On the mucoadhesive properties of synthetic and natural polyampholytes.

HYPOTHESIS: The mucoadhesive characteristics of amphoteric polymers (also known as polyampholytes) can vary and are influenced by factors such as the solution's pH and its relative position against their isoelectric point (pHIEP). Whilst the literature contains numerous reports on mucoadhesive properties of either cationic or anionic polymers, very little is known about these characteristics for polyampholytes EXPERIMENTS: Here, two amphoteric polymers were synthesized by reaction of linear polyethylene imine (l-PEI) with succinic or phthalic anhydride and their mucoadhesive properties were compared to bovine serum albumin (BSA), selected as a natural polyampholyte. Interactions between these polymers and porcine gastric mucin were studied using turbidimetric titration and isothermal titration calorimetry across a wide range of pHs. Model tablets were designed, coated with these polymers and tested to evaluate their adhesion to porcine gastric mucosa at different pHs. Moreover, a retention study using fluorescein isothiocyanate (FITC)-labelled polyampholytes deposited onto mucosal surfaces was also conducted FINDINGS: All these studies indicated the importance of solution pH and its relative position against pHIEP in the mucoadhesive properties of polyampholytes. Both synthetic and natural polyampholytes exhibited strong interactions with mucin and good mucoadhesive properties at pH < pHIEP.

Common microRNA regulated pathways in Alzheimer's and Parkinson's disease.

MicroRNAs (miRNAs) are small non-coding RNAs involved in gene regulation. Recently, miRNA dysregulation has been found in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The diagnosis of Alzheimer's and Parkinson's is currently challenging, mainly occurring when pathology is already present, and although treatments are available for both diseases, the role of treatment is primarily to prevent or delay the progress of the diseases instead of fully overcoming the diseases. Therefore, the challenge in the near future will be to determine effective drugs to tackle the dysregulated biological pathways in neurodegenerative diseases. In the present study, we describe the dysregulation of miRNAs in blood of Alzheimer's and Parkinson's patients with the aim to identify common mechanisms between the 2 pathologies and potentially to identify common therapeutic targets which can stop or delay the progression of two most frequent neuropathologies. Two independent systematic reviews, bioinformatic analysis, and experiment validation were performed to identify whether AD and PD share common pathways. A total of 15 common miRNAs were found in the literature and 13 common KEGG pathways. Among the common miRNAs, two were selected for validation in a small cohort of AD and PD patients. Let-7f-5p and miR-29b-3p showed to be good predictors in blood of PD patients.

Transdermal drug delivery in horses: An in vitro comparison of skin structure and permeation of two model drugs at various anatomical sites.

BACKGROUND: Oral and parenteral drug delivery in horses can be difficult. Equine-specific transdermal drug formulations offer improved ease of treatment; development of such formulations requires a deeper understanding of the structural and chemical tissue barrier of horse skin. HYPOTHESIS/OBJECTIVES: To compare the structural composition and barrier properties of equine skin. ANIMALS: Six warmblood horses (two males, four females) with no skin diseases. MATERIALS AND METHODS: Routine histological and microscopic analyses were carried out with image analysis for skin from six different anatomical locations. In vitro drug permeation was analysed using a standard Franz diffusion cell protocol coupled with reversed phase-high-performance liquid chromatography detailing flux, lag times and tissue partitioning ratios of two model drug compounds. RESULTS: Epidermal and dermal thicknesses varied between sites. The dermal and epidermal thicknesses of the croup were 1764 ± 115 µm and 36 ± 3.6 µm, respectively, and were significantly different (p < 0.05) from the inner thigh thicknesses which were 824 ± 35 µm and 49 ± 3.6 µm. Follicular density and size also varied. The highest flux for the model hydrophilic molecule (caffeine) was for the flank (3.22 ± 0.36 µg/cm2 /h), while that for the lipophilic molecule (ibuprofen) was for the inner thigh (0.12 ± 0.02 µg/cm2 /h). CONCLUSIONS AND CLINICAL RELEVANCE: Anatomical location differences in equine skin structure and small molecule permeability were demonstrated. These results can aid in the development of transdermal therapies for horses.

A Brief Overview: Sex Differences in Prevalent Chronic Musculoskeletal Conditions.

Musculoskeletal (MSK) pain disorders are some of the most prevalent and disabling chronic pain conditions worldwide. These chronic conditions have a considerable impact on the quality of life of individuals, families, communities, and healthcare systems. Unfortunately, the burden of MSK pain disorders does not fall equally across the sexes. Females consistently demonstrate more prevalent and severe clinical presentations of MSK disorders, and this disparity increases in magnitude with age. The aim of the present article is to review recent studies that have examined sex differences between males and females in four of the most common MSK pain disorders: neck pain, low back pain, osteoarthritis, and rheumatoid arthritis.

Synthesis and Evaluation of Poly(3-hydroxypropyl Ethylene-imine) and Its Blends with Chitosan Forming Novel Elastic Films for Delivery of Haloperidol.

This study aimed to develop novel elastic films based on chitosan and poly(3-hydroxypropyl ethyleneimine) or P3HPEI for the rapid delivery of haloperidol. P3HPEI was synthesized using a nucleophilic substitution reaction of linear polyethyleneimine (L-PEI) with 3-bromo-1-propanol. 1H-NMR and FTIR spectroscopies confirmed the successful conversion of L-PEI to P3HPEI, and the physicochemical properties and cytotoxicity of P3HPEI were investigated. P3HPEI had good solubility in water and was significantly less toxic than the parent L-PEI. It had a low glass transition temperature (Tg = -38.6 °C). Consequently, this new polymer was blended with chitosan to improve mechanical properties, and these materials were used for the rapid delivery of haloperidol. Films were prepared by casting from aqueous solutions and then evaporating the solvent. The miscibility of polymers, mechanical properties of blend films, and drug release profiles from these formulations were investigated. The blends of chitosan and P3HPEI were miscible in the solid state and the inclusion of P3HPEI improved the mechanical properties of the films, producing more elastic materials. A 35:65 (%w/w) blend of chitosan-P3HPEI provided the optimum glass transition temperature for transmucosal drug delivery and so was selected for further investigation with haloperidol, which was chosen as a model hydrophobic drug. Microscopic and X-ray diffractogram (XRD) data indicated that the solubility of the drug in the films was ~1.5%. The inclusion of the hydrophilic polymer P3HPEI allowed rapid drug release within ~30 min, after which films disintegrated, demonstrating that the formulations are suitable for application to mucosal surfaces, such as in buccal drug delivery. Higher release with increasing drug loading allows flexible dosing. Blending P3HPEI with chitosan thus allows the selection of desirable physicochemical and mechanical properties of the films for delivery of haloperidol as a poorly water-soluble drug.

Smartphone mindfulness meditation training reduces Pro-inflammatory gene expression in stressed adults: A randomized controlled trial.

Mindfulness meditation training has been shown to be an effective stress reduction strategy, but less is known about its immunoregulatory impact. In a randomized controlled trial of stressed customer service workers, the present study tested whether a 30-day smartphone-based mindfulness meditation training program (compared to a problem-solving control program) would affect pro-inflammatory gene expression. Both interventions led to reductions in stress levels, but there was no difference in stress reduction between conditions. Consistent with predictions, mindfulness training reduced activity of the pro-inflammatory NF-κB transcription control pathway compared to the active control. These results suggest that mindfulness training may be a particularly effective method for improving immune cell gene expression in stressful work environments.

Accelerating topical formulation development for inflammatory dermatoses; an ex vivo human skin culture model consistent with clinical therapeutics.

Although animal models have been extensively used to evaluate human topical therapeutics, they exhibit marked physiological differences to human skin. Our objective was to develop a human ex vivo skin culture model to explore the pathophysiology of inflammatory dermatoses and for preclinical testing of potential therapeutic treatments. Ex vivo skin barrier integrity and metabolic activity was retained for 5 days and stimulation of T-helper cells (Th1), which produce proinflammatory cytokines, provided inflammatory responses similar to those reported from in vivo biopsy. Tissue responses to established therapies of pimecrolimus (Elidel) and clobetasol propionate (Dermovate) were evaluated using the human ex vivo skin culture, assessing pharmacodynamic changes in gene expression alongside the pharmacokinetics of drug penetration with both products showing time dependent efficacies. The translational utility of the human ex vivo skin culture model of inflammatory dermatoses was demonstrated through comparison with an in vivo clinical study, with similar reductions in inflammatory gene expression recorded for both drug treatments. Thus, this model can reduce, replace or refine animal testing and also mitigate the risk of failure in costly and time-consuming clinical trials associated with novel topical therapeutic development.

A new ex vivo skin model for mechanistic understanding of putative anti-inflammatory topical therapeutics.

Several in vitro models have been designed as test systems for inflammatory skin conditions, commonly using cell-culture or reconstructed human epidermis approaches. However, these systems poorly recapitulate the physiology and, importantly, the metabolism and biochemical activity of skin in vivo, whereas ex vivo skin culture models can retain these features of the tissue. Our objective was to develop a human ex vivo skin culture model to explore the pathophysiology of inflammatory dermatoses and for preclinical testing of potential therapeutic treatments. Following exogenous stimulation, tissue integrity and ability to induce inflammatory gene expression was retained, and stimulant concentrations and duration was optimised to mimic published data from inflammatory clinical biopsies of dermatitis and psoriasis patients. The validity and utility of the model was demonstrated when challenged with 5 drugs including a corticosteroid and vitamin D3 analogue, where inflammatory biomarkers were regulated in a manner consistent with the drugs' reported in vivo mechanisms of action. This model retains important inflammatory gene signals observed in human inflammatory dermatoses for preclinical evaluation of novel therapeutics.

Mutual Effects of Hydrogen Bonding and Polymer Hydrophobicity on Ibuprofen Crystal Inhibition in Solid Dispersions with Poly(N-vinyl pyrrolidone) and Poly(2-oxazolines).

Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were used to prepare solid dispersions with ibuprofen (IB), a model poorly-water soluble drug. Dispersions, prepared by solvent evaporation, were investigated using powder X-ray diffractometry, differential scanning calorimetry, and FTIR spectroscopy; hydrogen bonds formed between IB and all polymers in solid dispersions. PMOZ, the most hydrophilic polymer, showed the poorest ability to reduce or inhibit the crystallinity of IB. In contrast, the more hydrophobic polymers PVP, PEOZ, PnPOZ, and PiPOZ provided greater but similar abilities to reduce IB crystallinity, despite the differing polymer hydrophobicity and that PiPOZ is semi-crystalline. These results indicate that crystallinity disruption is predominantly due to hydrogen bonding between the drug molecules and the polymer. However, carrier properties affected drug dissolution, where PnPOZ exhibited lower critical solution temperature that inhibited the release of IB, whereas drug release from other systems was consistent with the degree of ibuprofen crystallinity within the dispersions.

A Novel Polymer Insect Repellent Conjugate for Extended Release and Decreased Skin Permeation of Para-Menthane-3,8-Diol.

BACKGROUND: We developed a novel polymer insect repellent conjugate for extended release and decreased skin permeation of the volatile insect repellent p-menthane-3,8-diol (PMD). METHODS: PMD was conjugated with acryloyl chloride via an ester bond to form acryloyl-PMD, which was subsequently copolymerised with acrylic acid at varying molar ratios. Copolymer structures were characterised by 1H NMR and FT-IR, analysed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), molecular weights and reactivity ratios determined, and repellent loading assessed. RESULTS: Using porcine liver esterases, ~45% of the insect repellent was released over five days. Penetration and permeation studies of the copolymer and free repellent using excised, full-thickness porcine ear skin showed no detectable permeation of the copolymer through skin compared to the PMD. Moreover, tape stripping revealed that over 90% of the copolymer remained on the outer surface of the skin, whereas free PMD was within all skin layers. A planarian toxicity fluorescence assay indicated that that the copolymer is unlikely to be a significant irritant when applied topically. CONCLUSIONS: this study demonstrates the feasibility of the copolymer approach to develop extended-release insect repellents while reducing skin uptake and transdermal permeation of the small-molecular-weight active ingredient, in order to minimise any adverse effects.

Understanding the temperature induced aggregation of silica nanoparticles decorated with temperature-responsive polymers: Can a small step in the chemical structure make a giant leap for a phase transition?

Temperature-responsive nanomaterials have gained increasing interest over the past decade due their ability to undergo conformational changes in situ, in response to a change in temperature. One class of temperature-responsive polymers are those with lower critical solution temperature, which phase separate in aqueous solution above a critical temperature. When these temperature-responsive polymers are grafted to a solid nanoparticle, a change in their surface properties occurs above this critical temperature, from hydrophilic to more hydrophobic, giving them a propensity to aggregate. This study explores the temperature induced aggregation of silica nanoparticles functionalised with two isomeric temperature-responsive polymers with lower critical solution temperature (LCST) behavior, namely poly(N-isopropyl acrylamide) (PNIPAM), and poly(2-n-propyl-2-oxazoline) (PNPOZ) with similar molecular weights (5000 Da) and grafting density. These nanoparticles exhibited striking differences in the temperature of aggregation, which is consistent with LCST of each polymer. Using a combination of small-angle neutron scattering (SANS) and dynamic light scattering (DLS), we probed subtle differences in the aggregation mechanism for PNIPAM- and PNPOZ-decorated silica nanoparticles. The nanoparticles decorated with PNIPAM and PNPOZ show similar aggregation mechanism that was independent of polymer structure, whereby aggregation starts by the formation of small aggregates. A further increase in temperature leads to interaction between these aggregates and results in full-scale aggregation and subsequent phase separation.

Thiolated and PEGylated silica nanoparticle delivery to hair follicles.

Targeting drug delivery to hair follicles is valuable to treat conditions such as alopecia's and acne, and this shunt route may also allow drug delivery to deeper skin layers and the systemic circulation by avoiding the intact stratum corneum. Here, we investigated the effects of nanoparticle surface chemistry on their delivery into hair follicles by synthesizing fluorescent thiolated silica nanoparticles and functionalizing with 750 Da and 5000 Da methoxypolyethylene glycol maleimide (PEG). The stability of the nanoparticles in skin homogenate was verified before tape stripping of porcine-dosed tissue showed the distribution of the free fluorescent dye and different nanoparticles in the skin. Analysis of microscopic images of the skin sections revealed penetration of nanoparticles functionalized with PEG into the appendages whereas thiolated nanoparticles stayed on the surface of the skin and were removed by tape stripping. Nanoparticles functionalized with PEG 5000 Da penetrated deeper into the hair follicles compared to counterparts functionalized with PEG 750 Da. PEGylation can thus enhance targeted delivery of nanoparticulates into hair follicles.

Human skin explant model for the investigation of topical therapeutics.

The development of in vitro and ex vivo models to mimic human illness is important not only for scientific understanding and investigating therapeutic approaches but also to mitigate animal testing and bridge the inter-species translational gap. While in vitro models can facilitate high-throughput and cost-efficient evaluation of novel therapeutics, more complex ex vivo systems can better predict both desirable and adverse in vivo effects. Here we describe an ex vivo cultured human skin explant model in which we have characterized pathological tissue integrity, barrier function and metabolic stability over time. Our findings suggest that human skin can be successfully cultured for pharmacodynamic use up to and beyond 9 days without any adverse physiological consequence.

Planarian toxicity fluorescent assay: A rapid and cheap pre-screening tool for potential skin irritants.

Here we report a new planarian (Dugesia lugubris) fluorescent assay as a rapid and cheap pre-screening tool to predict strong skin irritants. Our aim was to provide a simple and cost-effective in vivo method that avoided use of higher vertebrates. Adapting previously reported methods for planaria mobility alongside an acute toxicity assay, different irritants at five concentrations (0.1%, 0.05%, 0.025%, 0.01% and 0.005% w/v) were tested but both methods failed to discriminate the irritation potential of the test compounds. Therefore, a new alternative fluorescence assay was developed, hypothesising that increasing damage from the irritant to the planarian outer protective membrane will increase accumulation of sodium fluorescein in the flatworm. Fourteen test chemicals were selected representing strong, moderate, mild and non-irritants. In general, results showed increasing sodium fluorescein accumulation within planaria following acute exposure to increasingly strong skin irritants; on exposure to the strong irritants, benzalkonium chloride, citronellal, methyl palmitate, 1-bromohexane and carvacrol, fluorescence within the planaria was significantly greater (P < 0.05) than the negative controls and the common non-irritants PEG-400, dipropylene glycol and isopropyl alcohol; fluorescence values of planaria tested with negative controls and non-irritants were not significantly different. For all test compounds, Fluorescence Intensity of the planaria was compared with literature Primary Irritation Index data and generated a statistically significant (P < 0.005) Pearson correlation (r) of 0.87. Thus, the planarian fluorescent assay is a promising tool for rapid early testing of potential strong skin irritants, and non-irritants, and avoids use of higher vertebrate models.

Nicotinamide restricts neural precursor proliferation to enhance catecholaminergic neuronal subtype differentiation from mouse embryonic stem cells.

Emerging evidence indicates that a strong relationship exists between brain regenerative therapies and nutrition. Early life nutrition plays an important role during embryonic brain development, and there are clear consequences to an imbalance in nutritional factors on both the production and survival of mature neuronal populations and the infant's risk of diseases in later life. Our research and that of others suggest that vitamins play a fundamental role in the formation of neurons and their survival. There is a growing body of evidence that nicotinamide, the water-soluble amide form of vitamin B3, is implicated in the conversion of pluripotent stem cells to clinically relevant cells for regenerative therapies. This study investigated the ability of nicotinamide to promote the development of mature catecholaminergic neuronal populations (associated with Parkinson's disease) from mouse embryonic stem cells, as well as investigating the underlying mechanisms of nicotinamide's action. Nicotinamide selectively enhanced the production of tyrosine hydroxylase-expressing neurons and serotonergic neurons from mouse embryonic stem cell cultures (Sox1GFP knock-in 46C cell line). A 5-Ethynyl-2´-deoxyuridine (EdU) assay ascertained that nicotinamide, when added in the initial phase, reduced cell proliferation. Nicotinamide drove tyrosine hydroxylase-expressing neuron differentiation as effectively as an established cocktail of signalling factors, reducing the proliferation of neural progenitors and accelerating neuronal maturation, neurite outgrowth and neurotransmitter expression. These novel findings show that nicotinamide enhanced and enriched catecholaminergic differentiation and inhibited cell proliferation by directing cell cycle arrest in mouse embryonic stem cell cultures, thus driving a critical neural proliferation-to-differentiation switch from neural progenitors to neurons. Further research into the role of vitamin metabolites in embryogenesis will significantly advance cell-based regenerative medicine, and help realize their role as crucial developmental signalling molecules in brain development.

Polymer structure and property effects on solid dispersions with haloperidol: Poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies.

Poly(2-methyl-2-oxazoline) (PMOZ), poly(2-propyl-2-oxazoline) (PnPOZ) and poly(2-isopropyl-2-oxazoline) (PiPOZ) were synthesized by hydrolysis of 50 kDa poly(2-ethyl-2-oxazoline) (PEOZ) and subsequent reaction of the resulting poly(ethylene imine) with acetic, butyric and isobutyric anhydrides, respectively. These polymers were characterized by proton nuclear magnetic resonance, FTIR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The poly(2-oxazolines) as well as poly(N-vinyl pyrrolidone) (PVP) were used to prepare solid dispersions with haloperidol, a model poorly soluble drug. Dispersions were investigated by powder X-ray diffractometry, differential scanning calorimetry and FTIR spectroscopy. Increasing the number of hydrophobic groups (-CH2- and -CH3) in the polymer resulted in greater inhibition of crystallinity of haloperidol in the order: PVP > PnPOZ = PEOZ > PMOZ. Interestingly, drug crystallization inhibition by PiPOZ was lower than with its isomeric PnPOZ because of the semi-crystalline nature of the former polymer. Crystallization inhibition was consistent with drug dissolution studies using these solid dispersions, with exception of PnPOZ, which exhibited lower critical solution temperature that affected the release of haloperidol.

Nicotinamide N-Methyltransferase: Genomic Connection to Disease.

Single-nucleotide polymorphisms (SNPs) in and around the nicotinamide N-methyltransferase (NNMT) gene are associated with a range of cancers and other diseases and conditions. The data on these associations have been assembled, and their strength discussed. There is no evidence that the presence of either the major or minor base in any SNP affects the expression of nicotinamide N-methyltransferase. Nevertheless, suggestions have been put forward that some of these SNPs do affect NNMT expression and thus homocysteine metabolism. An alternative idea involving non-coding messenger RNAs (mRNAs) is suggested as a possible mechanism whereby health is influenced. It is postulated that these long, non-coding NNMT mRNAs may exert deleterious effects by interfering with the expression of other genes. Neither hypothesis, however, has experimental proof, and further work is necessary to elucidate NNMT genetic interactions.

The 4 D's of Pellagra and Progress.

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.

Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions.

Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1A and 5-HT2A subtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.

Nicotinamide as Independent Variable for Intelligence, Fertility, and Health: Origin of Human Creative Explosions?

Meat and nicotinamide acquisition was a defining force during the 2-million-year evolution of the big brains necessary for, anatomically modern, Homo sapiens to survive. Our next move was down the food chain during the Mesolithic 'broad spectrum', then horticultural, followed by the Neolithic agricultural revolutions and progressively lower average 'doses' of nicotinamide. We speculate that a fertility crisis and population bottleneck around 40 000 years ago, at the time of the Last Glacial Maximum, was overcome by Homo (but not the Neanderthals) by concerted dietary change plus profertility genes and intense sexual selection culminating in behaviourally modern Homo sapiens. Increased reliance on the 'de novo' synthesis of nicotinamide from tryptophan conditioned the immune system to welcome symbionts, such as TB (that excrete nicotinamide), and to increase tolerance of the foetus and thereby fertility. The trade-offs during the warmer Holocene were physical and mental stunting and more infectious diseases and population booms and busts. Higher nicotinamide exposure could be responsible for recent demographic and epidemiological transitions to lower fertility and higher longevity, but with more degenerative and auto-immune disease.