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The proximal femur is a frequent site of cancer dissemination in the extremities. Patients treated surgically for skeletal metastases have poorer overall health compared to other orthopedic patients, with only one-third expected to survive two years post-surgery. Choosing a treatment that minimizes revision risk and ensures the implant outlives the patient is therefore crucial. We conducted a systematic review to assess the revision rate following internal fixation (IF) or endoprosthetic reconstruction (EPR) of the proximal femur for metastatic bone disease (MBD). This study adhered to the PRISMA guidelines. MEDLINE and Embase were searched, identifying 10,299 records. After removing duplicates, 7731 unique records were screened, 334 of which were retrieved for full-text screening. We included 34 studies in the qualitative synthesis. The MINORS instrument was used for quality assessment. The quality of the included studies was low to moderate, with median scores of 6/16 for non-comparative studies and 10/24 for comparative studies. We therefore refrained from a comparative analysis. Revision rates varied between 0 and 12.4% following EPR (25 studies) and between 0 and 26.7% following IF, while implant removal rates ranged between 0 and 8.3% and 0 and 26.7%, respectively. Revision and implant removal rates for various methods of EPR and IF are satisfactory. However, a meta-analysis or comparison between IF and EPR is not feasible due to a lack of prospective studies, randomized trials and high-quality studies.

Pathological pain is defined as pain that outlives its usefulness as a protective warning system and becomes debilitating, disrupting normal life function. Understanding the mechanism of transition from physiological to pathological pain is essential to provide the effective prevention of chronic pain. The main subcategories of pathological pain are nociceptive pain, neuropathic pain, and nociplastic pain. Glial cells play pivotal roles in the development and maintenance of each of these pathological pain states, specifically neuropathic pain. Consequently, targeting these cells has emerged as a promising therapeutic strategy, as limited efficacy and harmful adverse effects are associated with current pharmacotherapies. This paper aims to review specific antibiotics that modulate glial cells, which can be used to treat neuropathic pain. These antibiotics include minocycline, doxycycline, ceftriaxone, and azithromycin. The potential of these antibiotics appears promising, particularly given the extensive prior research and use of these antibiotics in humans for other illnesses. However, each presents its own set of limitations, ultimately making the translation from preclinical findings to human therapies for neuropathic pain challenging.

Humans are able to estimate head movements accurately despite the short half-life of information coming from our inner ear motion sensors. The observation that the central angular velocity estimate outlives the decaying signal of the semicircular canal afferents led to the concept of a velocity storage mechanism (VSM). The VSM can be activated via visual and vestibular modalities and becomes manifest in ocular motor responses after sustained stimulation like whole-body rotations, optokinetic or galvanic vestibular stimulation (GVS). The VSM has been the focus of many computational modelling approaches; little attention though has been paid to discover its actual structural correlates. Animal studies localized the VSM in the medial and superior vestibular nuclei. A significant modulation by cerebellar circuitries including the uvula and nodulus has been proposed. Nevertheless, the corresponding neuroanatomical structures in humans have not been identified so far. The aim of the present study was to delineate the neural substrates of the VSM using high-resolution infratentorial fMRI with a fast T2* sequence optimized for infratentorial neuroimaging and via video-oculography (VOG). The neuroimaging experiment (n=20) gave first in vivo evidence for an involvement of the vestibular nuclei in the VSM and substantiate a crucial role for cerebellar circuitries. Our results emphasize the importance of cerebellar feedback loops in VSM most likely represented by signal increases in vestibulo-cerebellar hubs like the uvula and nodulus and lobule VIIIA. The delineated activation maps give new insights regarding the function and embedment of Crus I, Crus II, and lobule VII and VIII in the human vestibular system.

Almost since its inception, punk has been declared dead. What does it mean to live attached to something that is always, at least a little bit, gone? Examining how Justin Pearson merges personal accounts of death and mourning with a sense of punk that is rooted in loss in his memoir of his participation in a North American punk culture since the 1990s, From the Graveyard of the Arousal Industry, this article considers how a focus on living in the wake of the death of punk might shift scholarly and popular narratives told about punk. Punk outlives its death in the 1970s with a redemptive rebirth in which it became the subject of an anti-capitalist narrative. The article considers how Pearson's memoir explores a different framework by insisting that punk may not be able to separate itself from the wider world, and that while this might appear to deal a death blow to punk, it also names a persistent set of conditions that define punk. After placing the memoir in the context of this redemptive account of punk as well as among those who see its limits, the article offers an analysis of several scenes addressing personal losses that merge with Pearson's attachment to punk-as-something-dead-and-gone. The deaths that Pearson associates with punk rock are personal, but they also register the larger significance of loss for a subculture that cannot stop declaring its own demise, including especially the loss of a fantasy that sees punk as a refuge from the world.

Hepatitis D is caused by the hepatitis D virus (HDV); it is the most severe form of viral hepatitis in humans, running an accelerated course to cirrhosis. There is no efficacious therapy, and liver transplantation provides the only therapeutic option for terminal HDV disease. However, HDV infection is prevalent in poor countries of the world with no access to liver transplant programs; liver grafting has been performed in high-income countries, where the prevalence of the infection has much diminished as a secondary effect of hepatitis B virus vaccination, and the demand for liver transplantation outlives in aging cirrhotics who acquired hepatitis D decades ago. This review describes the evolution of liver transplantation for HDV disease from its inception in 1987 to the present time, with an outlook to its future. It reports the progress in the prophylaxis of HDV reinfections to the success of the current standard of indefinite combination of hepatitis B virus antivirals with immunoglobulins against the hepatitis B surface antigen; however, the unique biology of the virus provides a rationale to reducing costs by limiting the administration of the immunoglobulins against the hepatitis B surface antigen.

Decades of literature indicate that the AMPA-type glutamate receptor is among the fastest acting of all neurotransmitter receptors. These receptors are located at excitatory synapses, and conventional wisdom says that they activate in hundreds of microseconds, deactivate in milliseconds due to their low affinity for glutamate and also desensitize profoundly. These properties circumscribe AMPA receptor activation in both space and time. However, accumulating evidence shows that AMPA receptors can also activate with slow, indefatigable responses. They do so through interactions with auxiliary subunits that are able promote a switch to a high open probability, high-conductance 'superactive' mode. In this review, we show that any assumption that this phenomenon is limited to heterologous expression is false and rather that slow AMPA currents have been widely and repeatedly observed throughout the nervous system. Hallmarks of the superactive mode are a lack of desensitization, resistance to competitive antagonists and a current decay that outlives free glutamate by hundreds of milliseconds. Because the switch to the superactive mode is triggered by activation, AMPA receptors can generate accumulating 'pedestal' currents in response to repetitive stimulation, constituting a postsynaptic mechanism for short-term potentiation in the range 5-100 Hz. Further, slow AMPA currents span 'cognitive' time intervals in the 100 ms range (theta rhythms), of particular interest for hippocampal function, where slow AMPA currents are widely expressed in a synapse-specific manner. Here, we outline the implications that slow AMPA receptors have for excitatory synaptic transmission and computation in the nervous system.

Despite decades of investigation, mechanistic details of aqueous permanganate photo-decomposition remain unclear. Here we follow photoinduced dynamics of aqueous permanganate with femtosecond spectroscopy. Photoexcitation of KMnO4(aq) in the visible unleashes a sub-picosecond cascade of non-radiative transitions, leading to a distinct species which relaxes to S0 with a lifetime of 16 ps. Tuning excitation to the UV shows increasing formation of a metastable intermediate, which outlives our ∼1 ns window of detection. Guided by electronic structure calculations and observations from three pulse excitation experiments, we assign the 16 ps species as the lowest Jahn-Teller component of the 3T1 triplet state and suggest a plausible sequence of radiationless transitions, which rapidly populate it. In conjunction with photodecomposition quantum yields obtained from the literature, these results demonstrate that aqueous permanganate photo-decomposition proceeds through a long-lived intermediate which is formed in parallel to the triplet in less than one ps upon UV absorption. The possibility that this is the postulated highly oxidative peroxo species, a fraction of which leads to the stable (MnO2- + O2) fragments, is discussed. Finally, periodic modulations detected in the pump-probe signal are assigned to ground-state vibrational coherences excited by impulsive Raman. Their wavelength-dependent absolute phases outline the borders between adjacent electronic transitions in the linear spectrum of permanganate.

Neurogenesis is initiated by the transient expression of the highly conserved proneural proteins, bHLH transcriptional regulators. Here, we discover a conserved post-translational switch governing the duration of proneural protein activity that is required for proper neuronal development. Phosphorylation of a single Serine at the same position in Scute and Atonal proneural proteins governs the transition from active to inactive forms by regulating DNA binding. The equivalent Neurogenin2 Threonine also regulates DNA binding and proneural activity in the developing mammalian neocortex. Using genome editing in Drosophila, we show that Atonal outlives its mRNA but is inactivated by phosphorylation. Inhibiting the phosphorylation of the conserved proneural Serine causes quantitative changes in expression dynamics and target gene expression resulting in neuronal number and fate defects. Strikingly, even a subtle change from Serine to Threonine appears to shift the duration of Atonal activity in vivo, resulting in neuronal fate defects.

The use of bone allografts involves the risk of transmitting infectious agents from the donor to the recipient as shown by historical surveys. A study was therefore undertaken to test the hypothesis that human immunodeficiency virus (HIV) activity can still be present after the freezing and thawing of ribs taken from an acquired immune deficiency syndrome (AIDS) patient at autopsy. Rib samples were harvested under sterile conditions and frozen at -80 degrees C. After different freezing periods, the samples were cultured with activated lymphocytes. P24 antigen determination in the supernatant fluid was used to test for viral activity. Confirmation of viral activity was obtained after freezing periods ranging from 1 to 12 weeks. HIV activity can be found in ribs of AIDS patients, and this outlives the cryoprotection of bone banking. Donor selection remains the main security in the use of frozen bone allografts.

Longer patient survival and the extension of joint arthroplasty to older patients means that osteoporotic fractures of the femur are often associated with joint implants. This poses a significant trauma work load. This problem is likely to increase over time. The management of these periprosthetic fractures may be difficult and strategies are not universally agreed. Revision arthroplasty, single or double plate fixation with or without augmentation with methylmethacrylate or bone grafting, are all variously advocated in the literature for different indications. We retrospectively identified 28 elderly patients consecutively treated in our institution with Less Invasive Stabilisation System (LISS) plate fixation for osteoporotic and periprosthetic fractures of the femur. We present prospectively collected data for clinical and radiographic follow-up and patient outcomes. Patients had a mean age of 86.7 years. A fall from a standing height was the most common mechanism of injury. No cases of non-union were seen in survivors. Mortality in the first year was a major complication (5 patients). Rates of revision surgery were low (2 patients). Most patients required a formal period of rehabilitation, however, only half of the patients were successfully discharged to their own homes. The LISS plate provides good fixation in osteoporotic periprosthetic fractures of the femur. It restores a stable limb allowing early weight bearing as well as achieving clinical and radiographic union. Patients return to mobility levels approaching their pre-injury status although most benefit from a formal period of rehabilitation. In this patient group, the LISS plate often outlives the patient.

Neuropathic pain responds inconsistently to opioids and nonsteroidal antiinflammatory drugs. However, oral anticonvulsants have a proven analgesic effect on neuropathic pain, but may not be practical in an acute flare-up. Phenytoin was the first oral anticonvulsant used as an analgesic for neuropathic pain. There have been few studies on the parenteral analgesic effect of this drug. In this randomized, double-blind, placebo-controlled, crossover study of 20 patients with acute flare-ups of neuropathic pain, we compared a 2-h placebo infusion with a 2-h infusion of 15 mg/kg phenytoin. Overall pain, shooting pain, burning pain, paresthesia, numbness, and sensitivity were measured using a 10-cm linear visual analog score. Numbness and sensitivity were reduced in the placebo group during infusion, but not in the 7 days after infusion. In the phenytoin group, there were significant reductions in burning pain (P < 0.05), shooting pain (P < 0.001), sensitivity (P < 0.001), numbness (P < 0.05), and overall pain (P < 0.005) during the infusion period. The reduction in overall pain persisted for 1 day, in sensitivity for 2 days, and in shooting pain for 4 days after infusion. We conclude that IV infusion of 15 mg/kg phenytoin has an analgesic effect in acute flare-ups of neuropathic pain and that this relief outlives both the infusion time and plasma half-life of phenytoin. Oral phenytoin can relieve neuropathic pain. The aim of this study was to examine the effect of IV phenytoin on neuropathic pain. The results indicate that IV phenytoin may be used to treat flare-ups of chronic neuropathic pain.

Males and females often age at different rates resulting in longevity 'gender gaps', where one sex outlives the other. Why the sexes have different lifespans is an age-old question, still fiercely debated today. One cellular process related to lifespan, which is known to differ according to sex, is the rate at which the protective telomere chromosome caps are lost. In humans, men have shorter lifespans and greater telomere shortening. This has led to speculation in the medical literature that sex-specific telomere shortening is one cause of sex-specific mortality. However, telomere shortening may be a cause for and/or a consequence of the processes that govern survival, and to infer general principles from single-taxon studies may be misleading. Here, we review recent work on telomeres in a variety of animal taxa, including those with reverse sexual lifespan dimorphism (i.e., where males live longer), to establish whether sex-specific survival is generally associated with sex differences in telomere dynamics. By doing this, we attempt to tease apart the potential underlying causes for sex differences in telomere lengths in humans and highlight targets for future research across all taxa.

Interactions between organisms are ubiquitous and have important consequences for phenotypes and fitness. Individuals can even influence those they never meet, if they have extended phenotypes that alter the environments others experience. North American red squirrels (Tamiasciurus hudsonicus) guard food hoards, an extended phenotype that typically outlives the individual and is usually subsequently acquired by non-relatives. Hoarding by previous owners can, therefore, influence subsequent owners. We found that red squirrels breed earlier and had higher lifetime fitness if the previous hoard owner was a male. This was driven by hoarding behaviour, as males and mid-aged squirrels had the largest hoards, and these effects persisted across owners, such that if the previous owner was male or died in mid-age, subsequent occupants had larger hoards. Individuals can, therefore, influence each other's resource-dependent traits and fitness without ever meeting, such that the past can influence contemporary population dynamics through extended phenotypes.

The transcription factor Sox9 is necessary for early chondrogenesis, but its subsequent roles in the cartilage growth plate, a highly specialized structure that drives skeletal growth and endochondral ossification, remain unclear. Using a doxycycline-inducible Cre transgene and Sox9 conditional null alleles in the mouse, we show that Sox9 is required to maintain chondrocyte columnar proliferation and generate cell hypertrophy, two key features of functional growth plates. Sox9 keeps Runx2 expression and &#x3b2;-catenin signaling in check and thereby inhibits not only progression from proliferation to prehypertrophy, but also subsequent acquisition of an osteoblastic phenotype. Sox9 protein outlives Sox9 RNA in upper hypertrophic chondrocytes, where it contributes with Mef2c to directly activate the major marker of these cells, Col10a1. These findings thus reveal that Sox9 remains a central determinant of the lineage fate and multistep differentiation program of growth plate chondrocytes and thereby illuminate our understanding of key molecular mechanisms underlying skeletogenesis.

Acute kidney injury (AKI) is one of the most common clinical syndromes. AKI is associated with significant morbidity and subsequent chronic kidney disease (CKD) development. Thus, it is urgent to develop a strategy to hinder AKI progression. Renal tubules are responsible for the reabsorption and secretion of various solutes and the damage to this part of the nephron is a key mediator of AKI. As we know, many common renal insults primarily target the highly metabolically active proximal tubular cells (PTCs). PTCs are the most energy-demanding cells in the kidney. The ATP that they use is mostly produced in their mitochondria by fatty acid &#x3b2;-oxidation (FAO). But, when PTCs face various biological stresses, FAO will shut down for a time that outlives injury. Recent studies have suggested that surviving PTCs can adapt to FAO disruption by increasing glycolysis when facing metabolic constraints, although PTCs do not perform glycolysis in a normal physiological state. Enhanced glycolysis in a short period compensates for impaired energy production and exerts partial renal-protective effects, but its long-term effect on renal function and AKI progression is not promising. Deranged FAO and enhanced glycolysis may contribute to the AKI to CKD transition through different molecular biological mechanisms. In this review, we concentrate on the recent pathological findings of AKI with regards to the metabolic reprogramming in PTCs, confirming that targeting metabolic reprogramming represents a potentially effective therapeutic strategy for the progression of AKI.