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North-South variation in the supply of meat has always been present. Sharing of meat was the rule but in the multi-centric Neolithic revolution when domestication of animals and plants co-evolved class differences became pronounced-aristocrats and inferior proletariats and “lesser breeds and lower orders” started to form. The distribution of natural domesticates was uneven with the near-east and a temperate band across Europe well off compared with Africa and the Americas. The Columbian exchange changed this as meat became abundant in the New World who then exported to Europe. Wars, expropriations and genocides were over the meat supply and acquiring pastureland or water. Colonial plantation profits paid for meat imports from “settler colonies” indigenous or poor peoples on low meat pro-pellagrous diets were considered inferior whatever their colour and had poorer health and life expectancy. Attempts to correct hunger in the resultant ramshackle “Third world” concentrated on calories fuelling population booms and busts and delaying demographic, epidemiological and economic transitions. High meat variances are narrowing in China and Asia but need help elsewhere in the South. Dangers of not developing with a safe and sufficient meat supply include the emergence of zoonoses and mass migration. Reparations, rehabilitation and rejuvenation should concentrate on reconstituting a meat commons giving us a shot at redemption and survival.

Pellagra is caused by a dietary deficiency of milk and meat leading to insufficient nicotinamide (vitamin B3), the precursor to nicotinamide adenine dinucleotide (NAD). “Pellagra sine pellagra” was well recognised and may be common as supplementation was never globally implemented and a screening test never developed. Meat and milk intake varies 30-fold globally so there are perhaps 2 billion at risk of deficiency. Such patients will have physical and cognitive stunting, poor conduct and be prone to acute and chronic infections, including TB, and premature ageing, including dementia. Resilience may be poor to NAD-consuming insults whether chemical, microbial or traumatic that conspires to cause brain injury but comes with the opportunity for pre-conception dietary corrections breaking cycles of deprivation and poor educational outcomes. Such individuals may otherwise be subject to discrimination as was the pellagra ridden “Butterfly” caste causing racial and ethic tensions. Poor countries with many having to spend 50-80% of income on food and very little on animal produce cannot develop properly unlike wealthier meat rich empires, past and present. The many benefits of experiments with food programmes and basic income support are because, as Engels curves predict, more is spent on milk and meat enabling demographic, epidemiological, and economic transitions and modernity.

We evolved from herbivores to a meat eating “commons” in hunter-gatherer days and then to a non-egalitarian meat power struggle between classes and countries. Egalitarian-ism, trans-egalitarianism and extremes of inequality and hierarchy revolve around the fair-unfair distribution of meat surpluses and ownership of the means of meat production. Poor people on poor diets with too few micronutrients may explain many inequalities of human capital, height and health and divergent development of individuals and nations. Learning from past successes and collapses from switching trophic levels the lesson is that meat moderation toward the top of Engel’s curves, not calorie-centrism, is the best recipe for countries and classes. Improved health with longer lives and higher crystallised intelligence comes with an ample supply of micronutrients from animal products namely iron, zinc, vitamin A, vitamin B12 and other methyl-donors (such as choline), and nicotinamide (vitamin B3). We concentrate on nicotinamide whose deficits cause the degenerative condition pellagra that manifests as poor emotional and degenerative cognitive states with stunted lives and complex antisocial and dysbiotic effects caused by and causing poverty.

Pellagra has largely been forgotten. This is unfortunate as important lessons are to be learnt about the diseases and social and economic consequences of poverty – and for the root cause of poverty (and of affluence) – that involve dietary nicotinamide and nicotinamide adenine dinucleotide (NAD) homeostasis. NAD disruption can occur not only from poor diet but from increased consumption from genotoxic, infectious and metabolic stresses. NAD deficiency is closely linked to poor physical and intellectual development, premature ageing and diseases of ageing. Acute infections, many with NAD-consuming toxins, that may differentially affect the NAD-depleted, now include COVID-19. Some Covid manifestations, such as myoclonic encephalopathy and “Long Covid,” resemble pellagra clinically and biochemically as both have disturbed nicotinic and tryptophan metabolism. Symbionts that supply nicotinic acid, such as TB and some gut micro-organisms, can become dysbiotic if the diet is very deficient in milk and meat, as it is for 1–2 billion or more. High doses of nicotinamide lead to inhibition of NAD-consuming enzymes and excessive induction of nicotinamide-n-methyl transferase (NNMT) with consequent effects on the methylome: this gives a mechanism for an unrecognised hypervitaminosis-B3 with adverse effects of nicotinamide overload for consumers on a high meat diet with “fortified” foods and “high energy” drinks. Methods of measuring NAD metabolism routinely for screening the populations at risk of deficiency and in metabolically ill or infectious disease patients should be developed urgently. Successful intervention should improve human capital and prevent many aspects of poverty, reduce discrimination and even the drive to emigrate.

Heterotopic ossification (HO), the pathological formation of ectopic bone, is a debilitating condition which can cause chronic pain, limit joint movement, and prevent prosthetic limb fitting. The prevalence of this condition has risen in the military population, due to increased survivorship following blast injuries. Current prophylaxes, which aim to target the complex upstream biological pathways, are inconsistently effective ​and have a range of side-effects that make them unsuitable for combat-injured personnel. As such, many patients must undergo further surgery to remove the formed ectopic bone. In this study, a non-toxic, U.S. Food and Drug Administration (FDA) -approved calcium chelator, hexametaphosphate (HMP), is explored as a novel treatment paradigm for this condition, which targets the chemical, rather that biological, ​bone formation pathways. This approach allows not only prevention of pathological bone formation ​but also uniquely facilitates reversal, which current drugs cannot achieve. Targeted, minimally invasive delivery is achieved by loading HMP into an injectable colloidal alginate. These formulations significantly reduce ​the length of the ectopic bone formed in a rodent model of HO, with no effect on the adjacent skeletal bone. This study demonstrates the potential of localized dissolution as a new treatment ​and an alternative to surgery ​for pathological ossification and calcification conditions., Graphical abstract Image 1

Nicotinamide homeostasis is a candidate common denominator to explain smooth transitions, whether demographic, epidemiological or economic. This ‘NAD world’, dependent on hydrogen-based energy, is not widely recognised as it is neither measured nor viewed from a sufficiently multi-genomic or historical perspective. Reviewing the importance of meat and nicotinamide balances during our co-evolution, recent history suggests that populations only modernise and age well with low fertility on a suitably balanced diet. Imbalances on the low meat side lead to an excess of infectious disease, short lives and boom-bust demographics. On the high side, meat has led to an excess of degenerative, allergic and metabolic disease and low fertility. A ‘Goldilocks’ diet derived from mixed and sustainable farming (preserving the topsoil) allows for high intellectual capital, height and good health with controlled population growth resulting in economic growth and prosperity. Implementing meat equity worldwide could lead to progress for future generations on ‘spaceship’ earth by establishing control over population quality, thermostat and biodiversity, if it is not already too late.

Mitochondrial dynamics are regulated by a complex system of proteins representing the mitochondrial quality control (MQC). MQC balances antagonistic forces of fusion and fission determining mitochondrial and cell fates. In several neurological disorders, dysfunctional mitochondria show significant changes in gene and protein expression of the MQC and contribute to the pathophysiological mechanisms of cell damage. In this study, we evaluated the main gene and protein expression involved in the MQC in rats receiving traumatic brain injury (TBI) of different severities. At 6, 24, 48 and 120 hours after mild TBI (mTBI) or severe TBI (sTBI), gene and protein expressions of fusion and fission were measured in brain tissue homogenates. Compared to intact brain controls, results showed that genes and proteins inducing fusion or fission were upregulated and downregulated, respectively, in mTBI, but downregulated and upregulated, respectively, in sTBI. In particular, OPA1, regulating inner membrane dynamics, cristae remodelling, oxidative phosphorylation, was post-translationally cleaved generating differential amounts of long and short OPA1 in mTBI and sTBI. Corroborated by data referring to citrate synthase, these results confirm the transitory (mTBI) or permanent (sTBI) mitochondrial dysfunction, enhancing MQC importance to maintain cell functions and indicating in OPA1 an attractive potential therapeutic target for TBI.

Traumatic brain injury (TBI) is set to become the leading cause of neurological disability across all age groups. Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries. Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions. Inflammatory markers are particularly suited for biomarker discovery as TBI leads to very early alterations in inflammatory proteins. Using the Proseek Multiplex Inflammation assay, we measured in patients that had suffered mild TBI (n = 10) or severe TBI (n = 10) with extra-cranial injury or extracranial injury only (EC) (n = 10), 92 inflammation-associated proteins in serum obtained

Purpose: To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection.Methods: CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV.Results: CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment.Conclusions: CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

Meat and vitamin B 3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B 3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B 3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.

Traumatic brain injury (TBI) is the leading cause of death and disability in people younger than 45 in Western countries. Despite many studies, no reliable biomarkers have been found to assess TBI severity and predict recovery. MicroRNA (miRNA) profiling has become widely used to identify biomarkers and therapeutic targets. Through use of the TaqMan Array Human MicroRNA A+B Cards, the expression of 754 miRNAs was analyzed in serum of five mild TBI (mTBI) patients with extra-cranial injury (EC), five severe TBI (sTBI) patients with EC, and five healthy volunteers (HV) at 1 day and 15 days post-injury. The aim was to find candidate biomarkers able to discriminate between mTBI and sTBI. Following this, it was possible to select 10 miRNAs for further study in an enlarged validation cohort of 120 patients by using single TaqMan assays at the following time-points: T0-1 h, T4-12 h, T48-72 h, and 15 days from the injury. Analysis revealed two miRNAs (miR-425-5p and miR-502) that were significantly downregulated (p 0.05) in mTBI at early time-points and are ideal candidates for diagnosis of mTBI, and two miRNAs (miR-21 and miR-335) that were significantly upregulated (p 0.01) and are valid biomarkers for the diagnosis of sTBI. In addition, miR-425-5p was a strong predictor of 6-month outcome at T0-1 h and T4-12 h, while miR-21 was predictive of the outcome at T4-12 h. The panel of selected miRNAs shows promise as biomarkers to discriminate mTBI from sTBI. In addition, the selected miRNAs represent new potential therapeutic targets.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

PURPOSE:\ud\udTo investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis.\udMETHODS:\ud\udAdult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed.\udRESULTS:\ud\udTransforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss.\udCONCLUSIONS:\ud\udHuman recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

INTRODUCTION: Current treatments for Glioblastoma (GBM) are inadequate and immunotherapeutics may provide better outcomes for patients. Human recombinant Decorin is a glycoprotein that modulates inflammation & GBM growth by inhibiting Transforming Growth Factor, Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptor. As Decorin is found in human tissue rich in fibrillar collagen (e.g. skin, heart, bone lung & liver) it is a potentially safe drug to be trialled in humans. METHOD: The local immune and microglial response to intracerebral injections of Decorin was investigated. Rats (n = 6 for each group) received either an injection of PBS (control) or 5¼l 5mg/ml Decorin and were sacrificed at 30min, 3 & 24 hrs or after continuous infusion of either PBS (control) or Decorin for 7 days. CSF samples were taken and analysed by ELISA and Luminex for presence of Decorin and change in inflammatory markers. Immunohistochemistry was also performed to investigate the effects of Decorin on microglia using OX42. RESULTS: There was no inflammatory reaction or cavity formation in brain. Decorin supressed the microglial response after direct injections into the brain compared to PBS control. At 30 mins, low levels of decorin were detected (with ELISA) in CSF and serum but none was detected at 3hrs and 24hrs after injection. CONCLUSION: Decorin showed no dose limiting toxicity, whilst maintaining its immunomodulatory effects in brain. These findings show a safe pharmacokinetic and toxicological profile.

In this perspective, we discuss the use of an anti-fibrotic agent Decorin to treat established fibrosis associated with glaucoma originally published by Hill et al. (2015). Glaucoma describes a group of progressive optic neuropathies that have the potential to cause irreversible blindness, for which it is recognized that a main risk factor is raised intraocular pressure (IOP). Currently, there is no precise explanation of why high IOP causes retinal ganglion cell (RGC) death. Factors contributing to IOP-related RGC death include compromised retrograde axonal transport of target derived neurotrophic factors, leading to activation of apoptosis and mitochondrial dysfunction after the biomechanical and ischemic insult of optic nerve head compression. In open-angle glaucoma (OAG), increases in IOP occur when aqueous humour (AqH) outflow through the trabecular meshwork (TM) is reduced, usually as a result of progressive abnormalities in TM cellularity and extracellular matrix (ECM) levels culminating in TM fibrosis (Prendes et al., 2013). These cellular and ECM changes (which includes upregulation of collagen IV, laminin, and fibronectin) in the TM, together with altered TM cell contractility, result in TM dysfunction and ultimately loss of the tightly controlled AqH outflow. Currently, treatments for glaucoma are symptomatic and focus on the use of drugs formulated as eye drops to lower IOP either by reducing AqH production or increasing AqH outflow through non-TM pathways. Alternatively, surgical insertion of shunts through the TM can drain AqH directly to the exterior of the eye, although these often become blocked. For some patients it seems that primary open-angle glaucoma is a fibroproliferative condition and no current treatment addresses the TM fibrosis that is the predominant underlying causes of TM dysregulation. The mechanisms that lead to TM dysfunction in OAG are multifactorial and may relate to dysregulated ocular inflammation since pathologically high levels of the pro-inflammatory cytokine transforming growth factor β (TGF-β) within the AqH and TM have been implicated. For example, some OAG patients have elevated levels of TGF-β1 and/or TGF-β2 in their AqH compared to age-matched patients with other forms of glaucoma (e.g., primary angle closure glaucoma and uveitis-associated secondary glaucoma) and with cataracts (Prendes et al., 2013). Other studies have shown that it is the TGF-β2 isoform that is significantly elevated in eyes with primary OAG compared with non-glaucomatous eyes, and have shown elevated TGF-β1 and TGF-β3 isoforms in pseudoexfoliative glaucoma and in primary angle closure glaucoma (Prendes et al., 2013). TGF-β1 and TGF-β2 are known potent fibrogenic factors and, at pathologically high levels in the eye, can induce the overexpression of ECM proteins that lead to TM dysfunctions (Prendes et al., 2013). TGF-βs also prevent the breakdown of ECM by inhibiting matrix metalloproteinases (MMP) (Ahmed et al. 2014), creating a pro-fibrotic microenvironment within the TM. TGF-β is directly implicated in the pathogenesis of ocular hypertension since: (1) infusion of TGF-β2 for 14 days in an anterior eye segment perfusion culture model significantly increased IOP (Battacharya et al., 2009); (2) adenoviral gene delivery of human TGF-β2 into the anterior segment to the rodent eye reduced AqH outflow and increased IOP (Shepard et al., 2010); and (3) TGF-β1 gene delivery by adenovirus to the anterior segment of the rat eye increased IOP (Robertson et al., 2010). Thus, treatment of the TM in OAG with a TGF-β antagonist may help to ablate TM fibrogenesis, thereby perturbing the progression of OAG pathology. The matrikine Decorin is a small leucine-rich proteoglycan that regulates cell proliferation, survival and differentiation by antagonizing a panel of growth factors and/or their receptors, including TGF-β, epidermal growth factor, vascular endothelial growth factor, hepatocyte growth factor and insulin-like growth factor-1. Decorin also ‘decorates’ collagen, interfering with collagen fibrillogenesis and stabilizing collagen fibres. In addition, Decorin enhances matrix metalloproteinases (MMP) activity by increasing levels of tissue plasminogen activator (tPA), thus enabling plasmin-dependent activation of MMP by cleavage of plasminogen to plasmin, and reducing levels of PAI-1 and tissue inhibitors of MMPs, further facilitating MMP activation. The fibrolytic actions of Decorin have been harnessed to attenuate the progression of tissue damage in other fibroproliferative pathologies, including juvenile communicating hydrocephalus (Botfield et al., 2013) and spinal cord injury (Ahmed et al., 2014), making Decorin an ideal candidate for treating TM fibrosis and progressive RGC loss in glaucoma. Modelling raised IOP in OAG using intracameral (IC) injections of TGF-β: In the study by Hill et al. (2015), we used immunohistochemistry to visualize fibrosis and count RGCs, tonometry to measure IOP and visual evoked potentials (VEP) to measure function of the visual pathway, and found that repeated (twice a week) intracameral injections of TGF-β in adult rats promoted TM fibrosis, elevated IOP and led to RGC death and retinal dysfunction. Consistent with other fibrotic models of raised IOP, our rodent model generated a sustained and significant increase in IOP by 14 days compared with PBS controls. The baseline level of IOP (before any treatment) in our study was similar to that observed previously in rats (Robertson et al. 2010). However, overexpression of TGF-β by gene transfer (Robertson et al. 2010) led to greater levels of IOP (20 mmHg) compared to IOP levels (14 mmHg) achieved in our study, differences that maybe explained by the constant production of TGF-β through gene transcription compared with our discontinuous bolus regime of biweekly IC injections. One feature of our method was that TGF-β treatment for 17 days led to TM fibrosis and elevated IOP that persisted for at least 30 days despite withdrawal of TGF-β from this time point. To confirm that there was no natural resolution of the TM fibrosis and raised IOP (due to continued ECM turnover in the TM) after the cessation of TGF-β treatment we used a control group in which intracameral injection of TGF-β injections for 17 days was followed by intracameral injection of PBS from 21–30 days with no resolution of IOP. Thus, in this in vivo model of TGF-β-induced TM fibrosis, IOP was increased by 17 days and sustained through to 30 days, resulting in 42% RGC death and associated functional VEP deficits, consequences that were similar to those seen in other experimental models of raised IOP (Belforte et al., 2010). Of note, in the study of Hill et al. (2015) it was important to identify and account for any inflammatory reactions induced by the intracameral injections that may have perpetuated TM fibrosis. This was addressed by counting the number of ED1+ macrophages situated within the proximity of the TM. The results showed that intracameral TGF-β and PBS did increase the number of macrophages in the angle compared with numbers in the intact control eyes. These results suggest that, since there were similar macrophage numbers in the PBS and TGF-β-treated groups, the induced differences between the two treatments were not a consequence of post-surgical inflammation. Evaluating the utility of human recombinant Decorin hrDecorin for the treatment of OAG: Once the model was successfully established, hrDecorin was injected intracamerally after TM fibrosis was established to ascertain if the induced TM fibrosis and increased IOP could be resolved. hrDecorin significantly reduced the laminin and fibronectin levels within the fibrosed TM, an effect that was correlated with raised levels of MMP and their TIMP inhibitors. Thus, hrDecorin reversed the TM microenvironment back to MMP/TIMP ratios favourable for tissue remodelling, causing the dissolution of established ECM protein deposits in and around the TM, an anti-scarring response reminiscent of that seen to Decorin in models of spinal cord injury (Ahmed et al., 2013), hydrocephalus (Botfield et al., 2013) and conjunctival scarring for post-filtration surgery (Grisanti et al., 2005). The study of Hill et al. (2015) in the OAG model also showed that the anti-scarring Decorin treatment lowered IOP when compared with controls in vivo, with associated enhancement of RGC survival. Primary retinal cultures containing RGC demonstrated that the neuroprotective effects of Decorin were indirectly related to the resolution of TM fibrosis and lowering of IOP rather than by direct actions on neurons. However, other studies have shown contradictory results on other cell types. For example, Seidler et al. (2006) reported an anti-apoptotic effect of Decorin on cultured fibroblasts by prevention of DNA fragmentation. By contrast, studies using cancer cells have convincingly demonstrated the ability of Decorin to induce cell death through apoptosis (Goldoni et al., 2008). Therefore, we suggest that the actions of Decorin are dependent on the cell type and their environment. Conclusion: Our observations show that intracameral hrDecorin reverses established TM fibrosis and normalizes IOP, indirectly protecting RGC from progressive IOP-related death. Further confirmatory studies will be required to understand the exact mechanism of Decorin's fibrolytic actions within the TM but we believe that hrDecorin is an ideal candidate therapy to develop into a treatment for patients with OAG associated with TM fibrosis. LJH was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), No. BB/F017553/1.