G protein-biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer's disease mouse model.

Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein or ß-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer's disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated ß-arrestin signaling modulates amyloid-ß (Aß) generation in vitro and that Gpr3 deficiency ameliorates Aß pathology in vivo. However, Gpr3-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated ß-arrestin signaling in vivo. In contrast to Gpr3-deficient mice, G protein-biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein-biased signaling reduces soluble Aß levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein-biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and ß-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD.

Post-void bladder ultrasound in suspected cauda equina syndrome-data from medicolegal cases and relevance to magnetic resonance imaging scanning.

OBJECTIVE: Post-void residual (PVR) scans of less than 200 ml are increasingly being used to rule out the likelihood of cauda equina syndrome (CES) and to delay emergency MRI scanning in suspected cases. This study was done to review a series of 50 MRI confirmed cases of CES and to test the hypothesis that a PVR of less than 200 ml was unlikely to be present. METHODS: Fifty consecutive medicolegal cases involving CES were audited. Records were reviewed to see if PVR scans were done. MRI scans were reviewed, clinical and radiological diagnosis reviewed, and treatment recorded. RESULTS: Out of 50 CES cases, 26 had had PVR scans. In 14/26 (54%) the PVR scan was ≤ 200 ml. In one case, the CES diagnosis was in question leaving 13/26 (50%) cases where there was a clear clinical and MRI diagnosis of CES despite the PVR being ≤ 200 ml. All 13 were classified as incomplete cauda equina syndrome (CESI) and all proceeded to emergency decompression. CONCLUSIONS: This study is the first in the literature to demonstrate that there is a significant group of CES patients who require emergency decompression but have PVRs ≤ 200 ml. The results demonstrate the existence of a significant group of CESI patients whose bladder function may be deteriorating, but they have not yet reached the point where the PVR is over 200 ml. Given the accepted understanding that CESI is best treated with emergency decompression, such patients are likely to have worse outcomes if MRI scanning and therefore surgery is delayed. We recommend the following: PVR is recommended as an assessment tool in suspected CES. A PVR of ≤ 200 reduces the likelihood of having CES but does not exclude it; clinical suspicion of CES should always lead to an MRI scan. Further investigation of PVR as a prognostic tool is recommended.

Cauda equina syndrome-a practical guide to definition and classification.

PURPOSE: International uniformity of definition and classification are crucial for diagnosis and management of cauda equina syndrome (CES). They are also useful for clinicians when discussing CES with patients and relatives, and for medicolegal purposes. METHODS: We reviewed published literature using PubMed on definition and classification of cauda equina syndrome since 2000 (21 years). Using the search terms 'cauda equina' and 'definition' or 'classification', we found and reviewed 212 papers. RESULTS: There were 17 different definitions of CES used in the literature. There were three well-defined methods of classification of CES. The two-stage system of incomplete CES (CESI) versus CES with retention (CESR) is the most commonly used classification, and has prognostic value although the details of this continue to be debated. CONCLUSION: We used the existing literature to propose a clear definition of CES. We also drew on peer-reviewed published literature that has helped to amplify and expand the CESI/CESR dichotomy, adding categories that are both less severe than CESI, and more severe than CESR, and we propose clear definitions in a table form to assist current and future discussion and management of CES.

Failed consent in spinal surgery again. Minimum standards for consent must be adopted by all surgeons.

AIM: To report another case of failed consent in spinal surgery leading to an award in damages of £4.4 million and to suggest an improved method of recording discussions in respect of consent. METHODS: A recent Court Judgment, previous Judgments and the relevant medical law were reviewed. RESULTS: A standardised proforma recording the necessary preoperative discussions that must be had with our patients is described. CONCLUSIONS: Spinal surgeons must adhere to new standards in respect of the consenting process and, crucially, in recording the dialogue that has occurred between the patient and the surgeon.

First Metatarsophalangeal Joint Space Area Decreases Within 1 Month After Implantation of a Polyvinyl Alcohol Hydrogel Implant: A Retrospective Radiographic Case Series.

In 2016, the U.S. Food and Drug Administration approved the first and only polyvinyl alcohol hydrogel implant for the treatment of hallux rigidus. The implant functions as a bumper to maintain first metatarsophalangeal joint space to prevent contact of the phalangeal base with the first metatarsal head. Short-term and intermediate outcomes with this implant have reported positive outcomes with no radiographic outcomes of implant wear or subsidence. We performed a retrospective radiographic review of 27 consecutive patients who received the implant and measured preoperative and postoperative joint space area (JSA). We found a significant improvement in JSA (p < .001) between the preoperative JSA and JSA at the first postoperative visit at 1 to 2 weeks. We also found a significant decrease in JSA (p < .001) between the first postoperative visit and the second postoperative visit at 5 to 12 weeks. This information could have further implications for implant design as well as how we can better achieve functional improvements in the first metatarsophalangeal joint in patients with hallux rigidus.

Quantifying the clinical aspects of the cauda equina syndrome - The Cauda Scale (TCS).

AIM: To quantify the clinical findings in patients with potential cauda equina syndrome (CES). METHODS: Three domains were selected: bladder function (B), perianal sensation (S) and anal tone/squeeze (T). A quantified score was given to symptoms and signs in each domain. RESULTS: The lowest score in each domain and the lowest sum score (the most severe lesion) is 0. The best sum score is 9 (the normal patient). CONCLUSION: TCS can improve the clinical assessment and management of patients with possible CES and improve communication between the doctors who are called upon to assess and treat such patients.

Titanium Scaffolding: An Innovative Modality for Salvage of Failed First Ray Procedures.

Shortening of the first ray is a potential complication associated with first metatarsal procedures. Correction of this deformity conventionally has required the use of a tricortical bone graft to lengthen the bone. Graft complications, including donor site morbidity, poor graft stability, and graft resorption, have revealed a need for an alternative procedure. The present report shows that titanium cage scaffolding has lower extremity applications beyond its previous uses in the ankle and spine. Two patients underwent surgical correction for failed first ray procedures using a titanium cage apparatus with a calcaneal autograft and other biologic agents. The scaffolds were appropriately sized to fill the defect. Patients remained non-weightbearing until radiographic evidence of healing appeared. Success was determined by diminished pain, a return to activity, ambulation, and patient satisfaction. Patients exhibited faster-than-anticipated healing, including a return to protected weightbearing activities and increased stability within 6 weeks. Titanium cage implants provide long-term stability and resistance to stress and strain in the forefoot. The implant we have described, newly applied to the first ray, is analogous to a system used in salvage of failed ankle replacements. In addition to reducing reliance on the iliac crest bone graft, the titanium cage apparatus is advantageous because it is customized to fill a defect using computed tomography scanning, thereby reducing graft failure secondary to an improper shape. These cases demonstrate the potential beneficial applications for titanium cages in failed first ray reconstruction.

Surgical Treatment of Lisfranc Injury With Plantar Plate Approach.

Midfoot injuries are the second most common athletic foot injury documented in the published data. High-energy Lisfranc dislocations are commonly seen secondary to traumatic etiologies and disrupt the strong midfoot ligaments supporting the arch. These injuries require immediate surgical intervention to prevent serious complications such as compartment syndrome and amputation. The present case series reports a new Lapidus plate system used in 3 patients who underwent arthrodesis procedures for Lisfranc joint dislocation. Three patients in their fourth to fifth decade of life presented with a traumatic injury at the Lisfranc joint and subsequently underwent open reduction and internal fixation using the plantar Lapidus Plate System (LPS; Arthrex, Naples, FL). The LPS was placed in a predetermined safe zone, with measures taken to avoid the insertional points of the tibialis anterior and peroneus longus tendons. Radiographs were obtained for ≤6 months postoperatively and revealed consolidation across the fusion site, intact hardware, and satisfactory alignment. On examination, the corrections were well maintained and free of signs of infection. Clinical evaluation showed no indication of motion within the tarsometatarsal joint and no tenderness to palpation surrounding the fusion sites. All 3 patients successfully returned to their activities of daily living without discomfort or pain. Modern surgical treatment of Lisfranc injuries most commonly includes open reduction and internal fixation, accompanied by arthrodesis. The present case series has demonstrated that the LPS provides relief, stability, and compression of the joint in our small cohort of patients who experienced a traumatic injury to the Lisfranc joint.

Guidelines for cauda equina syndrome. Red flags and white flags. Systematic review and implications for triage.

INTRODUCTION: Patients with cauda equina syndrome (CES) are frequently referred late when neurological damage cannot be reversed. National Guidelines for emergency referral, imaging and treatment of CES contain symptoms and/or signs that are those of late often, irreversible CES. Referral at this stage may be too late for that patient. METHODS: Seven sources were reviewed. Advice re emergency referral/imaging/treatment were reviewed. Symptoms/signs were compared with a standard classification of CES. RESULTS: 37 recommendations: 12 (32%) were symptoms/signs of bilateral radiculopathy (treatment usually leads to favourable outcomes). Thirteen recommendations (35%) were described in an imprecise way (could be interpreted as early or late CES). Twelve sets of symptoms/signs (32%) were those of late, often irreversible CES where an unfavourable outcome would be expected. CONCLUSIONS: Thirty-two percent of the so-called "red flag" symptoms and signs of CES in seven sources were definitely those of late, irreversible CES. These could be seen as "white flags" [flags of defeat and surrender]. Thirty-five percent of the recommendations if interpreted pessimistically (e.g. absent perineal sensation or urinary incontinence) would also be white flags; potentially therefore two-thirds of the so-called "red flag" symptoms/signs of CES could be those of late irreversible CES. Only 32% of the symptoms/signs were true "red flags" i.e. they warn of further, avoidable damage ahead. Guidelines should be redrawn to emphasise referral of patients who are at risk of developing CES or who have early CES. It is illogical for these guidelines to emphasise the clinical features of severe, often untreatable, CES. Demand for emergency MRI will increase; MRI is part of triage and should be performed at the DGH.

Minimally Invasive Approach to Achilles Tendon Pathology.

Many surgical procedures have been described for Achilles tendon pathology; however, no overwhelming consensus has been reached for surgical treatment. Open repair using a central or paramedian incision allows excellent visualization for end-to-end anastomosis in the case of a complete rupture and detachment and reattachment for insertional pathologies. Postoperative wound dehiscence and infection in the Achilles tendon have considerable deleterious effects on overall functional recovery and outcome and sometimes require plastic surgery techniques to achieve coverage. With the aim of avoiding such complications, foot and ankle surgeons have studied less invasive techniques for repair. We describe a percutaneous approach to Achilles tendinopathy using a modification of the Bunnell suture weave technique combined with the use of interference screws. No direct end-to-end repair of the tendon is performed, rather, the proximal stump is brought in direct proximity of the distal stump, preventing overlengthening and proximal stump retraction. This technique also reduces the suture creep often seen with end-to-end tendon repair by providing a direct, rigid suture to bone interface. We have used the new technique to minimize dissection and exposure while restoring function and accelerating recovery postoperatively.

Neurological deterioration in cauda equina syndrome is probably progressive and continuous. Implications for clinical management.

Fifty-six human and animal studies of cauda equina syndrome (CES) were reviewed. The evidence from human studies was poor (level IV). Evidence from animal studies and limited evidence from human studies suggest that structural and functional neurological losses are a progressive, continuous process. The longer the cauda equina nerve roots are compressed the greater the harm and the poorer the extent of recovery. This should prompt diagnosis and surgery for all CES patients as soon as practicably possible.

Pulmonary pleomorphic carcinoma metastasis to the midfoot.

Metastases to the bones in the foot are extremely uncommon, occurring in approximately 0.01% of all metastatic bone disease. We describe a case of an 82-year-old female with a metastatic pulmonary sarcomatoid carcinoma lesion to the midfoot. This rare and aggressive pulmonary malignancy has a poor prognosis. The purpose of the present case report was to highlight the key roles that medical history and biopsy, combined with a multispecialty approach, play in accurately diagnosing and appropriately treating a patient with metastatic bone disease.

Medical negligence. Legal theory and neurosurgical practice: informed consent.

This article discusses the principles of the law in relation to informed consent as applied to neurosurgical practice. Patient autonomy, forms of consent, capacity to consent, the nature of information that should be given to patients, the level of information given, alternatives to treatment, which doctor should consent and when, consenting children, differing opinions, euthanasia and respect for the state of scientific knowledge are discussed.

Medical negligence. An overview of legal theory and neurosurgical practice: causation.

This article discusses the principles of the law in relation to legal causation as applied to neurosurgical practice. Causation is a causal link between a breach of duty of care and the final harm. The fundamental "but-for" test for causation will be discussed, together with Chester v Afshar modified causation, prospective and retrospective probabilities of harm, loss of a chance, causation following breach of duty of care by omission, breaking the chain of causation, material contribution and the law in relation to multiple defendants, with neurosurgical examples.

Medical negligence. An overview of legal theory and neurosurgical practice: duty of care.

A working knowledge of the legal principles of medical negligence is helpful to neurosurgeons. It helps them to act in a "reasonable, responsible and logical" manner, that is a practice that is consistent with the surgical practice of their peers. This article will review and explain the relevant medical law in relation to duty of care with illustrative neurosurgical cases.

Metastatic calcaneal lesion associated with uterine carcinosarcoma.

Metastatic lesions of uterine carcinosarcoma most commonly occur in the abdomen and lungs and less frequently in highly vascularized bone. We report a rare case of an 86-year-old female with uterine carcinosarcoma with metastasis to the left calcaneus. The patient had a history of uterine carcinosarcoma with hysterectomy and bilateral salpingo-oophorectomy, along with bilateral pelvic and aortic lymphadenectomy, with no adjuvant therapy. The initial pedal complaint was that of left foot pain. The initial radiographic findings were negative; however, magnetic resonance imaging scans revealed a substantial area of marrow edema in the calcaneus. An excisional biopsy was performed, and histopathologic analysis revealed adenocarcinoma with features consistent with the patient's previous uterine tumor specimen. The patient was given one treatment of chemotherapy and was discharged to a hospice, where she died of her disease 2 weeks later.

Medico-legal implications of dementia following concussion in rugby football.

There is litigation in respect of dementia in ex-rugby football players. The allegation is that these ex-players have suffered a traumatic encephalopathy syndrome causing dementia and other neurological problems. The syndrome is alleged to have been caused by repeated concussion during play. It is alleged that governing bodies of rugby should have been aware, and players should have been warned, of this risk. The dilemma, for both claimants and defendants, is that there is no agreed definition of the syndrome nor are there any diagnostic tests that confirm or refute this diagnosis. This paper reviews the literature of traumatic encephalopathy syndrome and when governing bodies were aware of the possibility of rugby concussion causing dementia. The legal principles are discussed and a framework for determining the probability of an ex-rugby player having the syndrome is proposed.

Demonstrating the expertise of an expert witness in the civil court: Use of a concise CV after the judgment in Re C.

The suitability of an unregistered expert psychologist to give evidence to the Family Court was considered in Re C [2023] EWHC 345 (Fam). An important part of the judgment focused on the need for an expert witness to demonstrate, in a short, concise and relevant CV, why they have the expertise to give opinion evidence in the case. The judgment has important implications for experts in civil litigation, where the same issues arise. The case of Re C is reviewed and recommendations for a new format for part of expert reports provided in civil litigation are discussed.

The failure of subcategorization of cauda equina syndrome.

The diagnostic sub-categorization of cauda equina syndrome (CES) is used to aid communication between doctors and other healthcare professionals. It is also used to determine the need for, and urgency of, MRI and surgery in these patients. A recent paper by Hoeritzauer et al (2023) in this journal examined the interobserver reliability of the widely accepted subcategories in 100 patients with cauda equina syndrome. They found that there is no useful interobserver agreement for the subcategories, even for experienced spinal surgeons. This observation is supported by the largest prospective study of the treatment of cauda equina syndrome in the UK by Woodfield et al (2023). If the accepted subcategories are unreliable, they cannot be used in the way that they are currently, and they should be revised or abandoned. This paper presents a reassessment of the diagnostic and prognostic subcategories of cauda equina syndrome in the light of this evidence, with a suggested cure based on a more inclusive synthesis of symptoms, signs, bladder ultrasound scan results, and pre-intervention urinary catheterization. This paper presents a reassessment of the diagnostic and prognostic subcategories of CES the light of this evidence, with a suggested cure based on a more inclusive synthesis of symptoms, signs, bladder ultrasound scan results, and pre-intervention urinary catheterization.