Intra-operative extracorporeal irradiation of tumour-invaded craniotomy bone flap in meningioma: a case series.

BACKGROUND: Extracorporeal irradiation of tumorous calvaria (EITC) can be performed to restore function and form of the skull after resection of bone-invasive meningioma. We sought to examine the rate of tumour recurrence and other selected outcomes in patients undergoing meningioma resection and EITC. METHODS: Retrospective single-centre study of adult patients undergoing meningioma resection and EITC between January 2015 and November 2022 at a tertiary neurosurgical centre. Patient demographics, surgery data, tumour data, use of adjuvant therapy, surgical complications, and tumour recurrences were collected. RESULTS: Eighteen patients with 11 (61%) CNS WHO grade 1, 6 (33%) grade 2, and 1 (6%) grade 3 meningiomas were included. Median follow-up was 42 months (range 3-88). Five (28%) patients had a recurrence, but none were associated with the bone flap. Two (11%) wound infections requiring explant surgery occurred. Six (33%) patients required a further operation. Two operations were for recurrences, one was for infection, one was a washout and wound exploration but no evidence of infection was found, one patient requested the removal of a small titanium implant, and one patient required a ventriculoperitoneal shunt for a persistent CSF collection. There were no cases of bone flap resorption and cosmetic outcome was not routinely recorded. CONCLUSION: EITC is feasible and fast to perform with good outcomes and cost-effectiveness compared to other reconstructive methods. We observed similar recurrence rates and lower infection rates requiring explant compared to the largest series of cranioplasty in meningioma. Cosmetic outcome is universally under-reported and should be reported in future studies.

Bipyridinium and Phenanthrolinium Dications for Metal-Free Hydrodefluorination: Distinctive Carbon-Based Reactivity.

The development of novel Lewis acids derived from bipyridinium and phenanthrolinium dications is reported. Calculations of Hydride Ion Affinity (HIA) values indicate high carbon-based Lewis acidity at the ortho and para positions. This arises in part from extensive LUMO delocalization across the aromatic backbones. Species [C10 H6 R2 N2 CH2 CH2 ]2+ (R=H [1 a]2+ , Me [1 f]2+ , tBu [1 g]2+ ), and [C12 H4 R4 N2 CH2 CH2 ]2+ (R=H [2 a]2+ , Me [2 b]2+ ) were prepared and evaluated for use in the initiation of hydrodefluorination (HDF) catalysis. Compound [2 a]2+ proved highly effective towards generating catalytically active silylium cations via Lewis acid-mediated hydride abstraction from silane. This enabled the HDF of a range of aryl- and alkyl- substituted sp3 (C-F) bonds under mild conditions. The protocol was also adapted to effect the deuterodefluorination of cis-2,4,6-(CF3 )3 C6 H9 . The dications are shown to act as hydride acceptors with the isolation of neutral species C16 H14 N2 (3 a) and C16 H10 Me4 N2 (3 b) and monocationic species [C14 H13 N2 ]+ ([4 a]+ ) and [C18 H21 N2 ]+ ([4 b]+ ). Experimental and computational data provide further support that the dications are initiators in the generation of silylium cations.

Synthesis of Fluorinated Aminoalkylboronic Acids from Amphoteric α-Boryl Aldehydes.

Our ongoing search for underdeveloped functional group combinations has brought to light α-fluorinated aminoalkylboronic acids, a new class of molecules featuring the B-CF linkage. These compounds can now be generated from secondary amines and α-boryl aldehydes through electrophilic fluorination of boryl enamines or enamides. Fluorinated ß-aminoalkylboronic acids show no signs of degradation under ambient conditions. We present evidence for the involvement of chair-like motifs, favored over the acyclic forms by up to 1.7±0.1 kcal mol-1 in water and held together by an amine-boronate hydrogen bond. Fluorinated ß-aminoalkylboronic acids are stable over a wide pH range and are characterized by a pKa of 3.4, which is the lowest of any alkylboronic acid.

Synthesis of Urea Derivatives from CO2 and Silylamines.

A series of thirty-three N,N'-diaryl, dialkyl, and alkyl-aryl ureas have been prepared in pyridine or toluene by reaction of silylamines with CO2 . This protocol is shown to provide facile access to 13 C-labeled ureas, as well as chiral and macrocyclic ureas. These reactions proceed through initial generation of the corresponding silylcarbamates, which subsequently react with silylamine under thermal conditions to afford the thermodynamically favored urea and disilyl ether.

Enantioselective Intramolecular Copper-Catalyzed Borylacylation.

An enantioselective copper-catalyzed intramolecular borylacylation is reported. The reaction proceeds through an initial enantioselective borylcupration of the styrene, followed by a nucleophilic attack on the tethered carbamoyl chloride. The products, chiral borylated 3,3-disubstituted oxindoles, were generated in excellent yields and enantioselectivities. The versatile carbon-boron bond provides a platform for a wide array of diversification.

Rhythmic Trafficking of TRPV2 in the Suprachiasmatic Nucleus is Regulated by Prokineticin 2 Signaling.

The mammalian circadian clock is composed of single-cell oscillators. Neurochemical and electrical signaling among these oscillators is important for the normal expression of circadian rhythms. Prokineticin 2 (PK2), encoding a cysteine-rich secreted protein, has been shown to be a critical signaling molecule for the regulation of circadian rhythms. PK2 expression in the suprachiasmatic nucleus (SCN) is highly rhythmic, peaking during the day and being essentially absent during the night. Mice with disrupted PK2 gene or its receptor PKR2 display greatly reduced rhythmicity of broad circadian parameters such as locomotor activity, body temperature and sleep/wake patterns. PK2 has been shown to increase the firing rate of SCN neurons, with unknown molecular mechanisms. Here we report that TRPV2, an ion channel belonging to the family of TRP, is co-expressed with PKR2 in the SCN neurons. Further, TRPV2 protein, but not TRPV2 mRNA, was shown to oscillate in the SCN in a PK2-dependent manner. Functional studies revealed that TRPV2 enhanced signaling of PKR2 in calcium mobilization or ion current conductance, likely via the increased trafficking of TRPV2 to the cell surface. Taken together, these results indicate that TRPV2 is likely part of the downstream signaling of PK2 in the regulation of the circadian rhythms.

Shame if you do--shame if you don't: women's experiences of infant feeding.

Emotions such as guilt and blame are frequently reported by non-breastfeeding mothers, and fear and humiliation are experienced by breastfeeding mothers when feeding in a public context. In this paper, we present new insights into how shame-related affects, cognitions and actions are evident within breastfeeding and non-breastfeeding women's narratives of their experiences. As part of an evaluation study of the implementation of the UNICEF UK Baby Friendly Initiative Community Award within two primary (community based) care trusts in North West England, 63 women with varied infant feeding experiences took part in either a focus group or an individual semi-structured interview to explore their experiences, opinions and perceptions of infant feeding. Using a framework analysis approach and drawing on Lazare's categories of shame, we consider how the nature of the event (infant feeding) and the vulnerability of the individual (mother) interact in the social context to create shame responses in some breastfeeding and non-breastfeeding mothers. Three key themes illustrate how shame is experienced and internalised through 'exposure of women's bodies and infant feeding methods', 'undermining and insufficient support' and 'perceptions of inadequate mothering'. The findings of this paper highlight how breastfeeding and non-breastfeeding women may experience judgement and condemnation in interactions with health professionals as well as within community contexts, leading to feelings of failure, inadequacy and isolation. There is a need for strategies and support that address personal, cultural, ideological and structural constraints of infant feeding.

A Prospective Study of Longitudinal Risks of Cognitive Deficit for People Undergoing Glioblastoma Surgery Using a Tablet Computer Cognition Testing Battery: Towards Personalized Understanding of Risks to Cognitive Function.

Glioblastoma and the surgery to remove it pose high risks to the cognitive function of patients. Little reliable data exist about these risks, especially postoperatively before radiotherapy. We hypothesized that cognitive deficit risks detected before surgery will be exacerbated by surgery in patients with glioblastoma undergoing maximal treatment regimens. We used longitudinal electronic cognitive testing perioperatively to perform a prospective, longitudinal, observational study of 49 participants with glioblastoma undergoing surgery. Before surgery (A1), the participant risk of deficit in 5/6 cognitive domains was increased compared to normative data. Of these, the risks to Attention (OR = 31.19), Memory (OR = 97.38), and Perception (OR = 213.75) were markedly increased. These risks significantly increased in the early period after surgery (A2) when patients were discharged home or seen in the clinic to discuss histology results. For participants tested at 4-6 weeks after surgery (A3) before starting radiotherapy, there was evidence of risk reduction towards A1. The observed risks of cognitive deficit were independent of patient-specific, tumour-specific, and surgery-specific co-variates. These results reveal a timeframe of natural recovery in the first 4-6 weeks after surgery based on personalized deficit profiles for each participant. Future research in this period could investigate personalized rehabilitation tools to aid the recovery process found.

The opportunity costs of caring for people with dementia in Southern Spain.

OBJECTIVE: The aim of this paper is to study the opportunity costs (OC) that are involved in being a caregiver and to compare them with the direct costs assumed by the State and the families. We evaluate direct cost (those that imply a payment-out-of-pocket) and indirect cost (those that imply a dedication in time). We hypothesized that costs increase with the severity of the dementia, with the educational level and active occupational situation of caregiver. They are greater if the caregiver is male, but if the patient and caregiver cohabit they are reduced. METHOD: 778 surveys were analyzed. Data was collected using a questionnaire specifically designed for the purpose, with the collaboration of Alzheimer's Diseases Associations in Andalusia (Spain). For the indirect cost, we used the reveal preferences method. For the comparison between groups an ANOVA and a MANOVA was done. RESULTS: The hypotheses were confirmed. The OC exponentially increases with severity. More than 55% of costs are assumed by families. Occupied people have higher educational level and incomes and contract more external support. Costs are significantly higher for male caregivers. Cohabiting reduces all kinds of costs. CONCLUSIONS: The relationship between educational level and employment situation lead to think that if these variables are greater more people will seek professional support. Cultural reasons still maintain women as main caregivers for all educational levels. The existence of these informal caregivers as the main care providers is a saving for the State, and a brake for the development of professional supply.

Palladium-Catalyzed Hydride Addition/C-H Bond Activation Cascade: Cycloisomerization of 1,6-Diynes.

The use of ammonium halide salts as metal hydride precursors in a new Pd-catalyzed cycloisomerization of 1,6-diynes, which affords unexplored silylated 2-azafluorenes, is reported. This cascade process includes the addition of a Pd-hydride species to a π-system, intramolecular carbopalladation, and C(sp2)-H bond activation. A variety of functional groups are tolerated, and the synthetic utility of the resulting products has been demonstrated by a series of derivatizations.

Expression of prokineticin 2 and its receptor in the macaque monkey brain.

Prokineticin 2 (PK2) has been indicated as an output signaling molecule for the suprachiasmatic nucleus (SCN) circadian clock. Most of these studies were performed with nocturnal animals, particularly mice and rats. In the current study, the PK2 and its receptor, PKR2, was cloned from a species of diurnal macaque monkey. The macaque monkey PK2 and PKR2 were found to be highly homologous to that of other mammalian species. The mRNA expression of PK2 and PKR2 in the macaque brain was examined by in situ hybridization. The expression patterns of PK2 and PKR2 in the macaque brain were found to be quite similar to that of the mouse brain. Particularly, PK2 mRNA was shown to oscillate in the SCN of the macaque brain in the same phase and with similar amplitude with that of nocturnal mouse brain. PKR2 expression was also detected in known primary SCN targets, including the midline thalamic and hypothalamic nuclei. In addition, we detected the expression of PKR2 mRNA in the dorsal raphe nucleus (DR) of both macaque and mouse brains. As a likely SCN to dorsal raphe projection has previously been indicated, the expression of PKR2 in the raphe nuclei of both macaque and mouse brain signifies a possible role of DR as a previously unrecognized primary SCN projection target.

Differential arousal regulation by prokineticin 2 signaling in the nocturnal mouse and the diurnal monkey.

The temporal organization of activity/rest or sleep/wake rhythms for mammals is regulated by the interaction of light/dark cycle and circadian clocks. The neural and molecular mechanisms that confine the active phase to either day or night period for the diurnal and the nocturnal mammals are unclear. Here we report that prokineticin 2, previously shown as a circadian clock output molecule, is expressed in the intrinsically photosensitive retinal ganglion cells, and the expression of prokineticin 2 in the intrinsically photosensitive retinal ganglion cells is oscillatory in a clock-dependent manner. We further show that the prokineticin 2 signaling is required for the activity and arousal suppression by light in the mouse. Between the nocturnal mouse and the diurnal monkey, a signaling receptor for prokineticin 2 is differentially expressed in the retinorecipient suprachiasmatic nucleus and the superior colliculus, brain projection targets of the intrinsically photosensitive retinal ganglion cells. Blockade with a selective antagonist reveals the respectively inhibitory and stimulatory effect of prokineticin 2 signaling on the arousal levels for the nocturnal mouse and the diurnal monkey. Thus, the mammalian diurnality or nocturnality is likely determined by the differential signaling of prokineticin 2 from the intrinsically photosensitive retinal ganglion cells onto their retinorecipient brain targets.

Short term arterial remodelling in the aortae of cholesterol fed New Zealand white rabbits shown in vivo by high-resolution magnetic resonance imaging - implications for human pathology.

High-resolution, non-invasive imaging methods are required to monitor progression and regression of atherosclerotic plaques. We investigated the use of MRI to measure changes in plaque volume and vessel remodelling during progression and regression of atherosclerosis in New Zealand White rabbits. Atherosclerotic lesions were induced in the abdominal aorta by balloon injury and cholesterol feeding. MR images (2D) of the abdominal aorta were acquired with cardiac and respiratory gating using a fast spin echo sequence with and without fat-suppression. In an initial study on rabbits treated for 30 weeks we imaged the aortae with a spatial resolution of 250x250 micrometers with a slice thickness of 2 mm and achieved a close correlation between MRI-derived measurements and those made on perfusion pressure-fixed histological sections (r(1) = 0.83, slope p(1) < 0.01). We subsequently imaged 18 rabbits before and periodically during 12 weeks of cholesterol feeding (progression) followed by 12 weeks on normal diet (regression). Aortic wall (atherosclerotic lesion) volume increased significantly during progression and decreased during regression. In contrast, lumen volume increased during progression and did not change during regression. In conclusion, this study confirms that non-invasive, high-resolution MRI can be used to monitor progression and regression of atherosclerosis, each within 3 months and shows, for the first time in a short-term model, that positive remodelling occurs early during progression and persists through regression of atherosclerotic lesions.

Surgical management of vestibular schwannomas and hearing rehabilitation in neurofibromatosis type 2.

OBJECTIVES: To report our approach to the surgical management of vestibular schwannomas (VSs) and hearing rehabilitation in neurofibromatosis Type 2 (NF2). DESIGN: Retrospective cohort study. SETTING: Tertiary referral NF2 unit. PATIENTS: Between 1981 and 2011, seventy-five patients were managed in our NF2 unit, of which, 58 patients are under current review. MAIN OUTCOME MEASURES: Patients who underwent VS excision were evaluated for tumor size, surgical approach, and outcomes of hearing and facial nerve function. All current patients were evaluated for NF2 mutation, hearing, and auditory implantation outcomes. RESULTS: Forty-four patients underwent resection of 50 VS in our unit, of which, 14% had facial neuroma excision and reinnervation during the same operation. At 12 months after surgery, facial nerve outcomes were House-Brackmann (HB) 1 in 33%, HB2 in 21%, and HB3 in 30%. Total VS resection was achieved in 78% of patients using a translabyrinthine approach. Seventy-two percent of the current patients have American Association of Otolaryngology-Head and Neck Surgery class A to C hearing (maximum speech discrimination score over 50%) in the better hearing ear, and a further 14% are full-time users of cochlear implants or auditory brainstem implants. The remaining patients have been assessed for auditory implantation. CONCLUSION: By following a policy of treating VS in NF2 patients where tumor growth is observed, complete tumor resection can be achieved through a translabyrinthine approach while achieving comparable facial nerve outcomes to published series. We advocate proactive hearing rehabilitation in all patients with timely assessment for auditory implantation to maintain quality of life.

Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei.

The suprachiasmatic nuclei (SCN) serve as the principal circadian pacemakers that coordinate daily cycles of behavior and physiology for mammals. A network of transcriptional and translational feedback loops underlies the operating molecular mechanism for circadian oscillation within the SCN neurons. It remains unclear how timing information is transmitted from SCN neurons to eventually evoke circadian rhythms. Intercellular communication between the SCN and its target neurons is critical for the generation of coherent circadian rhythms. At the molecular level, neuropeptides encoded by clock-controlled genes have been indicated as important output mediators. Arginine vasopressin (AVP) is the product of one such clock-controlled gene. Previous studies have demonstrated a circadian rhythm of AVP levels in the cerebrospinal fluid and the SCN. The physiological effects of AVP are mediated by three types of AVP receptors, designated as V1a, V1b, and V2. In this study, we report that V1a mRNA levels displayed a circadian rhythm in the SCN, peaking during night hours. The circadian rhythmicity of locomotor activities was significantly reduced in V1a-deficient (V1a(-/-)) mice (50-75% reduction in the power of fast Fourier transformation). However, the light masking and light-induced phase shift effects are intact in V1a(-/-) mice. Whereas the expression of clock core genes was unaltered, the circadian amplitude of prokineticin 2 (PK2) mRNA oscillation was attenuated in the SCN of V1a(-/-) mice ( approximately 50% reduction in the peak levels). In vitro experiments demonstrated that AVP, acting through V1a receptor, was able to enhance the transcriptional activity of the PK2 promoter. These studies thus indicate that AVP-V1a signaling plays an important role in the generation of overt circadian rhythms.

Differential activation of "social" and "solitary" variants of the Caenorhabditis elegans G protein-coupled receptor NPR-1 by its cognate ligand AF9.

Natural variations of wild Caenorhabditis elegans isolates having either Phe-215 or Val-215 in NPR-1, a putative orphan neuropeptide Y-like G protein-coupled receptor, result in either "social" or "solitary" feeding behaviors (de Bono, M., and Bargmann, C. I. (1998) Cell 94, 679-689). We identified a nematode peptide, GLGPRPLRF-NH2 (AF9), as a ligand activating the cloned NPR-1 receptor heterologously expressed in mammalian cells. Shifting cell culture temperatures from 37 to 28 degrees C, implemented 24 h after transfections, was essential for detectable functional expression of NPR-1. AF9 treatments linked both cloned receptor variants to activation of Gi/Go proteins and cAMP inhibition, thus allowing for classification of NPR-1 as an inhibitory G protein-coupled receptor. The Val-215 receptor isoform displayed higher binding and functional activity than its Phe-215 counterpart. This finding parallels the in vivo observation of a more potent repression of social feeding by the npr-1 gene encoding the Val-215 form of the receptor, resulting in dispersing (solitary) animals. Since neuropeptide Y shows no sequence homology to AF9 and was functionally inactive at the cloned NPR-1, we propose to rename NPR-1 and refer to it as an AF9 receptor, AF9-R1.

Cloning and functional expression of the first Drosophila melanogaster sulfakinin receptor DSK-R1.

Described in this report is a successful cloning and characterization of a functionally active Drosophila sulfakinin receptor designated DSK-R1. When expressed in mammalian cells, DSK-R1 was activated by a sulfated, Met(7-->Leu(7)-substituted analog of drosulfakinin-1, FDDY(SO(3)H)GHLRF-NH(2) ([Leu(7)]-DSK-1S). The interaction of [Leu(7)]-DSK-1S with DSK-R1 led to a dose-dependent intracellular calcium increase with an EC(50) in the low nanomolar range. The observed Ca(2+) signal predominantly resulted from activation of pertussis toxin (PTX)-insensitive signaling pathways pointing most likely to G(q/11) involvement in coupling to the activated receptor. The unsulfated [Leu(7)]-DSK-1 was ca. 3000-fold less potent than its sulfated counterpart which stresses the importance of the sulfate moiety for the biological activity of drosulfakinin. The DSK-R1 was specific for the insect sulfakinin since two related vertebrate sulfated peptides, human CCK-8 and gastrin-II, were found inactive when tested at concentrations up to 10(-5) M. To our knowledge, the cloned DSK-R1 receptor is the first functionally active Drosophila sulfakinin receptor reported to date.