Suppression of MMQ cells by fulvestrant: possible mechanism of action and potential application for bromocriptine-resistant prolactinomas

Bromocriptine is an effective treatment for most prolactinomas. Estrogen receptor (ER) antagonists are an alternative for treating patients with bromocriptine-resistant prolactinomas (BCRP). Previously, we reported that fulvestrant, a selective ER antagonist, significantly inhibited the proliferation of, and prolactin secretion by, MMQ cells, a prolactin-secreting rat pituitary cell line, an exemplary model for prolactinoma. In this study, we used fulvestrant to block ERα expression by MMQ cells and analyzed the expression of β-catenin and Wnt inhibitory factor-1 (WIF1) to investigate the effects of fulvestrant on the Wnt signaling pathway. In addition, we examined the gene expression of ERα, β-catenin and WIF1 in clinical BCRP specimens to explore the correlation between gender and clinical features. There was no significant difference in β-catenin expression between fulvestrant-treated cells and untreated cells, whereas WIF1 expression was higher in the treated cells. In clinical BCRP specimens, ERα expression was higher (especially in male patients), whereas β-catenin expression was similar to normal pituitaries. In addition, WIF1 expression was significantly lower in BCRP specimens than in normal pituitaries. The tumor volume was larger in male patients than in female patients. Prolactin concentration was positively correlated with tumor volume, and a positive linear correlation was observed between ERα expression and tumor volume. In conclusion, the anti-tumor activity of fulvestrant on MMQ cells seems to be associated with ERα and the non-canonical Wnt pathway, and higher ERα levels in male patients with BCRP may contribute to the larger tumor volumes observed. Fulvestrant holds promise as a therapeutic agent for BCRP.     

Enriched environment has limited capacity for the correction of hippocampal memory-dependent schizoid behaviors in rats with early postnatal NMDAR dysfunction

Pre- and early postnatal stress can cause dysfunction of the N-methyl-d-aspartate receptor (NMDAR) and thereby promote the development of hippocampus memory-dependent schizoid abnormalities of navigation in space, time, and knowledge. An enriched environment improves mental abilities in humans and animals. Whether an enriched environment can prevent the development of schizoid symptoms induced by neonatal NMDAR dysfunction was the central question of our paper. The experimental animals were Wistar rats. Early postnatal NMDAR dysfunction was created by systemic treatment of rat pups with the NMDAR antagonist MK-801 at PD10–20 days. During the development period (PD21–90 days), the rats were reared in cognitively and physically enriched cages. Adult age rats were tested on navigation based on pattern separation and episodic memory in the open field and on auto-hetero-associations based on episodic and semantic memory in a step-through passive avoidance task. The results showed that postnatal NMDAR antagonism caused abnormal behaviors in both tests. An enriched environment prevented deficits in the development of navigation in space based on pattern separation and hetero-associations based on semantic memory. However, an enriched environment was unable to rescue navigation in space and auto-associations based on episodic memory. These data may contribute to the understanding that an enriched environment has a limited capacity for therapeutic interventions in protecting the development of schizoid syndromes in children and adolescents.     

Outcomes of basal ganglia and thalamic cavernous malformation surgery: A meta-analysis

Surgical resection of basal ganglia (BG) and thalamic cavernous malformations (CMs) has not yet become standardized in the field of neurosurgery due to the eloquent location of these lesions and the relative paucity of literature on the subject. This review presents a consolidation of the available literature on outcomes and complication rates after surgical resection of these lesions. A systematic literature review was performed via PubMed database for articles published between 1985 and 2019. Studies comprising ≥2 patients receiving surgery for BG or thalamic CMs with available follow-up data were included. Pooled data included patient demographics, CM preoperative characteristics, and surgical outcomes Twenty studies comprising 227 patients were included for analysis. Complete resection was achieved in 94.7% (fixed-effects pooled estimate [FE]: 94.9%[91.0%–97.8%]; random-effects pooled estimate [RE]: 90.0%[79.8%–96.9%]), and hemorrhage of incompletely resected CMs occurred in 50% (FE: 55.9%[25.9%–83.6%]; RE: 55.9%[25.9%–83.6%]) of patients. Early morbidity was observed in 24.0% (FE: 24.9%[17.8%–32.6%]; RE: 24.9%[17.8%–32.6%]). At final follow-up, 67.3% (FE: 67.7%[58.8%–76.0%]; RE: 67.8%[52.2%–81.6%]) and 20.6% (FE: 20.6%[13.6%–28.6%]; RE: 20.9%[9.8%–34.9%]) had improvement and stability of preoperative symptoms, respectively. Mortality rate was 1.3% (FE: 2.3%[0.6%–5.1%]; RE: 2.3%[0.6%–5.1%]). Therefore, high cure rates with low rates of postoperative morbidity can be achieved in BG or thalamic CM surgery. Most patients had improved neurological function at final follow-up. Complete resection should be attempted to reduce rates of repeat hemorrhage.     

Cognitive behavioral therapy reduces illness perceptions and anxiety symptoms in patients with unruptured intracranial aneurysm

The main purpose of this study was to assess the relation between cognitive behavioral therapy and possible changes in illness perceptions and anxiety in patients diagnosed with unruptured intracranial aneurysm. An observational study of an intervention with 67 patients with an unruptured intracranial aneurysm from two medical centers in a Colombian city (n = 35 on the intervention group) was carried out. To assess changes, measurements were taken at baseline and at one-year follow-up with the Beck Anxiety Inventory and the Illness Perception Questionnaire, brief version, taking into account the importance of perceptions in the process of adjusting to illness and acquiring healthy life habits. Hypotheses were tested by a structural model. The results obtained from this study showed that illness perceptions were related to anxiety levels at both time points; however, the relations were stronger before cognitive behavioral therapy (βt0 = 0.61, p < 0.01; βt1 = 0.37, p < 0.01). Cognitive behavioral therapy was found to be a moderator of changes in both illness perceptions and anxiety at the time of follow-up (β = −0.31, p < 0.01; β = −0.26, p < 0.01). The structural model suggests that cognitive behavioral therapy is associated with less anxiety (β = −0.17, p < 0.05) and better illness perceptions (β = −0.35, p < 0.01) in patients diagnosed with unruptured intracranial aneurysms.     

Differential value of external anal- and urethral-sphincter electromyography in multiple system atrophy cerebellar type and spinocerebellar ataxias

ObjectiveClinically differentiating multiple system atrophy cerebellar type (MSA-C) and spinocerebellar ataxias (SCAs) is challenging, especially at early disease stages, because of their similarities in clinical manifestation and imaging results. The purpose of this study was to explore the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) for distinguishing between MSA-C and SCAs.MethodsA total of 51 subjects, including 33 MSA-C and 18 SCAs, were recruited. Average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contraction and recruitment pattern during maximal voluntary contraction were recorded and analyzed to identify differential diagnostic results of EAS-EMG and US-EMG for MSA-C and SCAs.ResultsSignificant differences in average MUP duration, percentage of polyphasic MUPs, and ratio of simple phase and simple-mix phase using EAS-EMG were noted between patients with MSA-C and SCAs. These same parameters also differed significantly between MSA-C and SCAs male patients using US-EMG.ConclusionsEAS-EMG may serve as a potential method for early differential diagnosis between patients with MSA-C and SCAs. Furthermore, US-EMG could be a supplementary method for males when EAS-EMG is not available.     

Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients

The pathophysiology of posterior reversible encephalopathy syndrome (PRES) is incompletely understood; however, an underlying state of immune dysregulation and endothelial dysfunction has been proposed. We examined alterations of serum lactate dehydrogenase (LDH), a marker of endothelial dysfunction, relative to the development of PRES in patients receiving chemotherapy. A retrospective Institutional Review Board approved database of 88 PRES patients was examined. PRES diagnosis was confirmed by congruent clinical diagnosis and MRI. Clinical features at presentation were recorded. Serum LDH values were collected at three time points: prior to, at the time of, and following PRES diagnosis. Student’s t-test was employed. LDH values were available during the course of treatment in 12 patients (nine women; mean age 57.8 years [range 33–75 years]). Chemotherapy-associated PRES patients were more likely to be normotensive (25%) versus the non-chemotherapy group (9%). LDH levels at the time of PRES diagnosis were higher than those before and after (p = 0.0263), with a mean difference of 114.8 international units/L. Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES onset was 11.1 days. In conclusion, serum LDH, a marker of endothelial dysfunction, shows statistically significant elevation at the onset of PRES toxicity in cancer patients receiving chemotherapy. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not the prime event, in the pathophysiology of PRES.     

Different pulmonary adenocarcinoma growth patterns significantly affect survival

ObjectiveAdenocarcinoma (AC) is the number one pathological entity of lung cancer with approximately 30–40% of cases. It is known to be heterogeneous and has 5 histopathological growth patterns. We evaluated the long-term survival rates of patients with predominant subtypes.Methods290 patients with AC underwent pulmonary resection between 2012 and 2017 at our institution. We excluded all patients with lymph node involvement and distant metastases. Hence, 163 patients were included for further analysis. Predominant growth pattern was defined if more than 10% of cells showed a growth pattern. 1, 3, and 5-year survival rates were evaluated. Survival was assessed by Kaplan-Meier curves and the Cox proportional hazards model was used to identify prognostic factors for overall survival.ResultsPredominant growth patterns >10% were compared to <10% growth patterns of the same subtype. 1-year, 3-year, and 5-year overall survival rates of patients with predominant solid tumor growth >10% differed significantly from patients with <10% (88.4% vs. 97.6%, p = 0.04; 65.8% vs. 87.4% p = 0.001, 36.4% vs. 65.9% p = 0.01). Survival rates did not differ between >10% papillary and acinar growth compared to <10%. Kaplan-Meier curves showed reduced overall survival for patients with solid tumor growth >10% (log-rank 0.002). Solid tumor growth >10% was an independent prognostic factor for worse long-term survival (Hazard ratio: 3.05, p = 0.01).ConclusionOur study demonstrates that the presence of a predominant solid pattern in pulmonary adenocarcinoma is a factor for an unfavorable prognosis. This should be kept in mind in daily clinical practice.     

Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by Fractalkine pathway in Parkinson’s disease rat model

Subthalamic nucleus deep brain stimulation (STN-DBS) is widely used to treat patients with Parkinson’s disease (PD), and recent studies have shown that it is more beneficial for early stages, suggesting a potential neuroprotective effect. And the neuroinflammation plays an indispensable role in progress of PD. However, the underlying mechanisms are not well understood. The aim of this study was to investigate the effect of STN-DBS on neuroinflammation and the potential pathway. To address this question, we established a rat PD model by unilateral 6-hydroxydopamine injection into the left striatum and implanted stimulation leads into the ipsilateral STN to deliver electrical stimulation for a week. The neuroprotective effects of STN-DBS were examined by molecular biology techniques, including western blotting, immunohistochemistry and so on. We found that motor deficits were alleviated by STN-DBS, with increased survival of dopaminergic neurons in the substantia nigra (SN). Furthermore, STN-DBS decreased Fractalkine (CX3CL1) and its receptor (CX3CR1) expression. Meanwhile, the suppressed microglia activation and nuclear factor-κB expression, decrease in the levels of pro-inflammatory cytokine interleukin (IL)-1β and IL-6 and increase in anti-inflammatory cytokine IL-4, downregulated IL-1 receptor, extracellular signal-regulated kinase (ERK) and cleaved-caspase3 were also observed in SN of PD models received STN-DBS. In conclusion, we observed a significant association between the suppressed neuroinflammation and STN-DBS, which may be attributed to CX3CL1/CX3CR1 signaling. These results provide novel insight into the mechanistic basis of STN-DBS therapy for PD.