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Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation. Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery. Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure. Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase.

Posttraumatic stress disorder subjects usually show impaired recall of extinction memory, leading to extinguished fear relapses. However, little is known about the neural mechanisms underlying the impaired recall of extinction memory. We show here that the activity of dorsal hippocampus (dHPC) to infralimbic (IL) cortex circuit is essential for the recall of fear extinction memory in male mice. There were functional neural projections from the dHPC to IL. Using optogenetic manipulations, we observed that silencing the activity of dHPC-IL circuit inhibited recall of extinction memory while stimulating the activity of dHPC-IL circuit facilitated recall of extinction memory. “Impairment of extinction consolidation caused by” conditional deletion of extracellular signal-regulated kinase 2 (ERK2) in the IL prevented the dHPC-IL circuit-mediated recall of extinction memory. Moreover, silencing the dHPC-IL circuit abolished the effect of intra-IL microinjection of ERK enhancer on the recall of extinction memory. Together, we identify a dHPC to IL circuit that mediates the recall of extinction memory, and our data suggest that the dysfunction of dHPC-IL circuit and/or impaired extinction consolidation may contribute to extinguished fear relapses.

The paraventricular nucleus of the thalamus (PVT), which serves as a hub, receives dense projections from the medial prefrontal cortex (mPFC) and projects to the lateral division of central amygdala (CeL). The infralimbic (IL) cortex plays a crucial role in encoding and recalling fear extinction memory. Here, we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval. Silencing PVT neurons inhibited extinction retrieval at recent time point (24 h after extinction), while activating them promoted extinction retrieval at remote time point (7 d after extinction), suggesting a critical role of the PVT in extinction retrieval. In the mPFC-PVT circuit, projections from IL rather than prelimbic cortex to the PVT were dominant, and disrupting the IL-PVT projection suppressed extinction retrieval. Moreover, the axons of PVT neurons preferentially projected to the CeL. Silencing the PVT-CeL circuit also suppressed extinction retrieval. Together, our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00603-6) contains supplementary material, which is available to authorized users.

Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons., Chronic pain usually induces anxiety. Here, the authors report that vmPFC nNOS-expressing neurons are activated by excitatory inputs from pPVT during chronic pain and subsequently induce anxiety-like behaviors in mice through promoting AMPAR trafficking.

(1) Background: We used four-dimensional phase-contrast magnetic resonance imaging (4D PC-MRI) to evaluate the impact of an endovascular aortic repair (TEVAR) on aortic dissection. (2) Methods: A total of 10 patients received 4D PC-MRI on a 1.5-T MR both before and after TEVAR. (3) Results: The aortas were repaired with either a GORE TAG Stent (Gore Medical; n = 7) or Zenith Dissection Endovascular Stent (Cook Medical; n = 3). TEVAR increased the forward flow volume of the true lumen (TL) (at the abdominal aorta, p = 0.047). TEVAR also reduced the regurgitant fraction in the TL at the descending aorta but increased it in the false lumen (FL). After TEVAR, the stroke distance increased in the TL (at descending and abdominal aorta, p = 0.018 and 0.015), indicating more effective blood transport per heartbeat. Post-stenting quantitative flow revealed that the reductions in stroke volume, backward flow volume, and absolute stroke volume were greater when covered stents were used than when bare stents were used in the FL of the descending aorta. Bare stents had a higher backward flow volume than covered stents did. (4) Conclusions: TEVAR increased the stroke volume in the TL and increased the regurgitant fraction in the FL in patients with aortic dissection.

The adverse effect of cisplatin administration causes acute kidney injury (AKI) following renal inflammation and nephrotoxicity, characterized by proximal tubular cell apoptosis and necrosis. Pro-apoptotic and pro-inflammatory roles of glycogen synthase kinase (GSK)-3β have been reported. This study investigated the therapeutic blockade of GSK-3β in cisplatin-induced AKI. A renal cisplatin nephrotoxicity model showed activation of GSK-3β in vivo, particularly in proximal tubular epithelial cells. Pharmacologically inhibiting GSK-3β abolished cisplatin nephrotoxicity, including proximal tubular injury, cell cytotoxicity, and biochemical dysfunction. Additionally, GSK-3β inhibitor treatment ameliorated renal inflammation by reducing immune cell infiltration, cell adhesion molecule expression, and pro-inflammatory cytokine/chemokine production. Cisplatin treatment caused GSK-3β activation in vitro in the human renal proximal tubular epithelial cell line HK-2, whereas either pharmacological administration of GSK-3β inhibitors or genetic transduction of GSK-3β short-hairpin RNA impeded cisplatin-induced cytotoxicity. These results indicate that cisplatin activates GSK-3β followed by GSK-3β-mediated renal inflammation and nephrotoxicity, contributing to AKI.

(1) Background: To assess the effectiveness of triggered angiography non-contrast-enhanced (TRANCE)-magnetic resonance imaging (MRI) in superficial venous reflux and its difference from health controls. (2) Methods: Thirty patients underwent TRANCE MRI before surgical intervention of their superficial venous reflux of the legs. Ten healthy volunteers were included as a control. (3) Results: TRANCE MRI involves the major tributaries, thus enhances the additional ablations in 20% of patients. QFlow pattern of superficial venous reflux (QFlow GSV/PV MF ratio &gt, 1) was compared with the duplex scan (SFJ reflux) using Cohen’s kappa coefficient at 0.967. The 30 morbid legs undergoing TRANCE MRI-guide interventions and the healthy volunteers’ legs on the same side were compared. The stroke volumes (SV) are higher in EIV (p = 0.021) in the left-leg-intervention group. The mean flux (MF) is higher in the EIV (p = 0.012) and trend of increasing in GSV segment (p = 0.087) in the left-leg-intervention group. The QFlow of 10 patients with right leg intervention are higher in GSV in the right-leg-intervention group (SV p = 0.002, FFV p = 0.001, MF p = 0.001). QFlow data is shown for all legs for superficial venous intervention with GSV/PV (MF) ratio &gt, 1. (4) Conclusions: Typical figures in QFlow (GSV/PV MF ratio &gt, 1) could be observed in the morbid limbs but not in the controls.

Background: Venous interventions of the legs are less predictable owing to a lock of objective tools. Methods: One hundred and twenty patients with lower extremity venous disease were evaluated anatomically using TRANCE MRI. Then, a QFlow analysis was performed in 53 patients with only one leg affected for hemodynamic evaluation. Those patients with complete QFlow were classified into obstructive and nonobstructive. Results: The QFlow—namely, stroke volume, forward flow volume, mean flux, stroke distance (SD), and mean velocity (MV) in the external iliac vein (EIV), femoral vein (FV), popliteal vein (PV), and great saphenous vein (GSV). The obstructed group had a shorter SD and lower MV in the EIV, EIV/FV, and GSV/PV (SD: p-values of 0.025, 0.05, and 0.043, respectively; MV: p-values of 0.02, 0.05, and 0.048, respectively). A good performance in discriminating obstructive venous disease was reported for SD in the EIV (area under the curve (AUC) = 67.9%, 95% confidence interval (CI) = 53.2–82.7%), EIV/FV (AUC = 72.4%, 95% CI = 58.2–86.5%), and GSV/PV (AUC = 67.9%, 95% CI = 51.7–84.1%). The SD in the EIV, EIV/FV, and GSV/PV had the ability to discriminate between obstructive and nonobstructive diseases (p-values of 0.025, 0.005, and 0.043). The MV in the EIV, EIV/FV, and GSV/PV had ability to discriminate between obstructive and nonobstructive venous diseases (p-values of 0.02, 0.005, and 0.048). Conclusions: The SD and MV were lower for obstructive than nonobstructive disease in the EIV.

Background: Letermovir prophylaxis is currently the standard of care for the prevention of cytomegalovirus (CMV) infections in allogeneic hematopoietic stem-cell transplantation (allo-HSCT). However, drug–drug interactions between letermovir and azoles or calcineurin inhibitors and the high financial burden of letermovir remain problematic, especially in resource-limited countries. It has not been clarified whether a lower dose of valganciclovir would constitute an effective strategy for CMV prevention in patients with acute leukemia undergoing allo-HSCT. Methods: We retrospectively assessed 84 consecutive adult patients with acute leukemia who underwent allo-HSCT. These 84 patients were stratified into a valganciclovir prophylaxis group ( n = 20) and a non-valganciclovir prophylaxis group ( n = 64). Results: Patients in the valganciclovir prophylaxis group had a lower possibility of CMV DNAemia at week 14 after allo-HSCT than those in the non-valganciclovir prophylaxis group (15.0% versus 50.0%; p = 0.012). The cumulative incidence of CMV DNAemia at week 14 was also lower in patients with valganciclovir CMV prophylaxis than in those without (15.0% versus 50.4%; p = 0.006). Multivariate analysis validated these data, showing that a low dose of valganciclovir significantly reduced the risk of CMV DNAemia at week 14 by 88% (hazard ratio: 0.12; 95% confidence interval: 0.04–0.42; p = 0.001). However, these two groups had similar overall survival rates at week 48 (75.0% versus 76.6%; p = 0.805). Four of 20 (20%) patients discontinued valganciclovir prophylaxis because of adverse events. Conclusion: Low-dose valganciclovir prophylaxis could be an alternative to letermovir to prevent CMV infection in allo-HSCT, especially in resource-limited countries.

Background: Posaconazole prophylaxis during remission induction chemotherapy not only decreases the incidence of invasive aspergillosis (IA) but also improves the overall survival rate among patients with acute myeloid leukemia (AML). However, it remains debatable whether this result applies to patients in a real-world setting. Methods: We retrospectively assessed 208 adult patients with newly diagnosed AML who underwent remission induction therapy. These 208 patients were stratified into the posaconazole prophylaxis group ( n = 58) and no antifungal prophylaxis group ( n = 150). Results: Multivariate analyses showed that induction failure significantly increased the risk of proven or probable IA during the first induction chemotherapy [hazard ratio (HR), 10.47; 95% confidence interval (CI), 1.73–63.45; p = 0.011] and the entire course of AML treatment (HR, 4.48; 95% CI, 1.71–11.75; p = 0.002). However, posaconazole prophylaxis did not reduce the risk of IA during the first induction chemotherapy (HR, 1.47; 95% CI, 0.14–15.04; p = 0.746) and during the entire course of AML treatment (HR, 1.09; 95% CI, 0.29–4.09; p = 0.896). Furthermore, there was no significant difference in overall survival between these two groups of patients (514 versus 689 days; p = 0.454). Conclusion: Successful induction remains fundamental to reducing the risk of IA among AML patients undergoing remission induction chemotherapy.

Exposure therapy based on the extinction of fear memory is first-line treatment for post-traumatic stress disorder (PTSD). However, fear extinction is relatively easy to learn but difficult to remember, extinguished fear often relapses under a number of circumstances. Here, we report that extinction learning-induced association of neuronal nitric oxide synthase (nNOS) with its carboxy-terminal PDZ ligand (CAPON) in the infralimbic (IL) subregion of medial prefrontal cortex negatively regulates extinction memory and dissociating nNOS-CAPON can prevent the return of extinguished fear in mice. Extinction training significantly increases nNOS-CAPON association in the IL. Disruptors of nNOS-CAPON increase extracellular signal-regulated kinase (ERK) phosphorylation and facilitate the retention of extinction memory in an ERK2-dependent manner. More importantly, dissociating nNOS-CAPON after extinction training enhances long-term potentiation and excitatory synaptic transmission, increases spine density in the IL, and prevents spontaneous recovery, renewal and reinstatement of remote fear of mice. Moreover, nNOS-CAPON disruptors do not affect other types of learning. Thus, nNOS-CAPON can serve as a new target for treating PTSD.

Environmental enrichment (EE) is a generally accepted strategy to promote stroke recovery and its beneficial effect is positively correlated with neuroplasticity. However, the mechanisms underlying it remain elusive. Histone deacetylase 2 (HDAC2), a negative regulator of neuroplasticity, is up-regulated after stroke. Thus, we hypothesized that HDAC2 may participate in EE-mediated stroke recovery. In this study, focal stroke was induced by photothrombosis in male mice exposing to EE or standard housing (SH) conditions. Recombinant virus vectors, including Ad-HDAC2-Flag, AAV-CAG-EGFP-Cre, LV-shHDAC2, or their controls were microinjected into the motor cortex at 3 days before stroke. Grid-walking and cylinder tasks were conducted to assess motor function. Western blot and immunostaining were used to uncover the mechanisms underlying EE-mediated stroke recovery. We found that EE exposure reversed stroke-induced HDAC2 up-regulation, implicating HDAC2 in EE-mediated functional recovery. Importantly, EE-dependent stroke recovery was counteracted by over-expressing HDAC2, and HDAC2 knockdown promoted functional recovery from stroke to the similar extent as EE exposure. Moreover, the knockdown of HDAC2 epigenetically enhanced expressions of neurotrophins and neuroplasticity-related proteins, with similar effects as EE, and consequently, whole brain and corticospinal tract (CST) rewiring. Together, our findings indicate that HDAC2 is critical for EE-dependent functional restoration. Precisely targeting HDAC2 may mimic EE and serve as a novel therapeutic strategy for stroke recovery.

Fear extinction depends on N-methyl-D-aspartate glutamate receptors (NMDARs) and brain-derived neurotrophic factor (BDNF) activation in the limbic system. However, postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) coupling, the downstream signaling of NMDARs activation, obstructs the BDNF signaling transduction. Thus, we wondered distinct roles of NMDAR activation and PSD-95-nNOS coupling on fear extinction. To explore the mechanisms, we detected protein-protein interaction using coimmunoprecipitation and measured protein expression by western blot. Contextual fear extinction induced a shift from PSD-95-nNOS to PSD-95-TrkB association in the dorsal hippocampus and c-Fos expression in the dorsal CA3. Disrupting PSD-95-nNOS coupling in the dorsal CA3 up-regulated phosphorylation of extracellular signal-regulates kinase (ERK) and BDNF, enhanced the association of BDNF-TrkB signaling with PSD-95, and promoted contextual fear extinction. Conversely, blocking NMDARs in the dorsal CA3 down-regulated BDNF expression and hindered contextual fear extinction. NMDARs activation and PSD-95-nNOS coupling play different roles in modulating contextual fear extinction in the hippocampus. Because inhibitors of PSD-95-nNOS interaction produce antidepressant and anxiolytic effect without NMDAR-induced side effects, PSD-95-nNOS could be a valuable target for PTSD treatment.

Background and Purpose— Stroke is a major public health concern worldwide. Although clinical treatments have improved in the acute period after stroke, long-term therapeutics remain limited to physical rehabilitation in the delayed phase. This study is aimed to determine whether nNOS (neuronal NO synthase)-CAPON (carboxy-terminal postsynaptic density-95/discs large/zona occludens-1 ligand of nNOS) interaction may serve as a new therapeutic target in the delayed phase for stroke recovery. Methods— Photothrombotic stroke and transient middle cerebral artery occlusion were induced in mice. Adeno-associated virus (AAV)-cytomegalovirus (CMV)-CAPON-125C-GFP (green fluorescent protein)-3Flag and the other 2 drugs (Tat-CAPON-12C and ZLc-002) were microinjected into the peri-infarct cortex immediately and 4 to 10 days after photothrombotic stroke, respectively. ZLc-002 was also systemically injected 4 to 10 days after transient middle cerebral artery occlusion. Grid-walking task and cylinder task were conducted to assess motor function. Western blotting, immunohistochemistry, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms. Results— Stroke increased nNOS-CAPON association in the peri-infarct cortex in the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association substantially decreased the number of foot faults in the grid-walking task and forelimb asymmetry in the cylinder task, suggesting the promotion of functional recovery from stroke. Moreover, dissociating nNOS-CAPON significantly facilitated dendritic remodeling and synaptic transmission, indicated by increased dendritic spine density, dendritic branching, and length and miniature excitatory postsynaptic current frequency but did not affect stroke-elicited neuronal loss, infarct size, or cerebral edema, suggesting that nNOS-CAPON interaction may function via regulating structural neuroplasticity, rather than neuroprotection. Furthermore, ZLc-002 reversed the transient middle cerebral artery occlusion–induced impairment of motor function. Conclusions— Our results reveal that nNOS-CAPON coupling can serve as a novel pharmacological target for functional restoration after stroke.

Abtract Chronic pain is a major public health problem categorized as inflammatory or neuropathic, each involving impaired GABAergic control in the spinal cord of mammals. (+)-Borneol, a bicyclic monoterpene present in the essential oil of plants, is used for analgesia and anesthesia in traditional Chinese medicine. It has been reported that (+)-borneol directly potentiates GABA activity at recombinant human GABA A receptors. Although borneol has antinociceptive effect on acute pain models, little is known about its effect on chronic pain and its mechanism. Here we report that (+)-borneol has remarkable anti-hyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation (SNL), and inflammatory hypersensitivity was induced by intraplantar (i.pl.) injection of complete Freund׳s adjuvant (CFA). Both oral administration (125, 250 or 500 mg/kg) and intrathecal injection (i.t.) (15, 30 and 60 μg) of (+)-borneol reduced mechanical hypersensitivity dose-dependently in SNL and CFA models. The anti-hyperalgesic effects of (+)-borneol were abolished by a selective GABA A receptor (GABA A R) antagonist bicuculline (i.t., at 30 min after (+)-borneol injection). Furthermore, (+)-borneol (500 mg/kg, p.o. or 60 μg, i.t.) did not influence motor function. These findings suggest that (+)-borneol may ameliorate mechanical hyperalgesia by enhancing GABA A R-mediated GABAergic transmission in the spinal cord, and could serve as a therapeutic for chronic pain.

Background Stroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Methods and Results Focal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout ( Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. Conclusions Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.

Stroke is a major public health concern. The lack of effective therapies heightens the need for new therapeutic targets. Mammalian brain has the ability to rewire itself to restore lost functionalities. Promoting regenerative repair, including neurogenesis and dendritic remodeling, may offer a new therapeutic strategy for the treatment of stroke. Here, we report that interaction of neuronal nitric oxide synthase (nNOS) with the protein postsynaptic density-95 (PSD-95) negatively controls regenerative repair after stroke in rats. Dissociating nNOS–PSD-95 coupling in neurons promotes neuronal differentiation of neural stem cells (NSCs), facilitates the migration of newborn cells into the injured area, and enhances neurite growth of newborn neurons and dendritic spine formation of mature neurons in the ischemic brain of rats. More importantly, blocking nNOS–PSD-95 binding during the recovery stage improves stroke outcome via the promotion of regenerative repair in rats. Histone deacetylase 2 in NSCs may mediate the role of nNOS–PSD-95 association. Thus, nNOS–PSD-95 can serve as a target for regenerative repair after stroke.

The aim of the present study was to investigate the cardioprotective effects of anisodamine against myocardial ischemia/reperfusion (I/R) injury and the molecular mechanisms involved. The present results demonstrated that anisodamine attenuated myocardial infarct sizes, decreased the levels of creatine kinase and lactate dehydrogenase, whereas it increased the left ventricular (LV) systolic pressure, the LV end‑diastolic pressure, and the LV pressure maximum rising and falling rates in a myocardial I/R rat model. In addition, anisodamine was revealed to suppress oxidative stress, inflammatory factor production and myocardial cell apoptosis, as demonstrated by the downregulation of caspase‑3 and apoptosis regulator BAX protein expression. The production of reactive oxygen species was decreased and the protein expression of inducible nitric oxide synthase (iNOS) was downregulated, whereas the expression of endothelial NOS was enhanced. In addition, the activity of nicotinamide‑adenine dinucleotide phosphate oxidase (Nox) was suppressed and the expression of Nox4 was downregulated in rats with myocardial I/R injury. In conclusion, the results of the present study suggested that anisodamine exerted a cardioprotective effect against myocardial I/R injury in rats, through the inhibition of oxidative stress, the suppression of inflammatory processes and the inhibition of myocardial cell apoptosis.

New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.

BackgroundProlonged exposure to combination antiretroviral therapy (CART) may result in hyperlipidemia and other metabolic complications. This study aimed to evaluate the clinical, virologic, and immunologic outcomes in HIV-infected patients with hyperlipidemia whose CART was switched to atazanavir-containing antiretroviral regimens.MethodsIn this 48-week prospective, observational study that was conducted at designated hospitals for HIV care in Taiwan, HIV-infected patients aged 18 years or older who had developed hyperlipidemia after receiving CART that did not contain atazanavir were enrolled. Antiretroviral regimens were switched to regimens containing two nucleoside reverse-transcriptase inhibitors plus atazanavir 400mg once daily or atazanavir 300mg boosted with ritonavir 100mg once daily. The lipid profiles, including total triglycerides, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, CD4+ lymphocyte counts, and plasma HIV RNA load were determined every 3 months.ResultsSixty-six patients with hyperlipidemia were enrolled. At the end of the study, triglyceride levels declined by 49.0% (p=0.0002) and total cholesterol levels by 18.1% from baseline (p

A 34-year-old woman presented with septic shock, disseminated intravascular coagulation (DIC), and multiorgan dysfunction with a 1-week history of fever, abdominal pain in the right upper quadrant, and dull pain in the right flank. Physical and laboratory data showed cytopenia (thrombocytopenia and anemia), splenomegaly, hyperferritinemia, hypofibrinogenemia, and an elevated level of interleukin-2 receptor (soluble CD25). Bone marrow examinations disclosed hypercellular marrow with increased infiltration of histiocytes with hemophagocytosis. This diagnosis was confirmed by positive Weil-Felix test results (Proteus mirabilis OX-K titer, 1:80), the presence of IgG and IgM antibodies, and positive PCR results for Orientia tsutsugamushi. The patient developed a severe intracranial hemorrhage 3 days after admission and expired due to systemic inflammatory response syndrome with DIC and multiorgan failure on the 13th day of hospitalization. Scrub typhus with hemophagocytic syndrome can be complicated by DIC and multiorgan failure. Patients with scrub typhus usually have an excellent response to treatment; therefore, early diagnosis and prompt administration of antimicrobial therapy may prevent the development of serious complications.

The incidence of and risk factors for Jarisch-Herxheimer (JH) reaction were investigated prospectively among 240 human immunodeficiency virus (HIV)-infected and 115 HIV-uninfected patients with syphilis who received penicillin treatment. The overall rate of JH reaction was 31.5% (34.6% in HIV-infected patients and 25.2% in HIV-uninfected patients). In multivariate analysis, risk factors for JH reaction included high rapid plasma reagin (RPR) titers (per log(2) RPR increase, risk ratio [RR], 1.19; 95% confidence interval [CI], 1.04-1.37), early syphilis (RR, 8.59; 95% CI, 4.75-15.56), and prior penicillin treatment (RR, 0.39; 95% CI, 0.20-0.78).

Myasthenia gravis (MG) is a T-cell dependent disease mediated y antibodies against acetylcholine receptor (AChR) on skeletal uscles, however, the role of CD4+ T cell subsets in MG has not een well-understood [1]. The hallmark of human immunodefiiency virus (HIV) infection is the gradual decline of CD4+ T cell nd perturbed CD4+ T cell homeostasis. The co-occurrence of HIV nfection and MG may yield useful information with regard to the mmuno-pathogenesis of MG. We present a case of myasthenia ravis developed 3 years after known HIV infection and discuss he impacts of antiretroviral therapy.

The purpose of the study was to explore the effects of breast regression protein 39 (BRP-39) in bleomycin-induced pulmonary fibrosis and its mechanism in pulmonary fibrosis by studying change in BRP-39 to provide a novel direction for the treatment of idiopathic pulmonary fibrosis. SPF grade male C57BL/6 rats were randomly divided into three groups, including bleomycin group, bleomycin+ BRP-39 recombinant protein group and control group. HE and Masson staining were applied to test the change in lung tissue after being treated by BRP-39, ELISA was applied to test the expression of TGF-β1 in different groups, and Western blot was used to test the expression of BRP-39 in rat lung tissue. Expression of BRP-39 increased, the fibrosis was obvious, and lung tissue collagen increased in bleomycin-induced pulmonary fibrosis in rat lung tissue. Increasing BRP-39 protein level and intratracheal bleomycin medication to establish pulmonary fibrosis model can aggravate pulmonary fibrosis. Along with the increase in BRP-39 protein level, TGF-β1 expression level also increased in lung tissue. Western blot results showed the expression of BRP-39, and TGF-β1 had the same trend in different groups. BRP-39 has effects in bleomycin-induced rat pulmonary fibrosis. Change in BRP-39 can affect the process of bleomycin-induced pulmonary fibrosis. The mechanism of BRP-3 in pulmonary fibrosis may work by regulating TGF-β1.

Introduction : The Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated. Methods : In HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance. Results : The overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p< 0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log 2 increase, 1.21; confidence interval [CI], 1.04–1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19–0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08–0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the macrolide resistance mutation (A2058G). In subgroup analyses confined to the 75 patients infected with T. pallidum lacking resistance mutation, a statistically significantly lower risk for the Jarisch-Herxheimer reaction following azithromycin treatment was noted. Conclusions : Treatment with azithromycin was associated with a lower risk for the Jarisch-Herxheimer reaction than that with benzathine penicillin G in HIV-positive patients with early syphilis. Previous benzathine penicillin G therapy for syphilis decreased the risk, whereas higher RPR titres increased the risk, for the reaction. Keywords: sexually transmitted diseases; spirochetal disease; macrolides; macrolide resistance; immunomodulation. (Published: 28 August 2014) Citation: Tsai M-S et al. Journal of the International AIDS Society 2014, 17 :18993 http://www.jiasociety.org/index.php/jias/article/view/18993 | http://dx.doi.org/10.7448/IAS.17.1.18993

BACKGROUND: Among members of Cryptococcus neoformans- Cryptococcus gattii species complex, C. neoformans is distributed worldwide whereas C. gattii is considered to be more prevalent in the subtropics and tropics including Taiwan. This nationwide study was undertaken to determine the distribution of genotypes, clinical characteristics and outcomes of 219 patients with proven cryptococcosis at 20 hospitals representative of all geographic areas in Taiwan during 1997-2010. METHODS AND FINDINGS: Of 219 isolates analyzed, C. neoformans accounted for 210 isolates (95.9%); nine isolates were C. gattii (4.1%). The predominant genotype was VNI (206 isolates). The other genotypes included VNII (4 isolates), VGI (3 isolates) and VGII (6 isolates). Antifungal minimal inhibition concentrations higher than epidemiologic cutoff values (ECVs) were found in nine VNI isolates (7 for amphotericin B). HIV infection was the most common underlying condition (54/219, 24.6%). Among HIV-negative patients, liver diseases (HBV carrier or cirrhosis) were common (30.2%) and 15.4% did not have any underlying condition. Meningoencephalitis was the most common presentation (58.9%), followed by pulmonary infection (19.6%) and "others" (predominantly cryptococcemia) (18.7%). The independent risk factors for 10-week mortality, by multivariate analysis, were cirrhosis of liver (P = 0.014) and CSF cryptococcal antigen titer ≥ 512 (P = 0.020). All except one of 54 HIV-infected patients were infected by VNI genotype (98.1%). Of the 13 isolates of genotypes other than VNI, 12 (92.3%) were isolated from HIV-negative patients. HIV-infected patients compared to HIV-negative patients were more likely to have meningoencephalitis and serum cryptococcal antigen ≥ 1:512. Patients infected with C. gattii compared to C. neoformans were younger, more likely to have meningoencephalitis (100% vs. 57%), reside in Central Taiwan (56% vs. 31%), and higher 10-week crude mortality (44.4% vs. 22.2%). CONCLUSIONS: Cryptococcus neoformans in Taiwan, more prevalent than C. gatii, has a predominant VNI genotype. Isolates with antifungal MIC higher than ECVs were rare.

Background: In 2004, HIV-1 infection among Taiwanese injection drug users (IDUs) started to surge. In 2007, a resurgence of HIV-1 epidemic among men having sex with men (MSM) occurred. We conducted a molecular epidemiological study of HIV-1 among different risk groups in Taiwan from 2005 to 2008. Methods: In total 1133 HIV-1-infected adults including 576 IDUs, 464 MSM, and 93 heterosexuals were recruited. HIV-1 subtypes were determined using nested multiplex polymerase chain reaction and phylogenetic analysis. Dual infection was confirmed using cloning, sequencing, and heteroduplex mobility assay. Results: Among HIV-1/AIDS subjects, 96.1% MSM and 62.5% heterosexual males were infected with subtype B, whereas 66.7% female heterosexuals were infected with CRF01_AE. Most IDUs (84.5%) were infected with CRF07_BC. Four heterosexual males, 2 females and 2 MSM who were not IDUs had CRF07_BC. Forty-nine patients had CRF07_BC/subtype B dual infection and 44 (89.8%) were IDUs. Multivariate logistic regression showed that the odds ratio for dual infection among IDUs who shared syringes >5 times per month was 4.7 (95% confidence interval = 1.3 to 17.7). Phylogenetic analyses revealed that there were 2 main groups of CRF07_BC strains with sporadic transmission between different risk groups. Among 10 IDUs infected with CRF01_AE, 7 cases were clustered with an outbreak happened in 2005 and 3 cases were clustered with other strains from heterosexual population. Conclusions: In Taiwan, 7.8% of HIV-1-infected IDUs had dual infection. It may have important impact to their clinical management. Although CRF07_BC was still remained in IDUs, it has spread to MSM and heterosexual populations.

Non-small cell cancer (NSCLC) accounts for approximately 80% of all lung cancers. Reports suggested an association between the interleukin-1beta (IL-1beta) -31 and -511 gene loci and NSCLC, but few studies took into account the effect of smoking and/or alcohol drinking on the association.Two-hundred thirteen cases of NSCLC (aged 58.2 + or - 10.1) and 213 controls (aged 59.4 + or - 10.3y) were included in this research. Information about the smoking and drinking behaviors, dietary customs, and anamnesis were obtained from all subjects by questionnaires, and genomic DNA was extracted. IL-1beta -31 and -511 gene polymorphisms were detected using PCR-RFLP. The interactions between the genotypes and alcohol drinking/smoking were analyzed using multivariate logistic regression models.(The T/T genotype and the T allele of the IL-1beta -31 gene were associated with higher incidence of NSCLC (P0.05). For the IL-1beta -511 locus, no difference was found in different genotypes between the NSCLC and control groups. After the adjustment of confounding variables, such as age and gender, the binary logistic analysis showed a significant gene-environment interaction (P0.05).The IL-1beta -31T allele was positively associated with a risk of NSCLC, and the carriers of IL-1beta -31T/T or -511C/C would have a higher risk of suffering from NSCLC if they drank alcohol or smoke heavily.

We aimed to assess the impact of nationwide hepatitis B virus (HBV) vaccination program on the seroprevalence of HBV infection among human immunodeficiency virus (HIV)-positive persons in a country where most HBV exposure occurs during the perinatal period or in early childhood.Data on HBV surface antigen (HBsAg), anti-HBV surface (anti-HBs), anti-HBV core (anti-HBc), and anti-hepatitis C virus (anti-HCV) antibody were retrospectively collected from 3,164 HIV-positive and 2,594 HIV-negative persons between 2004 and 2007. Comparisons of serological markers of HBV and HCV were made between HIV-positive and -negative adults born before and after the implementation of the HBV vaccination program in Taiwan in July 1984.Compared with HIV-negative persons, the adjusted odds ratio for HBsAg seropositivity was 1.100 (95% confidence interval, 0.921-1.315) among HIV-positive persons. Although the seroprevalence of anti-HCV antibody remained similar between HIV-positive persons born before and those born after 1984, the seroprevalence of HBsAg declined from 20.3 to 3.3% in HIV-positive persons (P0.001) and from 15.5 to 8.5% in HIV-negative persons (P0.001). Despite the high seroprevalence of anti-HCV antibody (97.1%) in HIV-positive injecting drug users (IDUs), there was no statistically significant difference in the seroprevalence of HBsAg (5.6% vs. 8.5%, P=0.75) or anti-HBc antibody (40.7% vs. 27.9%, P=0.14) between HIV-positive IDUs and HIV-negative persons who were born after 1984.Our study showed a significant decline of seroprevalence of HBV infection among both HIV-negative and -positive persons who were born in the era of the nationwide HBV vaccination in Taiwan.

Background: Allergen exposure can lead to the development of allergic asthma, sensitized asymptomatic or nonallergic responses in different conditions. Regulatory T (Treg) cells are involved in controlling the immune response direction. The aim of this study was to determine whether allergic asthmatics had defects in CD4+CD25+ Treg cells and CD4+IL (interleukin)-10+ Treg cells after specific allergen exposure. Methods: Peripheral-blood mononuclear cells (PBMCs) were isolated from 20 patients with asthma sensitized to house dust mite, 24 asymptomatic subjects sensitized to house dust mite and 22 nonallergic subjects. Cells were cultured without stimulation and with rDer p 1. Frequencies and proliferations of CD4+CD25+ T cells and CD4+IL-10+ T cells were measured by flow cytometry. Concentrations of IL-10, IL-4, interferon (IFN)-γ and tumor growth factor β1 in culture supernatants and sera were determined by ELISA. Results: PBMCs derived from sensitized asthmatic patients had the lowest percentage of CD4+CD25+ Treg cells and the highest IL-4 level in response to allergen among the 3 groups. PBMCs derived from sensitized asymptomatic subjects had higher percentages of both CD4+CD25+ Treg cells and CD4+IL-10+ T cells than those from sensitized asthmatic patients in rDer-p-1-stimulated cultures, and they had the highest levels of IL-10 and IFN-γ responses to allergen among the 3 groups. Conclusions: Patients with allergic asthma had an insufficient CD4+CD25+ Treg cell response and an excessive Th2 response to specific allergen. The high levels of Treg cell response and IL-10 and IFN- γ responses to specific allergen can partly explain the immunological characteristics associated with sensitized asymptomatic subjects.

Background One dose of benzathine penicillin G (BPG) has been recommended for HIV-infected patients with early syphilis (primary, secondary, and early latent syphilis) in the sexually transmitted diseases treatment guidelines, but clinical data to support such a recommendation are limited. Methods We prospectively observed the serological response to 1 or 3 weekly doses of BPG in HIV-infected adults who sought treatment of early syphilis at 8 hospitals around Taiwan. Rapid plasma reagin (RPR) titers were followed every 3–6 months after treatment. The serological response was defined as a 4-fold or greater decline in RPR titers at 12 months of treatment. The missing values were treated by following the last-observed-carried-forward principle. We hypothesized that 1 dose was non-inferior to 3 weekly doses of BPG with the non-inferiority margin for the difference of serological response set to 10%. Results Between 2007 and 2012, 573 patients completed at least 12 months of follow-up: 295 (51.5%) receiving 1 dose of BPG (1-dose group) and 278 (48.5%) 3 doses (3-dose group). Overall, 198 patients (67.1%; 95% confidence interval [CI], 61.4–72.5%) in the 1-dose group achieved serological response at 12 months, as did 208 patients (74.8%; 95% CI, 69.3–79.8%) in the 3-dose group (one-sided 95% CI of the difference, 15.1%). In the multivariate analysis, secondary syphilis (adjusted odds ratio [AOR], 1.90; 95% CI 1.17–3.09), RPR titer ≥32 (AOR, 1.93; 95% CI, 1.38–2.69), and 3 doses of BPG (AOR, 1.68; 95% CI, 1.20–2.36) were independently associated with a serological response. The time to the first episode of treatment failure was 1184 (standard deviation [SD], 70.5) and 1436 (SD, 80.0) days for 1- and 3-dose group, respectively. Conclusions Single-dose BPG resulted in a higher serological failure rate and shorter time to treatment failure than 3 weekly doses of BPG in the treatment of early syphilis in HIV-infected patients.

Background Optimal timing for initiating highly active antiretroviral therapy (HAART) in HIV-TB coinfected patients is challenging for clinicians. We aim to evaluate the impact of different timing of HAART initiation on TB outcome of HIV-infected adults in Taiwan. Methods A population-based retrospective cohort study was conducted through linking the HIV and TB registries of Taiwan Centers for Disease Control (CDC) during 1997 to 2006. Clinical data of HIV-TB co-infected patients, including the presence of immune reconstitution inflammatory syndrome (IRIS), was collected through medical records review. The outcome of interest was all-cause mortality within 1 year following TB diagnosis. The Cox proportional hazard model was used to explore the probability of death and IRIS after TB diagnosis by adjusting for confounding factors and factors of interest. The probability of survival and TB IRIS were calculated by the Kaplan-Meier method and compared between different HAART initiation timing groups by the log-rank test. Results There were 229 HIV-TB co-infected patients included for analysis and 60 cases (26.2%) died within one year. Besides decreasing age and increasing CD4 lymphocyte count, having started HAART during TB treatment was significantly associated with better survival (adjusted Hazard Ratio was 0.11, 95% CI 0.06–0.21). As to the timing of HAART initiation, there was only non-significant benefit on survival among cases initiating HAART within 15 days, at 16–30 days and at 31–60 days of TB treatment than initiating after 60 days. Cases with HAART initiated after 30 days had lower risk in developing IRIS than cases with HAART initiated earlier. Cases with IRIS had significantly higher rate of re-hospitalization (49% vs. 4%, p

We report a case of gonococcal meningitis with an intraabdominal abscess in a 19-y-old woman, who had a ventriculoperitoneal shunt after craniotomy for astrocytoma. Percutaneous drainage was performed for the intraabdominal abscess. Ceftriaxone was administered with the ventriculoperitoneal shunt removal. The clinical course improved, but visual impairment last for 3 months following treatment.

Klebsiella pneumoniae has emerged as the leading liver abscess pathogen in Taiwan, with the percentage rising from 30% in the 1980s to over 80% in the 1990s. Most of the patients with K. pneumoniae liver abscess are diabetic and without biliary tract disease. Some patients develop serious extrahepatic complications such as endophthalmitis, meningitis, lung abscess, and necrotizing fasciitis. Pulsed-field gel electrophoresis (PFGE) was used for cluster analysis of 96 isolates from patients with liver abscess and 60 isolates from patients with other diseases. A total of 136 PFGE types were identified. Among the 96 liver abscess-associated isolates, 60 (62.5%) were classified in major cluster A. Cluster A included 41 PFGE types (types 1 to 41) which had a genetic similarity of at least 72.4% ± 9.4%. The PFGE patterns of cluster A strains are so similar that they could have originated from the same ancestor. This study demonstrates that cluster A plays an important role in the high incidence of K. pneumoniae liver abscess in Taiwan.

Pulsed-field gel electrophoresis (PFGE) typing was applied to the epidemiological investigation of 20 Serratia marcescens isolates collected from urine specimens of 17 patients and three urinals over a 2-month period. Twenty-five epidemiologically unrelated strains were also tested to determine the discriminatory power of PFGE. The PFGE fingerprints of each isolate were consistent in three different tests. The 20 outbreak isolates had an identical PFGE fingerprint pattern, while the epidemiologically unrelated strains demonstrated unique PFGE fingerprint patterns. The source of the outbreak was inadequately disinfected urinals. We conclude that PFGE served as a highly discriminatory and reproducible method for the epidemiological investigation of the outbreak of S. marcescens infection addressed by this study.

Endogenous endophthalmitis is a rare complication of Esche­ richia coli septicemia in the antibiotic era. Emphysematous en­ dophthalmitis due to E. coli is even more uncommon; only one case in a diabetic patient has been reported previously [1]. Herein, we describe a case ofendogenous emphysematous endophthalmitis due to E. coli in a patient with urinary tract infection and endocardi­ tis who did not have any medical history of diabetes mellitus. A 50-year-old man was hospitalized on 2 April 1994 because of a 10-day history of fever, chills, and ocular pain followed by loss of vision in both eyes. He had no history of ocular trauma or surgery. In 1993, he had undergone aortic valvuloplasty because of aortic stenosis. Three years before hospitalization, he had also had a left kidney stone and had received extracorporeal shock wave lithotripsy. He had no medical history of diabetes mellitus. Ten days before his admission, the patient had high fever, chills, and ocular pain. Erythematous change in both eyes was noted, and he complained of bilateral visual impairment during the following 2 days. He was treated with intravenous antibiotics (including amikacin) in a local medical clinic for the presumptive diagnosis of sepsis and endophthalmitis. A series of studies were done. Uri­ nalysis showed pyuria, and cultures ofurine and blood both yielded E. coli. He was later transferred to Taichung Veterans General Hospital (Taichung, Taiwan, ROC) because of deterioration of his clinical condition. At the time ofadmission, he was acutely ill-looking and drowsy. The temperature was 37°C, the blood pressure was 110/60 mm Hg, and the pulse rate was 76. Physical examination disclosed a grade 3/6 systolic murmur; the murmur was heard best at the aortic area and left sternal border, and the sound transmitted to the neck. Ophthalmologic examination showed bilateral periorbital swelling and moderate injected conjunctivae. Vision in both eyes was only light perception. The cornea of both eyes had an epithelial defect with superficial stromal haziness of the lower portion. Exudate and fibrinous material were present in the bilateral anterior cham­ bers, and there was mild opacity in the lenses of both eyes. The vitreous and fundi of both eyes could not be visualized. The other findings of the physical examination were unremarkable. ACT ofthe orbits demonstrated a gas bubble in the left eye globe, a finding indicating emphysematous endophthalmitis. The chest roent­ genogram obtained on admission did not show any abnormalities. Echographic examination of the heart revealed a vegetation over the tricuspid septal leaflet, with aortic stenosis, aortic regurgitation, and minimal pericardial effusion. An abdominal sonogram demonstrated left renal stones with cysts over both kidneys. Laboratory studies