Synthesis of Trifluoromethylated Alkenes: Hypervalent Iodine Meets High-Valent Copper.

The first trifluoromethylation of vinylbenziodoxolones (VBX) is reported herein. The synthetic method is based on the use of bench-stable, high-valent copper(III) species, and the reaction can be initiated under thermal conditions and/or irradiation (365 nm) giving access to trifluoromethylated alkenes in a stereoselective fashion. Various VBX reagents derived from tyrosine, cysteine, small peptides, thiols and amides can be used as precursors. The obtained alkenes could be further functionalized by reduction or epoxidation of the trifluoromethylated double bond. Furthermore, the method could be applied in a large-scale batch/flow synthesis and could be conducted under visible light irradiation.

Endovascular Thrombectomy for Pediatric Acute Ischemic Stroke.

BACKGROUND: Evidence regarding the utilization and outcomes of endovascular thrombectomy (EVT) for pediatric ischemic stroke is limited, and justification for its use is largely based on extrapolation from clinical benefits observed in adults. METHODS: Weighted discharge data from the National Inpatient Sample were queried to identify pediatric patients with ischemic stroke (<18 years old) during the period of 2010 to 2019. Complex samples statistical methods were used to characterize the profiles and clinical outcomes of EVT-treated patients. Propensity adjustment was performed to address confounding by indication for EVT based on disparities in baseline characteristics between EVT-treated patients and those medically managed. RESULTS: Among 7365 pediatric patients with ischemic stroke identified, 190 (2.6%) were treated with EVT. Utilization significantly increased in the post-EVT clinical trial era (2016-2019; 1.7% versus 4.0%; P<0.001), while the use of decompressive hemicraniectomy decreased (2.8% versus 0.7%; P<0.001). On unadjusted analysis, 105 (55.3%) EVT-treated patients achieved favorable functional outcomes at discharge (home or to acute rehabilitation), while no periprocedural iatrogenic complications or instances of contrast-induced kidney injury were reported. Following propensity adjustment, EVT-treated patients demonstrated higher absolute but nonsignificant rates of favorable functional outcomes in comparison with medically managed patients (55.3% versus 52.8%; P=0.830; adjusted hazard ratio, 1.01 [95% CI, 0.51-2.03]; P=0.972 for unfavorable outcome). Among patients with baseline National Institutes of Health Stroke Scale score >11 (75th percentile of scores in cohort), EVT-treated patients trended toward higher rates of favorable functional outcomes compared with those treated medically only (71.4% versus 55.6%; P=0.146). In a subcohort assessment of EVT-treated patients, those administered preceding thrombolytic therapy (n=79, 41.6%) trended toward higher rates of favorable functional outcomes (63.3% versus 49.5%; P=0.060). CONCLUSIONS: This cross-sectional evaluation of the clinical course and short-term outcomes of pediatric patients with ischemic stroke treated with EVT demonstrates that EVT is likely a safe modality which confers high rates of favorable functional outcomes.

Radiation-induced spinal cord glioblastoma subsequent to treatment of medulloblastoma: case report.

Medulloblastomas are one of the most common malignant pediatric brain tumors. Therapy has evolved into multimodality treatments consisting of surgery, radiation, and adjuvant chemotherapy. While craniospinal radiation remains standard for patients older than 3 years of age, it is not free of side effects and long-term complications. The development of malignant gliomas following therapy is a well-documented phenomenon. However, the majority of these radiation-induced glioblastomas (RIG) are intracranial, and intraspinal lesions are rare. The patient is a 22-year-old female with a history of a posterior fossa medulloblastoma diagnosed 8 years prior for which she underwent surgical resection followed by adjuvant chemotherapy and craniospinal radiation. Surveillance imaging showed no evidence of recurrence or new lesions for the following 5 years. She presented with nausea and vomiting and imaging revealing a new intramedullary cervical spinal cord lesion. She then developed acute quadriplegia several days after presentation. She underwent a cervical laminectomy and resection of this lesion, which was initially diagnosed as recurrent medulloblastoma before genomic analysis ultimately revealed it to be a RIG. Spinal RIGs that occur secondary to treatment for an intracranial neoplasm are exceedingly rare. The majority of spinal cord RIGs have been reported secondary to treatment for tumors outside of the neuroaxis, while the majority of RIGs secondary to treatment for intracranial tumors remain intracranial. Nevertheless, RIGs are associated with a short clinical history, aggressive progression, and poor outcome.

Porencephalic cyst after endoscopic third ventriculostomy and Ommaya reservoir placement: case report and review of the literature.

BACKGROUND: A 13-year-old female patient was diagnosed with a tectal glioma (TG), a subgroup of astrocytoma that can result in obstructive hydrocephalus secondary to aqueductal stenosis. Endoscopic third ventriculostomy (ETV) is used to treat this type of hydrocephalus with a good success rate. Our institution performs ETV and Ommaya reservoir (OR) placement in these cases. The OR allows measurement of intracranial pressure (ICP) and cerebrospinal fluid (CSF) access and a method for performing ventricular dye studies to evaluate third ventricular stoma (TVS) patency. In this case, a porencephalic cyst (PC) developed around the OR's ventricular catheter (OVC) two and a half months after surgery. CONCLUSION: The PC is thought to have developed in association with TVS stoma closure and resolved after ETV revision.

Decompressive craniectomy with scalp expansion graft using a temporary synthetic skin substitute in the pediatric population: case series and review of the literature.

INTRODUCTION: The use of decompressive craniectomy in children is controversial and often reserved for patients with refractory intracranial hypertension. Following decompression, skin closure in select cases can be challenging due to brain herniation and swelling through the craniectomy defect. In these cases, partial cortical debridement is sometimes performed. METHODS: We describe two cases in which a synthetic skin substitute was used to facilitate a tension-free closure, rather than performing a partial lobectomy. RESULTS: At 6-month follow-up, both patients are at preoperative cognitive baseline, with some residual hemiparesis. DISCUSSION: We believe that use of a synthetic skin substitute for skin closure after decompression is a suitable option for closure of traumatic scalp wounds and may contribute to improved functional outcome in patients with severe intraoperative brain swelling.

Recruitment of non-perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m.

KEY POINTS: A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries. In the present study, we report that high altitude-induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance. Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude-related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis. The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. ABSTRACT: A high altitude (HA) stay is associated with an increase in sublingual capillary total vessel density (TVD), suggesting microvascular recruitment. We hypothesized that microvascular recruitment occurs independent of cardiac output changes, that it relies on haemodynamic changes within the microcirculation as opposed to structural changes and that microcirculatory function is related to individual performance at HA. In 41 healthy subjects, sublingual handheld vital microscopy and echocardiography were performed at sea level (SL), as well as at 6022 m (C2) and 7042 m (C3), during ascent to 7126 m within 21 days. Sublingual topical nitroglycerin was applied to measure microvascular reactivity and maximum recruitable TVD (TVDNG ). HA exposure decreased resting cardiac output, whereas TVD (mean ± SD) increased from 18.81 ± 3.92 to 20.92 ± 3.66 and 21.25 ± 2.27 mm mm-2 (P < 0.01). The difference between TVD and TVDNG was 2.28 ± 4.59 mm mm-2 at SL (P < 0.01) but remained undetectable at HA. Maximal TVDNG was observed at C3. Those who reached the summit (n = 15) demonstrated higher TVD at SL (P < 0.01), comparable to TVDNG in non-summiters (n = 21) at SL and in both groups at C2. Recruitment of sublingual capillary TVD to increase microcirculatory oxygen extraction capacity at HA was found to be an intrinsic mechanism of the microcirculation independent of cardiac output changes. Microvascular reactivity to topical nitroglycerin demonstrated that HA-related capillary recruitment is a functional response as opposed to a structural change. The performance of the vascular microcirculation needed to reach the summit was found to be associated with a higher TVD at SL and the ability to further increase TVDNG upon ascent to extreme altitude.

Interactions of inbreeding and stress by poor host quality in a root hemiparasite.

BACKGROUND AND AIMS: Populations of many hemiparasitic plants are fragmented and threatened by inbreeding depression (ID). In addition, they may also be strongly affected by a lack of suitable host species. However, nothing is known about possible interactive effects of inbreeding and host quality for parasitic plants. Poor host quality represents a special type of biotic stress and the magnitude of ID is often expected to be higher in more stressful environments. METHODS: We studied the effects of inbreeding and the quality of host species for the declining root hemiparasite Rhinanthus alectorolophus Selfed and open-pollinated parasites from two natural populations were grown (1) with 13 potential host species and (2) with 15 four-species mixtures. KEY RESULTS: ID differed among host species and mixtures. In the first experiment, ID was highest in parasites grown with good hosts and declined with stress intensity. In the second experiment, ID was not influenced by stress intensity, but was highest in mixtures of hosts from only one functional group and lowest in mixtures containing three functional groups. Both parasite performance with individual host species and the damage to these host species differed between parasites from the two study populations. CONCLUSIONS: Our results contradict the common assumption that ID is generally higher in more stressful environments. In addition, they support the importance of diverse host communities for hemiparasitic plants. The differences in host quality between the two parasite populations indicate genetic variation in the adaptation to individual hosts and in host-specific virulence. However, inbreeding did not affect specific host-parasite interactions.

Total Synthesis and Biological Assessment of Mandelalide†A.

A new convergent total synthesis of the marine macrolide mandelalide A (1) has been developed that is based on macrocyclic ring closure by a Shiina-type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross-coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid-catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the α- and ß-AD-mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A (1) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK-N-SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 µm).

R-vine models for spatial time series with an application to daily mean temperature.

We introduce an extension of R-vine copula models to allow for spatial dependencies and model based prediction at unobserved locations. The proposed spatial R-vine model combines the flexibility of vine copulas with the classical geostatistical idea of modeling spatial dependencies using the distances between the variable locations. In particular, the model is able to capture non-Gaussian spatial dependencies. To develop and illustrate our approach, we consider daily mean temperature data observed at 54 monitoring stations in Germany. We identify relationships between the vine copula parameters and the station distances and exploit these in order to reduce the huge number of parameters needed to parametrize a 54-dimensional R-vine model fitted to the data. The new distance based model parametrization results in a distinct reduction in the number of parameters and makes parameter estimation and prediction at unobserved locations feasible. The prediction capabilities are validated using adequate scoring techniques, showing a better performance of the spatial R-vine copula model compared to a Gaussian spatial model.

AutoBioTech─A Versatile Biofoundry for Automated Strain Engineering.

The inevitable transition from petrochemical production processes to renewable alternatives has sparked the emergence of biofoundries in recent years. Manual engineering of microbes will not be sufficient to meet the ever-increasing demand for novel producer strains. Here we describe the AutoBioTech platform, a fully automated laboratory system with 14 devices to perform operations for strain construction without human interaction. Using modular workflows, this platform enables automated transformations of Escherichia coli with plasmids assembled via modular cloning. A CRISPR/Cas9 toolbox compatible with existing modular cloning frameworks allows automated and flexible genome editing of E. coli. In addition, novel workflows have been established for the fully automated transformation of the Gram-positive model organism Corynebacterium glutamicum by conjugation and electroporation, with the latter proving to be the more robust technique. Overall, the AutoBioTech platform excels at versatility due to the modularity of workflows and seamless transitions between modules. This will accelerate strain engineering of Gram-negative and Gram-positive bacteria.

Hemorrhagic ganglioglioma of the posterior fossa: case report.

Gangliogliomas are rare tumors of the central nervous system that are usually found in the supratentorial compartment, although cases throughout the nervous system have been described. They are generally low-grade malignancies that are amenable to cure by surgical resection. Most manifest as seizures, though, based on location, they can present with focal neurological deficits. We present here a rare case of an infratentorial ganglioglioma presenting with hemorrhage. To our knowledge this is the only reported case of a hemorrhagic ganglioglioma and, as such, we examine its possible prognosis.

Treatment of an Elusive Symptomatic Sinus Pericranii: Case Report and Review of the Literature.

Sinus pericranii (SP) are abnormal vascular connections between extracranial scalp venous channels and intracranial dural sinuses. This vascular abnormality rarely results in significant sequelae, but in select cases, it can be symptomatic. We describe the case of a 7-year-old girl with an SP who experienced intermittent visual, motor, and sensory symptoms not previously described in the literature. Her symptoms resolved after surgical treatment of the SP. We propose a mechanism for her symptoms and the rationale for the role of neurosurgical intervention along with a review of the literature.

Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma.

Aberrant signaling of mechanistic target of rapamycin (mTOR aka mammalian target of rapamycin) is shown to be linked to tumorigenesis of numerous malignancies including glioblastoma (GB). mTOR is a serine threonine kinase that functions by forming two multiprotein complexes. These complexes are named mTORC1 and mTORC2 and activate downstream substrates that execute cellular and metabolic functions. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Since rapamycin and its analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. Torin2 caused a concentration dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6KSer235/236 and 4E-BP1Thr37/46 as well as the mTORC2 substrate AKTSer473 resulting in suppression of tumor cell proliferation and migration. Torin1 showed similar effects only at higher doses. Another small molecule compound, XL388 suppressed cell proliferation at a higher dose but failed to inhibit cell migration. Torin1 suppressed phosphorylation of PRAS40Thr246, however, Torin2 completely abolished it. XL388 treatment inhibited the phosphorylation of PRAS40Thr246 at higher doses only. These findings underscore the use of novel compounds in treatment of cancer. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways.

Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions.

Medulloblastoma (MB) is the most common malignant pediatric posterior fossa tumor. Recent genetic, epigenetic, and transcriptomic analyses have classified MB into three subgroups, Wingless Type (WNT), Sonic Hedgehog (SHH), and non-WNT/non-SHH (originally termed Group 3 and Group 4), with discrete patient profiles and prognoses. WNT is the least common subgroup with the best prognosis, characterized by nuclear ß-catenin expression, mutations in Catenin beta-1 (CTNNB1), and chromosome 6 monosomy. SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway. Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor. However, recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations. The third non-WNT/non-SHH MB (Group3/4) subgroup is genetically highly heterogeneous and displays several molecular patterns, including MYC and OTX2 amplification, GFI1B activation, KBTBD4 mutation, GFI1 rearrangement, PRDM6 enhancer hijacking, KDM6A mutation, LCA histology, chromosome 10 loss, isochromosome 17q, SNCAIP duplication, and CDK6 amplification. However, based on molecular profiling and methylation patterns, additional non-WNT/non-SHH MB subtypes have been described. Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively. In this review, we discuss advancements in genetics, epigenetics, and transcriptomics for better characterization, prognostication, and treatment of MB using precision medicine.

Responsive Neurostimulation Targeting the Anterior, Centromedian and Pulvinar Thalamic Nuclei and the Detection of Electrographic Seizures in Pediatric and Young Adult Patients.

Background: Responsive neurostimulation (RNS System) has been utilized as a treatment for intractable epilepsy. The RNS System delivers stimulation in response to detected abnormal activity, via leads covering the seizure foci, in response to detections of predefined epileptiform activity with the goal of decreasing seizure frequency and severity. While thalamic leads are often implanted in combination with cortical strip leads, implantation and stimulation with bilateral thalamic leads alone is less common, and the ability to detect electrographic seizures using RNS System thalamic leads is uncertain. Objective: The present study retrospectively evaluated fourteen patients with RNS System depth leads implanted in the thalamus, with or without concomitant implantation of cortical strip leads, to determine the ability to detect electrographic seizures in the thalamus. Detailed patient presentations and lead trajectories were reviewed alongside electroencephalographic (ECoG) analyses. Results: Anterior nucleus thalamic (ANT) leads, whether bilateral or unilateral and combined with a cortical strip lead, successfully detected and terminated epileptiform activity, as demonstrated by Cases 2 and 3. Similarly, bilateral centromedian thalamic (CMT) leads or a combination of one centromedian thalamic alongside a cortical strip lead also demonstrated the ability to detect electrographic seizures as seen in Cases 6 and 9. Bilateral pulvinar leads likewise produced reliable seizure detection in Patient 14. Detections of electrographic seizures in thalamic nuclei did not appear to be affected by whether the patient was pediatric or adult at the time of RNS System implantation. Sole thalamic leads paralleled the combination of thalamic and cortical strip leads in terms of preventing the propagation of electrographic seizures. Conclusion: Thalamic nuclei present a promising target for detection and stimulation via the RNS System for seizures with multifocal or generalized onsets. These areas provide a modifiable, reversible therapeutic option for patients who are not candidates for surgical resection or ablation.

Non-Operative Management of a Pediatric Patient With Bilateral Subdural Hematomas in the Setting of Ruptured Arachnoid Cyst.

Pediatric subdural hematomas (SDH) are associated with arachnoid cysts (AC), particularly in the middle cranial fossa (MCF). Operative management of these hemorrhages is a mainstay of treatment. Conservative management may be an option if there is minimal mass effect and the patient is mildly symptomatic. A 14-year-old male presented with right frontal headaches that worsened with activity. He was found to have a large right MCF AC. Scheduled routine outpatient follow-up CT of the head demonstrated bilateral SDH. There was no history of significant head trauma. He was admitted for close observation and his inpatient scans remained stable. Outpatient follow-up imaging over the course of three and a half years demonstrated resolution of SDH and decreased AC size. He denied headaches and continued doing well in school. ACs are a risk factor for the development of SDH in young male patients after minor trauma. Development of intracranial hypotension secondary to AC rupture may have contributed to the development of bilateral SDH in our patient. We demonstrate here that close clinical follow up with serial imaging may be considered a management strategy in these patients.

Temporal variation of induction neurogenesis in a rat model of transient middle cerebral artery occlusion.

OBJECTIVE: The adult brain is capable of neurogenesis after cerebral ischemia. We investigated the presence of new neural precursors after transient middle cerebral artery ischemia adult rats. METHODS: Transient middle cerebral artery ischemia was induced in adult Wistar rats (n=13) using the monofilament method. In the experimental group (n=8), animals were harvested at days 3, 7, 10, 17 and 21 after ischemia. Five animals served as controls. Sagittal sections through the ischemic cortex were double-stained for neural (nestin and beta-tubulin, nestin and PCNA), glial (nestin and GFAP) and oligodendroglial (nestin and O4, CNP and PCNA) precursors. Double-stained cells were also counted under high-power view and tabulated over time. RESULTS: In the subventricular zone (SVZ), there was positive double-staining starting at day 3 showing proliferating astrocytic precursors (nestin + GFAP, 5-20% of cells), neuronal stem cells (nestin + PCNA, 95% of cells) and neuronal precursors (nestin + beta-tubulin, 50% of cells). Within the penumbra, a more robust response showed more astrocytic precursors (50-80% of cells), premature and differentiated oligodendrocytes, neuronal stem cells (85% of cells) and neuronal precursors (15% of cells). In the area of the stroke, there was an intermediate response consisting of more astrocytic precursors (10-20% of cells), premature oligodendrocytes (45-100% of cells), neuronal stem cells (95% of cells) and neuronal precursors (25% of cells). Results were confirmed with cell counting analysis. DISCUSSION: Our results show that not only do neural precursors proliferate in the SVZ, there is definite and real response in the penumbra and ischemic cortex, suggesting the ability of repair in the central nervous system.

Bone Overgrowth Causing Proximal Ventriculoperitoneal Shunt Malfunction.

BACKGROUND: Hydrocephalus is an international disease process that is commonly treated surgically with a ventriculoperitoneal shunt. This device may be prone to malfunction, most commonly from obstruction, disconnection, or infection. CASE DESCRIPTION: A 35-year-old female with hydrocephalus and a ventriculoperitoneal shunt presented with altered mental status and imaging concerning for a shunt malfunction. Intraoperatively, she was found to have bone growing over and compressing the proximal occluder of the shunt valve, causing a mechanical obstruction. Removal of the bone allowed for egress of cerebrospinal fluid and return of proper shunt function. The patient did well postoperatively. CONCLUSION: Hydrocephalus, ventriculoperitoneal shunts, and shunt revisions represent a significant health burden and cost. Here we present an unusual cause of a shunt malfunction caused by bony overgrowth.

An unusual case of hemophagocytic lymphohistiocytosis diagnosed by spinal nerve root biopsy.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease process characterized by aberrant immune system activation and an exaggerated inflammatory response. Establishing the diagnosis may be challenging and is achieved by satisfying a number of clinical criteria, in addition to demonstrating tissue hemophagocytosis. This syndrome is rapidly fatal if prompt diagnosis and treatment are not achieved. The authors present the case of a 17-year-old male patient with CNS HLH involving both the brain and spinal cord, highlighting the variable CNS manifestations in pediatric patients with HLH and the challenges that accompany establishing diagnosis.