Collateral Pathway Research Articles

Persistent primitive trigeminal artery played a role as a collateral pathway in spontaneous internal carotid artery dissection: a case report

Persistent primitive trigeminal artery played a role as a collateral pathway in spontaneous internal carotid artery dissection: a case report

Diploic Veins as Collateral Venous Pathway in Patients with Superior Sagittal Sinus Obstruction caused by Large Size Meningioma

Diploic Veins as Collateral Venous Pathway in Patients with Superior Sagittal Sinus Obstruction caused by Large Size Meningioma

Variations of the circle of willis determined via magnetic resonance angiography: A single-center analysis of the serbian population

Introduction: The circle of Willis (CoW) represents the collateral pathway between large brain-feeding arteries, the knowledge of which is important in interventional and neurosurgical procedures, in the diagnosis and planning of procedures in acute stroke and subarachnoid hemorrhage. Aim: The study aims to determine the prevalence of variations of the CoW in patients from Serbia via magnetic resonance angiography (MRA). Material and Methods: The study was conducted as a retrospective study at the Center for Imaging Diagnostics, Oncology Institute of Vojvodina. Magnetic resonance imaging was analyzed in 665 patients of both sexes (471 females and 194 males), who underwent MRA during 2018 and 2019. Results: Complete CoW was found in 48.42% of cases, mostly in females (68.01%). Partially complete CoW and incomplete CoW were encountered in 38.05% and 13.55% of patients, mostly in females (73.52% and 73.33%). Anterior circulation variations were seen in 27.41% of cases, higher in females (63.83%), most commonly A1 anterior cerebral artery hypoplasia (9.32%). Posterior circulation variations were seen in 46.36% of cases, higher in females (79.25%), most commonly posterior communicating (PCom) artery hypoplasia (25.56%). Combined variations were seen in 26.24% of patients, with higher prevalence in females (73.33%). The prevalence of variations of posterior circulation between male and female patients was statistically significant (P = 0.007) and was higher in females. Discussion and Conclusion: This study showed that the most common variations were that of the posterior circulation, most commonly PCom artery hypoplasia. Complete CoW was found in <50% of cases (48.42%).

Raymond de Vieussens (1641-1715): connoisseur of cardiologic anatomy and pathological forms thereof.

Raymond de Vieussens was an exemplary anatomist who made seminal contributions in the field of cardiology. During initial part of his academic career, he adopted human dissection based experiments as medium of his research. This was in accordance with prevailing trend among anatomists during 17th century. He discovered the presence of tiny venous tributaries communicating between cardiac veins and chambers of heart (ducti carnosi/venae cordis minimae). He reported the existence of a collateral circulatory pathway between right and left coronary arterial systems (Vieussens arterial ring). He was the first to note the valve at the junction of great cardiac vein and coronary sinus (valve of Vieussens) and the prominent oval margin of the fossa ovalis (Vieussens Annulus). All his findings were associated with considerable clinical significance as evidenced in literature that followed. Vieussens accurately demonstrated the three-layered orientation of myocardium and gave a precise description of coronary arteries and their branches. At the onset of 18th century, buoyed by royal patronage from King Louis XIV of France, the second half of Vieussens illustrious career was defined by pathologic anatomy (autopsy based) and anatomo clinical correlations. This was a new trend initiated by Vieussens in anatomical research and was later adopted as a signature method by anatomists of 18th century. As a true connoisseur of cardiologic anatomy, Vieussens accurately charted the anatomo clinical correlations of cardiac tamponade, mitral stenosis and aortic regurgitation. His contributions were pivotal elements in metamorphosis of cardiology as a robust discipline of medicine in modern times.

Stable Gastric Pentadecapeptide BPC 157 Therapy for Primary Abdominal Compartment Syndrome in Rats.

Recently, the stable gastric pentadecapeptide BPC 157 was shown to counteract major vessel occlusion syndromes, i.e., peripheral and/or central occlusion, while activating particular collateral pathways. We induced abdominal compartment syndrome (intra-abdominal pressure in thiopental-anesthetized rats at 25 mmHg (60 min), 30 mmHg (30 min), 40 mmHg (30 min), and 50 mmHg (15 min) and in esketamine-anesthetized rats (25 mmHg for 120 min)) as a model of multiple occlusion syndrome. By improving the function of the venous system with BPC 157, we reversed the chain of harmful events. Rats with intra-abdominal hypertension (grade III, grade IV) received BPC 157 (10 µg or 10 ng/kg sc) or saline (5 ml) after 10 min. BPC 157 administration recovered the azygos vein via the inferior–superior caval vein rescue pathway. Additionally, intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were reduced, as were the grossly congested stomach and major hemorrhagic lesions, brain swelling, venous and arterial thrombosis, congested inferior caval and superior mesenteric veins, and collapsed azygos vein; thus, the failed collateral pathway was fully recovered. Severe ECG disturbances (i.e., severe bradycardia and ST-elevation until asystole) were also reversed. Microscopically, transmural hyperemia of the gastrointestinal tract, intestinal mucosa villi reduction, crypt reduction with focal denudation of superficial epithelia, and large bowel dilatation were all inhibited. In the liver, BPC 157 reduced congestion and severe sinusoid enlargement. In the lung, a normal presentation was observed, with no alveolar membrane focal thickening and no lung congestion or edema, and severe intra-alveolar hemorrhage was absent. Moreover, severe heart congestion, subendocardial infarction, renal hemorrhage, brain edema, hemorrhage, and neural damage were prevented. In conclusion, BPC 157 cured primary abdominal compartment syndrome.

Microglia sense neuronal activity via GABA in the early postnatal hippocampus.

Microglia, the resident macrophages in the central nervous system, express receptors for classical neurotransmitters, such as γ-aminobutyric acid (GABA) and glutamate, suggesting that they sense synaptic activity. To detect microglial Ca2+ responses to neuronal activity, we generate transgenic mouse lines expressing the fluorescent Ca2+ indicator GCaMP6m, specifically in microglia and demonstrate that electrical stimulation of the Schaffer collateral pathway results in microglial Ca2+ responses in early postnatal but not adult hippocampus. Preceding the microglial responses, we also observe similar Ca2+ responses in astrocytes, and both are sensitive to tetrodotoxin. Blocking astrocytic glutamate uptake or GABA transport abolishes stimulation-induced microglial responses as well as antagonizing the microglial GABAB receptor. Our data, therefore, suggest that the neuronal activity-induced glutamate uptake and the release of GABA by astrocytes trigger the activation of GABAB receptors in microglia. This neuron, astrocyte, and microglia communication pathway might modulate microglial activity in developing neuronal networks.

Relationship between Circle of Willis Variations and Cerebral or Cervical Arteries Stenosis Investigated by Computer Tomography Angiography and Multitask Convolutional Neural Network.

Circle of Willis (CoW) is the most critical collateral pathway that supports the redistribution of blood supply in the brain. The variation of CoW is closely correlated with cerebral hemodynamic and cerebral vessel-related diseases. But what is responsible for CoW variation remains unclear. Moreover, the visual evaluation for CoW variation is highly time-consuming. In the present study, based on the computer tomography angiography (CTA) dataset from 255 patients, the correlation between the CoW variations with age, gender, and cerebral or cervical artery stenosis was investigated. A multitask convolutional neural network (CNN) was used to segment cerebral arteries automatically. The results showed the prevalence of variation of the anterior communicating artery (Aco) was higher in the normal senior group than in the normal young group and in females than in males. The changes in the prevalence of variations of individual segments were not demonstrated in the population with stenosis of the afferent and efferent arteries, so the critical factors for variation are related to genetic or physiological factors rather than pathological lesions. Using the multitask CNN model, complete cerebral and cervical arteries could be segmented and reconstructed in 120 seconds, and an average Dice coefficient of 78.2% was achieved. The segmentation accuracy for precommunicating part of anterior cerebral artery and posterior cerebral artery, the posterior communicating arteries, and Aco in CoW was 100%, 99.2%, 94%, and 69%, respectively. Artificial intelligence (AI) can be considered as an adjunct tool for detecting the CoW, particularly related to reducing workload and improving the accuracy of the visual evaluation. The study will serve as a basis for the following research to determine an individual's risk of stroke with the aid of AI.

Robert's Intragastric Alcohol-Induced Gastric Lesion Model as an Escalated General Peripheral and Central Syndrome, Counteracted by the Stable Gastric Pentadecapeptide BPC 157.

We redefined Robert’s prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we used Robert’s model to examine the cytoprotective effects of the stable gastric pentadecapeptide BPC 157. The intragastric administration of alcohol induced gastric lesions, intracranial (superior sagittal sinus) hypertension, severe brain swelling and lesions, portal and vena caval hypertension, aortal hypotension, severe thrombosis, inferior vena cava and superior mesenteric vein congestion, azygos vein failure (as a failed collateral pathway), electrocardiogram disturbances, and heart, lung, liver and kidney lesions. The use of BPC 157 therapy (10 µg/kg or 10 ng/kg given intraperitoneally 1 min after alcohol) counteracted these deficits rapidly. Specifically, BPC 157 reversed brain swelling and superior mesenteric vein and inferior vena caval congestion, and helped the azygos vein to recover, which improved the collateral blood flow pathway. Microscopically, BPC 157 counteracted brain (i.e., intracerebral hemorrhage with degenerative changes of cerebral and cerebellar neurons), heart (acute subendocardial infarct), lung (parenchymal hemorrhage), liver (congestion), kidney (congestion) and gastrointestinal (epithelium loss, hemorrhagic gastritis) lesions. In addition, this may have taken place along with the activation of specific molecular pathways. In conclusion, these findings clarify and extend the theory of cytoprotection, offer an approach to its practical application, and establish BPC 157 as a prospective cytoprotective treatment.

A rare case of sigmoid colon cancer in which the lower limbs received collateral blood flow from the inferior mesenteric artery owing to peripheral artery disease

BackgroundColorectal cancer and peripheral artery disease are common conditions in older adults and may coexist in this population. Lymph node dissection along the inferior mesenteric artery is a vital procedure in cases of left-sided colorectal cancer. However, the inferior mesenteric artery may show a collateral blood pathway in rare cases of peripheral artery disease. We report a case of advanced sigmoid colon cancer in which the lower limbs received inferior mesenteric artery flow owing to asymptomatic peripheral artery disease. The possibility of catastrophic lower-limb ischemia because of complete mesenteric excision with ligation of the inferior mesenteric artery was a matter of concern in this case.Case presentationA 73-year-old man with asymptomatic peripheral artery disease was diagnosed with stage IIIB advanced sigmoid colon cancer. Angiography using a balloon-occlusion catheter revealed that his lower limbs received prominent inferior mesenteric artery blood flow through a collateral pathway. Therefore, interventional radiologists and cardiovascular surgeons evaluated the indications for endovascular stents or bypass grafts. The patient also had dilated cardiomyopathy, so the cardiovascular physicians evaluated his tolerance in the worst-case scenario of a colorectal anastomotic leak. The patient underwent axillofemoral artery bypass and two-stage laparoscopic sigmoid colectomy without anastomosis. The postoperative course was uneventful, and he resumed his job within a month after the resection.ConclusionsAlthough collateral flow from the inferior mesenteric artery is rare in patients with peripheral artery disease, a few case reports have described fatal lower-limb ischemia following anterior resection. The perioperative multidisciplinary evaluation enabled us to understand the patient’s condition and risks, and allowed successful cancer treatment without ischemia of the lower limbs.

Collateral circulation pathway in patients with basilar artery occlusion/severe stenosis: a single-center case series

Objective: To investigate the collateral circulation compensation model in patients with favorable prognosis of basilar artery occlusion/severe stenosis treated with drugs or endovascular therapy. Methods: Clinical data of patients with basilar artery occlusion/severe stenosis and good clinical outcome were retrospectively collected in the Department of Neurology, Sixth Medical Center of PLA General Hospital from January 2019 to January 2020. They were divided into intensive drug therapy group and combined endovascular therapy group. The number and ways of collateral compensation pathway described by digital substraction angiography (DSA) were analyzed, and the characteristics of the collateral compensation model were summarized. SPSS22.0 software was used for statistical analysis, and the constituent ratio (%) was used for statistical description of the enumeration data. Results: A total of 32 eligible patients were included, including 27 males and 5 females, with an average age 45-76 (59±10) years. The compensation model included posterior communicating artery-posterior cerebral artery (13 cases, 40.6%), posterior communicating artery-posterior cerebral artery-basilar artery (10 cases, 31.2%), cerebellar artery-anastomotic branches of superior cerebellar artery (8 cases, 25.0%), anterior choroid artery-anastomotic branches of posterior choroid artery (2 cases, 6.2%), collateral circulation not established (11 cases, 34.4%).In drug treatment group, collateral compensation was found in the majority (14/15), with mainly posterior communicating artery (10/14).Most patients in combined treatment group did not develop collateral compensation (10/17), anastomotic branches of PICA-SCA were the main routes (6/7). Conclusion: In patients with basilar artery occlusion/severe stenosis, favorable clinical outcome can be achieved in both groups of patients treated with intensive drug therapy or endovascular therapy.

A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action.

SUMMARYKetamine produces rapid antidepressant action in patients with major depression or treatment-resistant depression. Studies have identified brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), as necessary for the antidepressant effects and underlying ketamine-induced synaptic potentiation in the hippocampus. Here, we delete BDNF or TrkB in presynaptic CA3 or postsynaptic CA1 regions of the Schaffer collateral pathway to investigate the rapid antidepressant action of ketamine. The deletion of Bdnf in CA3 or CA1 blocks the ketamine-induced synaptic potentiation. In contrast, ablation of TrkB only in postsynaptic CA1 eliminates the ketamine-induced synaptic potentiation. We confirm BDNF-TrkB signaling in CA1 is required for ketamine’s rapid behavioral action. Moreover, ketamine application elicits dynamin1-dependent TrkB activation and downstream signaling to trigger rapid synaptic effects. Taken together, these data demonstrate a requirement for BDNF-TrkB signaling in CA1 neurons in ketamine-induced synaptic potentiation and identify a specific synaptic locus in eliciting ketamine’s rapid antidepressant effects.

Leptomeningeal collateral activation indicates severely impaired cerebrovascular reserve capacity in patients with symptomatic unilateral carotid artery occlusion

For patients with symptomatic unilateral internal carotid artery (ICA) occlusion, impaired cerebrovascular reactivity (CVR) indicates increased stroke risk. Here, the role of collateral activation remains a matter of debate, whereas angio-anatomical collateral abundancy does not necessarily imply sufficient compensatory flow provided. We aimed to further elucidate the role of collateral activation in the presence of impaired CVR. From a prospective database, 62 patients with symptomatic unilateral ICA occlusion underwent blood oxygenation-level dependent (BOLD) fMRI CVR imaging and a transcranial Doppler (TCD) investigation for primary and secondary collateral activation. Descriptive statistic and multivariate analysis were used to evaluate the relationship between BOLD-CVR values and collateral activation. Patients with activated secondary collaterals exhibited more impaired BOLD-CVR values of the ipsilateral hemisphere (p = 0.02). Specifically, activation of leptomeningeal collaterals showed severely impaired ipsilateral hemisphere BOLD-CVR values when compared to activation of ophthalmic collaterals (0.05 ± 0.09 vs. 0.12 ± 0.04, p = 0.005). Moreover, the prediction analysis showed leptomeningeal collateral activation as a strong independent predictor for ipsilateral hemispheric BOLD-CVR. In our study, ipsilateral leptomeningeal collateral activation is the sole collateral pathway associated with severely impaired BOLD-CVR in patients with symptomatic unilateral ICA occlusion.

Losartan improved hippocampal long-term potentiation impairment induced by repeated LPS injection in rats.

Cognitive impairment has been known as a common consequence of brain inflammation. Long‐term potentiation (LTP), the generally accepted cellular mechanism for memory formation in the mammalian brain, has been shown to be suppressed by inflammation. Studies have shown that angiotensin II (Ang II) through the Ang II type 1 receptor (AT1R) has a role in brain and peripheral immune system communication and brain inflammation. Here, the effect of AT1R blockade on hippocampal LTP in rats undergoing repeated lipopolysaccharide (LPS) injection was investigated. Rats received intraperitoneal (ip) injections of LPS (250 μg kg−1 day−1) for seven days. Treatment with losartan (ip; 3 mg kg−1 day−1) was started 3 days before LPS injection and continued during the LPS injections. Rats were anesthetized, and field excitatory postsynaptic potential (fEPSP) was recorded from the stratum radiatum of the CA1 area of the hippocampus in response to stimulation of the Schaffer collateral pathway. Results showed that LTP was suppressed in the LPS‐injected rats as no significant differences were found in the fEPSP slope and amplitude before and after the LTP induction. AT1R blockade by losartan restored fEPSP to the control levels. These findings indicate that Ang II, through AT1R, has a role in LTP suppression induced by systemic inflammation.

Study on the correlation between the circle of Willis structure and collateral circulation in bilateral carotid artery occlusion

Background and purposeBilateral carotid artery occlusion (CAO) is a rare condition and the collateral circulation is more complicated than in unilateral CAO. The circle of Willis (CoW) is the most important collateral circulation compensation pathway in CAO. However, the specific role of CoW in the collateral circulation compensation pathway of CAO has not been fully elucidated. The purpose of this study is to investigate the role of CoW in the collateral circulation compensation pathway of CAO.Materials and methodsClinical, imaging, and hemodynamic data of 30 patients with bilateral CAO were collected to analyze the collateral blood flow compensation pathway and its characteristics, and to examine the correlation between the structure of the CoW and the collateral circulation of bilateral CAO.ResultsThis paper summarized 30 patients with bilateral CAO. There were 0 cases of the CoW complete type, 18 cases of the partially complete type (60%), and 12 cases of the incomplete type (40%). For the partially complete type cases, there were 14 complete anterior circulation cases (46.7%). The collateral circulation collateral circulation pathway included 14 cases with anterior communicating artery(ACoA), 7 cases with posterior cerebral artery (PCA)-middle cerebral artery (MCA) leptomeningeal anastomosis (LMA), 5 cases with ophthalmic artery(OA), 3 cases with lateral posterior communicating artery(PCoA), 1 case with internal carotid artery (ICA) stealing, 1 case with new Moyamoya vessels, and 4 cases of other types. There were four cases (13.3%) with complete posterior circulation, including four cases with bilateral PCoA, three cases with PCA-MCA LMA, and two cases with OA. There were 12 cases (40%) with incomplete CoW, including 8 cases with PCA-MCA LMA, 3 cases with lateral PCoA, 1 case with anterior cerebral artery (ACA)-MCA LMA, 4 cases with OA, and 1 other case.ConclusionThe collateral circulation pathway differs among patients with different CoW structure types. When the CoW is partially complete, it mainly provides blood flow compensation to the ischemic area through primary collateral circulation. When the CoW is incomplete, it mainly provides blood flow compensation to the ischemic area through secondary collateral circulation.

Frequency-dependent layer-specific differences in short-term synaptic plasticity in the dorsal and ventral CA1 hippocampal field.

Information from the entorhinal cortex arrives to the hippocampal CA1 microcircuit directly through the temporoammonic path (TA) that terminates in the stratum lacunosum-moleculare (SLM), and indirectly through Schaffer collateral pathway (SC) that terminates in the stratum radiatum (SR). By virtue of this input convergence, CA1 circuitry may act to compare and integrate incoming cortical information. Although a remarkable dorsal-ventral difference in short-term plasticity (STP) has been recently described at SC-CA1 synapses, the corresponding properties at TA-CA1 synapses have not been examined. Here, we report that stimulation of TA in the dorsal hippocampus produces significant facilitation of all conditioned responses evoked by 1-30Hz, peaking at 20-30Hz, and significant depression of steady-state responses to 50-100Hz. Dorsal SC-CA1 synapses display a similar pattern of responses, yet, facilitation peaked at 10Hz and depression (at 75-100Hz) is weaker. Strikingly, stimulation of TA in the ventral hippocampus produces facilitation of steady-state responses to 1-30Hz and highly contrasts with the depression of SC-CA1 synapses. Steady-state responses to 40-100Hz in the ventral hippocampus depress in both layers similarly. High-frequency TA input (40-100Hz) to the dorsal hippocampus depresses more in proximal than in distal SLM, while low-frequency (1-3Hz) TA input to the ventral hippocampus facilitates more in distal than in proximal SLM. The present evidence suggests that direct and indirect entorhinal cortical inputs across the septotemporal extent of hippocampal CA1 field display frequency selectivity both in the radial and transverse axes, and that a rapid information processing may take place through direct ventral hippocampal CA1-EC circuit interactions independently of trisynaptic circuit.

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma.

Simple SummaryNovel approaches to target RAS-signaling have led to the so called “RAS renaissance”. In HCC, it was demonstrated that wild-type RAS-RAF-ERK-signaling strongly contributes to HCC progression and drug resistance. In this context, microRNA-622 has emerged as one of the most promising tumorsuppressive microRNAs, targeting RAS-signaling in HCC. However, the majority of microRNA-622 target genes remained elusive. Moreover, limited chemoresponse of HCC was demonstrated by activation of MAPK14-ATF2-signaling which represents a RAS-collateral-pathway, but the expression and regulation of both MAPK14 and ATF2 remained to be clarified. In this study, we demonstrated co-overexpression of MAPK14 and ATF2 in HCC in vitro and in vivo. Moreover, in contrast to “one-microRNA-one-target” interactions, we identified common binding sites for microRNA-622 in both synergistic drug resistance-associated genes–MAPK14 and ATF2. Our data revealed that microRNA-622 functions as a superior pathway regulator inducing de-repression of the MAPK14-ATF2-axis in HCC.Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.

Deficiency of the RI\u03b2 subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats

The RIβ subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIβ subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIβ subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral–CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIβ subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIβ function.

An inferior vena cava discontinuity with an hepato-renal accessory vein development: A radio-anatomical morphometric case study

Inferior vena cava (IVC) agenesis is an uncommon congenital vascular anomaly stemming from aberrant development during embryogenesis. It results from the failure of one or more of the supracardinal veins, subcardinal veins, vitelline veins or postcardinal veins to connect. The symptomatology resulting from this vascular malformation can be either absent or extremely rich and varied. Thoracoabdominal-pelvic CT scan projections following iodine-based contrast product injection were analyzed and a three-dimensional model of vascularization constructed. Herein, an asymptomatic case of IVC agenesis with absence of the suprarenal and renal segments, with azygos continuation, presenting an accessory hepatorenal vein is reported. The presence of this type of accessory vein has never been described in the literature to date. The etiology of this case of IVC agenesis is explored in depth. We also analyzed the morphometric parameters of the IVC remnant segments and the azygos vein in order to quantify the dilatation of the collateral venous pathway overdeveloped to handle blood return. Using the findings from this case and those reported in the literature, we provide general recommendations that should be taken into account before managing a patient, symptomatic or asymptomatic, admitted to the hospital with IVC agenesis.

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system, and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the ubiquitin-proteasome system is inhibited. We further report that silencing the expression of HRI resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy, suggesting that HRI may control proteostasis in the cytosol at least in part through chaperone-assisted selective autophagy. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of overexpressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month-old Hri−/− mice as compared with Hri+/+ littermates. Moreover, aged Hri−/− mice showed accumulation of misfolded α-synuclein in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

NLRP3 deficiency-induced hippocampal dysfunction and anxiety-like behavior in mice

Neuroinflammation has been classified as a trigger of behavioral alterations and cognitive impairments in many neurological conditions, including Alzheimer's disease, major depression, anxiety and others. Regardless of the cause of neuroinflammation, key molecules, which sense neuropathological conditions, are intracellular multiprotein signaling inflammasomes. Increasing evidence shows that the inflammatory response, mediated by activated nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasomes, is associated with the onset and progression of a wide range of diseases of the CNS. However, whether the NLRP3 inflammasome in the CNS is involved in the learning, development of anxiety and adult neurogenesis remains elusive. Therefore, the present study was designed to assess NLRP3 inflammasome contribution in anxiety and reveal its potential involvement in the experimental acquisition of fear responses and hippocampal neurogenesis. Behavioral, immunohistochemical and electrophysiological alterations were measured to evaluate role of neuroinflammation in the limbic system of mice.In this study, we describe interrelated neurophysiological mechanisms, which culminate in absence of NLRP3 inflammasome in young 4 months mice. These include the following: anxious behavior and deterioration in learning and memory of fear conditioning; impairment of adult neurogenesis; reduction and altered morphology of astrocytes in the brain; hyperexcitability in basolateral amygdala (BLA); impaired activation in axons of pyramidal cells of CA1 hippocampal zone in NLRP3 KO mice particularly via the Schaffer collateral pathway; and impaired synaptic transduction in pyramidal cells mediated by an embarrassment of neurotransmitter release from presynaptic site in CA3 hippocampal zone.The present study has demonstrated the novel findings that basal level of NLRP3 inflammasome in the brain of young mice is required for conditioning-induced plasticity in the ventral hippocampus and the basolateral amygdala. The deletion of NLRP3 impair synaptic transduction and caused anxiety-like behavior and labored fear learning, suggesting that low grade inflammation, mediated by NLRP3 expression, play a key role in memory consolidation.