Customised pre-operative cranioplasty to achieve maximal surgical resection of tumours with osseous involvement-a case series.

PURPOSE: Surgical resection with bony margins would be the treatment of choice for tumours with osseous involvement such as meningiomas and metastasis. By developing and designing pre-operative customised 3D modelled implants, the patient can undergo resection of meningioma and repair of bone defect in the same operation. We present a generalisable method for designing pre-operative cranioplasty in patients to repair the bone defect after the resection of tumours. MATERIALS AND METHODS: We included six patients who presented with a tumour that was associated with overlying bone involvement. They underwent placement of customised cranioplasty in the same setting. A customised implant using a pre-operative imaging was designed with a 2-cm margin to allow for any intra-operative requirements for extending the craniectomy. RESULTS: Six patients were evaluated in this case series. Four patients had meningiomas, 1 patient had metastatic breast cancer on final histology, and 1 patient was found to have an intra-osseous arteriovenous malformation. Craniectomy based on margins provided by a cutting guide was fashioned. After tumour removal and haemostasis, the cranioplasty was then placed. All patients recovered well post-operatively with satisfactory cosmetic results. No wound infection was reported in our series. CONCLUSION: Our series demonstrate the feasibility of utilising pre-designed cranioplasty for meningiomas and other tumours with osseous involvement. Following strict infection protocols, minimal intra-operative handling/modification of the implant, and close follow-up has resulted in good cosmetic outcomes with no implant-related infections.

Impact of Hyperuricemia and Urate-Lowering Agents on Cardiovascular Diseases.

The association between hyperuricemia and cardiovascular diseases has been studied for many years. Research has shown a link between high uric acid levels and increased risk of including coronary artery disease hypertension and other cardiovascular conditions. Urate-lowering therapy, particularly with xanthine oxidase inhibitors like allopurinol, has shown promising results in reducing blood pressure in individuals with hyperuricemia and hypertension. Clinical trials and studies have demonstrated significant reductions in both systolic and diastolic blood pressure with urate-lowering treatment. Urate-lowering treatment has shown a favorable effect on reducing systolic blood pressure and major adverse cardiovascular events in patients with previous cardiovascular disease. In terms of cardiovascular safety, clinical trials have indicated that xanthine oxidase inhibitors such as febuxostat are non-inferior to allopurinol and do not increase the risk of death or serious adverse events. Overall, these findings highlight the importance of managing hyperuricemia and utilizing urate-lowering therapy to mitigate the adverse cardiovascular effects associated with elevated uric acid levels.

Pd-Catalyzed Cascade Heck/C(sp3)-H Activation for Spirocyclopropyl Oxindoles.

We have demonstrated a Pd(0)-catalyzed Heck/C(sp3)-H activation cascade for the synthesis of spirocyclopropyl oxindoles in high yields from easily accessible ortho-bromoacrylamides. The formation of spirocyclopropyl oxindole is guided by an unconventional four-membered palladacycle through C(sp3)-H activation. The reaction exhibits a wide range of substrate scope and operates efficiently with a mere 0.5 mol % of Pd-catalyst. In addition, the use of microwave conditions facilitates rapid completion of the reaction. Furthermore, this spirocyclopropanation strategy can be coupled with [3 + 2] cycloaddition to produce spiropyrrolidine oxindoles, offering a valuable approach for the preparation of alkaloids such as (±)-horsfiline and (±)-coerulescine.

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer's disease.

Maternal choline supplementation (MCS) improves cognition in Alzheimer's disease (AD) models. However, the effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated the effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice are generalized EEG spikes (interictal spikes [IIS]). IIS also are common in other mouse models and occur in AD patients. In mouse models, hyperexcitability is also reflected by elevated expression of the transcription factor ∆FosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. Therefore, we studied ΔFosB expression in GCs. We also studied the neuronal marker NeuN within hilar neurons of the DG because reduced NeuN protein expression is a sign of oxidative stress or other pathology. This is potentially important because hilar neurons regulate GC excitability. Tg2576 breeding pairs received a diet with a relatively low, intermediate, or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ∆FosB expression was reduced, and hilar NeuN expression was restored. Using the novel object location task, spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC ΔFosB protein expression. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB, and spatial memory in an animal model of AD.

Successful Extension of Vascularized Composite Allograft Perfusion Cold Storage to 24 h in a Rat Hindlimb Transplant Model.

Background: Vascularized composite allograft transplantation is a treatment option for complex tissue injuries; however, ischemia reperfusion injury and high acute rejection rates remain a challenge. Hypothermic machine perfusion using acellular storage perfusate is a potential solution. This study evaluated the University of Wisconsin Kidney Preservation Solution-1 (KPS-1) compared with normal saline (NS) for preservation of donor rat hindlimbs subjected to 24 h of ex vivo perfusion cold storage. Methods: Hindlimbs were subjected to 24-h perfusion cold storage with heparinized KPS-1 (n = 6) or heparinized NS (n = 6). Flow, resistance, and pH were measured continuously. At the end of the 24-h period, tissue was collected for histological analysis of edema and apoptosis. Results: KPS-1 perfused limbs showed significantly less edema than the NS group, as evidenced by lower limb weight gain (P < 0.001) and less interfascicular space (P < 0.001). KPS-perfused muscle had significantly less cell death than NS-perfused muscle based on terminal deoxynucleotidyl transferase dUTP nick-end labeling (P < 0.001) and cleaved caspase-3 staining (P = 0.045). During hypothermic machine perfusion, a significant decrease in pH over time was detected in both groups, with a significantly greater decline in pH in the KPS-1 group than in the NS group. There were no significant differences overall and over time in flow rate or vascular resistance between the KPS and NS groups. Conclusions: Perfusion with KPS-1 can successfully extend vascularized composite allograft perfusion cold storage for 24 h in a rat hindlimb model without significant edema or cell death.

Pleomorphic xanthoastrocytoma with NTRK fusion presenting as spontaneous intracranial hemorrhage-case report and literature review.

Background: Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that accounts for <1% of all gliomas. An in-depth understanding of PXA's molecular makeup remains a work in progress due to its limited numbers globally. Separately, spontaneous intracranial hemorrhage (pICH) is an uncommon but potentially devastating emergency in young children, often caused by vascular malformations or underlying hematological conditions. We describe an interesting case of a toddler who presented with pICH, later found to have a PXA as the underlying cause of hemorrhage. Further molecular interrogation of the tumor revealed a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and CDKN2A deletion more commonly seen in infantile high-grade gliomas. The unusual clinicopathological features of this case are discussed in corroboration with published literature. Case presentation: A previously well 2-year-old male presented with acute drowsiness and symptoms of increased intracranial pressure secondary to a large right frontoparietal intracerebral hematoma. He underwent an emergency craniotomy and partial evacuation of the hematoma for lifesaving measures. Follow-up neuroimaging reported a likely right intra-axial tumor with hemorrhagic components. Histology confirmed the tumor to be a PXA (WHO 2). Additional molecular investigations showed it was negative for BRAFV600E mutation but was positive for CDKN2A homozygous deletion and a unique neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The patient subsequently underwent second-stage surgery to proceed with maximal safe resection of the remnant tumor, followed by the commencement of adjuvant chemotherapy. Conclusion: To date, there are very few pediatric cases of PXA that present with spontaneous pICH and whose tumors have undergone thorough molecular testing. Our patient's journey highlights the role of a dedicated multidisciplinary neuro-oncology team to guide optimal treatment.

A remarkable genetic shift in a transmitted/founder virus broadens antibody responses against HIV-1.

A productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an α-helix (H173) to a ß-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines.

Diuretic resistance and the role of albumin in congestive heart failure.

Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.