 57% (95% CI 48–67%). The score had moderate accuracy in correctly identifying those requiring TR and those successfully extubated: 71% (95% CI 65–76%). The AUC of the score was 0.74 (95% CI 0.68–0.81). Multivariable logistic regression models were used to identify other independent predictors of TR. After including body mass index (BMI), African American (AA) race, ICH and a positive sputum culture in the SETscore, sensitivity, specificity, overall accuracy, and AUC improved to 90%, 78%, 85%, and 0.89 (95% CI 0.85–0.93), respectively. In our cohort, performing early TR was associated with improvement in the ICU median length of stay (LOS) (15 vs 20.5 days; p = 0.002) and mean ventilator duration (VD) (13.4 vs 18.2 days; p = 0.005) in comparison to late TR. Conclusions: SETscore is a simple score with a moderate accuracy and with a fair AUC used to predict the need for TR after MV for IS, ICH, and SAH patients. Our study also demonstrates that early TR was associated with a lower ICU LOS and VD in our cohort. The utility of this score may be improved when including additional variables such as BMI, AA race, ICH, and positive sputum cultures. © 2018, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society