Emerging drugs for the treatment of vitiligo.

Introduction: Vitiligo is a relatively common autoimmune depigmenting disorder of the skin. There has been a great advance in understanding the pathological basis, which has led to the development and utilization of various new molecules in treating vitiligo. This review aims at a comprehensively describing the treatments available and the emerging treatment aspects and the scope for future developments.Areas covered: This study comprehensively summarizes the current concepts in the pathogenesis of vitiligo with special focus on the cytokine and signaling pathways, which are the targets for newer drugs. JAK kinase signaling pathways and the cytokines involved are the focus of vitiligo treatment in current research, followed by antioxidant mechanisms and repigmenting mechanisms. Topical immunosuppressants may be an alternative to steroids in localized vitiligo. Newer repigmenting agents like basic fibroblast growth factors, afamelanotide have been included and a special emphasis is laid on the upcoming targeted immunotherapy.Expert opinion: The treatment of vitiligo needs to be multimodal with emphasis on targeting different limbs of the pathogenesis. Topical and oral JAK inhibitors are the most promising new class of drugs currently available for treating vitiligo and acts best in conjunction with NB-UVB.

Depression, isotretinoin, and folic acid: A practical review.

Isotretinoin (ISO) is a first-generation retinoid discovered in 1952 and approved by the FDA for the treatment of nodulocystic acne in 1982. The anti-inflammatory properties of ISO have found its use in disorders other than acne. ISO can create psychiatric problems, including depression and suicidal ideation. These neuropsychiatric problems are very similar to disorders secondary to hyperhomocysteinemia (HHcy), vitamin B12, and folic acid (vitamin B9) deficiencies. Given that previous literature suggested folate supplementation improved the efficacy of traditional antidepressant medications, clinicians may wish to consider folate supplementation for patients with depression or possible depressive symptoms, such as acne patients with genetic susceptibility. Brain-derived neurotrophic factor may be a cytokine-specific screening biomarker in immune-based antidepressive therapy.

Psychological Impact of Melanoma, How to Detect, Support and Help.

Incidence of melanoma is increasing every year. A few years ago, we could not speak about long term survivors with melanoma. Chemotherapy did not give a good effect in the past. Metastasis occurred very rapidly, and the progression of melanoma was very fast. But now, with new forms of therapy, especially immunotherapy and target therapy, for the first time, we have long-time survivors. For the prognosis of melanoma, the most important is the stage in which melanoma is detected. For all dermatologists, it is very important to be aware of the psychological impact of melanoma on patients. Dermatologists should recognise psychological disorders. Several different scales can be used for the detection of depression and anxiety - some of them are completed by researchers, some of them are completed by patients, and also, we have combined scales. The need for adequate social and family support as well as psychological help to achieve better coping with illness is necessary. Learning techniques to overcome fear and stress would help in better functioning of all affected, regardless of the stage of the disease. The most severe cases of anxiety and depression, in addition to psychotherapeutic interventions, should also be considered medication therapy.

Melanoma and Mastocytosis.

There are numerous cases reports and studies confirming the enhanced incidence of melanoma among patients with mastocytosis, especially with systemic mastocytosis. These two diseases are arising from two different types of cells; melanoma arises from neural crest cells and mastocytosis from hematopoietic stem cells. But there are a lot of similarities between the two diseases. The most important and significant is the dependence of the growth factor receptor c-KIT and c-KIT ligand (stem cell factor) for their growth and development. Also, expression of the STAT3 (signal transducer and activator of transcription 3) and transcription factors MITF (microphthalmia-associated transcription factor) make the connection between melanoma and mastocytosis.

Clinical Applications of System Regulation Medicine.

Increasing incidence and poor outcome of chronic non-communicable diseases in western population would require a paradigm shift in the treatments. Guidelines-based medical approaches continue to be the standard rule in clinical practice, although only less than 15% of them are based on high-quality research. For each person who benefits from the 10 best-selling drugs in the USA, a number between 4 and 25 has no one beneficial effect. The reductionist linear medicine method does not offer solutions in the non-manifest preclinical stage of the disease when it would still be possible to reverse the pathological progression and the axiom "a drug, a target, a symptom" are still inconclusive. Needs additional tools to address these challenges. System Medicine considers the disease as a dysregulation of the biological networks that changes throughout the evolution of the pathological process and with the comorbidities development. The strength of the networks indicates their ability to withstand dysregulations during the perturbation phases, returning to the state of stability. The treatment of dysregulated networks before the symptomatological manifestation emerges offers the possibility of treating and preventing pathologies in the preclinical phase and potentially reversing the pathological process, stopping it or preventing comorbidities. Furthermore, treating shared networks instead of individual phenotypic symptoms can reduce drug use, offering a solution to the problem of ineffective drug use.

The Impact of Immunological Factors on Depression Treatment - Relation Between Antidepressants and Immunomodulation Agents.

It is determined that 30% of patients with depression are resistant to antidepressant medication. The increased concentration of inflammation factors, such as C-reactive protein, and pro-inflammatory cytokines, have been detected in serum in these patients. It is necessary to establish new therapeutic possibilities and protocols that are created to overcome the difficulties caused by increased concentration of inflammatory biomarkers in depressive patients. The Selective Serotonin Reuptake Inhibitors (SSRIs) are considered to be the most powerful antidepressants, increasing the level of serotonin in endogenous depression, as well as in that caused by immunological mechanisms. It is believed that agents that influence cytokines, immunological signal pathways and cytokine syntheses, like the inhibitors of cyclooxygenase enzyme and other non-steroidal anti-inflammatory drugs (NSAIDs), are very important in the potential treatment of residual symptoms of depression. Treatment with cytokine antagonists is one of the potential adjuvant therapies, along with antidepressants. Signal pathways blockers, such as the inhibitors of cyclooxygenase and other NSAIDs, are in the phase of research, in terms of their antidepressant effects. Also, it has been shown that the inhibition of indolamin-2,3 deoxygenase (IDO) and kynurenine (KYN) signal pathways in the synthesis of neurotransmitters, by application of IDO antagonists, are leading to suppression of pro-inflammatory cytokine effects. Antidepressants may have anti-inflammatory effects, depending on dose and type, and they achieve this effect through the decrease of pro-inflammatory cytokine production and increase of anti-inflammatory cytokines. Also, antidepressants modulate the humoral and cellular immune system. This work aims to summarise certain neurobiological and neuroimmunological specificities that have been observed in patients with depression, antidepressants and immunomodulation agents. The understanding of complex and heterogenic pathophysiology of depression through the prism of the altered immune system, is of major importance, in terms of better optimisation of pharmacotherapy, and options for a personalised approach in depressive disorder treatment.

A Black Hole at the Center of Earth Plays the Role of the Biggest System of Telecommunication for Connecting DNAs, Dark DNAs and Molecules of Water on 4+N- Dimensional Manifold.

Recently, some scientists from NASA have claimed that there may be a black hole like structure at the centre of the earth. We show that the existence of life on the earth may be a reason that this black hole like object is a black brane that has been formed from biological materials like DNA. Size of this DNA black brane is 109 times longer than the size of the earth's core and compacted interior it. By compacting this long object, a curved space-time emerges, and some properties of black holes emerge. This structure is the main cause of the emergence of the large temperature of the core, magnetic field around the earth and gravitational field for moving around the sun. Also, this structure produces some waves which act like topoisomerase in biology and read the information on DNAs. However, on the four-dimensional manifold, DNAs are contracted at least four times around various axis's and waves of earth couldn't read their information. While, by adding extra dimensions on 4 +n-dimensional manifold, the separation distance between particles increases and all of the information could be recovered by waves. For this reason, each DNA has two parts which one can be seen on the four-dimensional universe, and another one has existed in extra dimensions, and only it's e_ects is observed. This dark part of DNA called as a dark DNA in an extra dimension. These dark DNAs not only exchange information with DNAs but also are connected with some of the molecules of water and helps them to store information and have memory. Thus, the earth is the biggest system of telecommunication which connects DNAs, dark DNAs and molecules of water.

Recovery of Brain in Chick Embryos by Growing Second Heart and Brain.

To recover chick embryos damaged the brain, two methods are presented. In both of them, somatic cells of an embryo introduced into an egg cell and an embryo have emerged. In one method, injured a part of the brain in the head of an embryo is replaced with a healthy part of the brain. In the second method, the heart of brain embryo dead is transplanted with the embryo heart. In this mechanism, new blood cells are emerged in the bone marrow and transmit information of transplantation to subventricular zone (SVZ) of the brain through the circulatory system. Then, SVZ produces new neural stem cells by a subsequent dividing into neurons. These neurons produce new neural circuits within the brain and recover the injured brain. To examine the model, two hearts of two embryos are connected, and their effects on neural circuits are observed.

Beta Blockers and Melanoma.

Understanding the mechanisms of cancer immune-tolerance is one of the most important challenges. Several studies have demonstrated the potential anticarcinogenic effects of beta-blockers, in patients with prostate cancer, breast cancer, and melanoma. At the other side variety of dermatoses may be caused or aggravated by ß-blockers-psoriasis, lichen planus-like drug eruptions (LDE), acrocyanosis, alopecia etc. Beta-blockers have been shown to improve the prognosis of melanoma patients significantly. Propranolol inhibits melanoma by downregulating the tumour angiogenesis but also tumour cell proliferation, invasiveness and local immune suppression. Studies showed that only ß3-but, not ß2-adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. They increased NK and CD8 number and cytotoxicity. Catecholamines may retard melanoma progression and that ß-blockers may have unrecognised potential as a therapeutic intervention for melanoma, in the prevention of the growth of melanoma in all stages and as adjuvant therapy with other targeted and immune therapies for melanoma.

Formation of Neural Circuits in an Expanded Version of Darwin's Theory: Effects of DNAs in Extra Dimensions and within the Earth's Core on Neural Networks.

AIM: In this paper, inspiring Darwin's theory, we propose a model which connects evolutions of neural circuits with evolutions of cosmos. In this model, in the beginning, there are some closed strings which decay into two groups of open strings. METHODS: First group couple to our universe from one side and produce matters like some genes of DNAs and couple to an anti-universe from another side with opposite sign and create anti-matters like some anti-genes of anti-DNAs. Second group couple to the star and planet's cores like the earth's core from one side and produce anti-matters like stringy black anti-DNA and couple to outer layers of stars and planets like the earth from other side and produce matters like some genes of DNAs on the earth. Each DNA or anti-DNA contains some genetic circuits which act like the circuits of receiver or sender of radio waves. To transfer waves of these circuits, some neurons emerge which some of them are related to genetic circuits of anti-DNAs in anti-universe, and some are related to genetic circuits of stringy black anti-DNA within the earth's core. A collection of these neural circuits forms the little brain on the heart at first and main brain after some time. RESULTS: To examine the model, we remove effects of matters in outer layers of earth in the conditions of microgravity and consider radiated signals of neural circuits in a chick embryo. We observe that in microgravity, more signals are emitted by neural circuits respect to normal conditions. This is a signature of exchanged waves between neural circuits and structures within the earth's core. CONCLUSION: These communications help some animals to predict the time and place of an earthquake.

Psychotherapy Role in Treatment of Chronic Spontaneous Urticaria in a 32 Years Old Female Patient.

As indicated by the latest scientific evidence, the lines between different fields of medicine gradually blur and overlap more and more. Psychiatry and dermatology have seen this trend in the last decade as an ever-increasing number of studies suggest the strong connection of many dermatological syndromes and diseases with psychiatric conditions and vice versa. It seems that the relationship is more intertwined than previously believed and the effects of different multidisciplinary approaches to diagnostic and treatment are being considered. The aim of this case report is to highlight the effect of psychotherapy on chronic spontaneous urticaria which is tightly related to the maladaptive stress response.

Autologous Fat Graft: Not Only an Aesthetic Solution.

Subcutaneous adipose tissue was defined as the "perfect filler" as is soft and malleable and is usually enough present in the body for correcting volume defects and small remodelling purposes. The first attempts to implant autologous adipose tissue dates back to the end of the twentieth century, and with the refinement of harvesting, processing and replanting techniques today a uniform and predictable amount of survival rate were achieved. Those improvements have led to wider use of autologous fat grafts in many medical specialities not only in aesthetic or reconstructive treatments.

Botulin Toxin Use in Scars/Keloids Treatment.

Botulinum toxin (BTX) is a neurotoxin protein derived from the Clostridium botulinum bacterium that inhibits the release of acetylcholine at the neuromuscular junction level whose effects has been used for many years to treat a variety of muscular/neuromuscular conditions and more recently also for cosmetic use. BTX has experimented in some dermatological conditions which include scar prevention and treatment with good results The complex mechanism underlying those results is not completely understood but several mechanisms were proposed release inhibition of different substances like (TGF)-ß, substance P, calcitonin gene-related peptide (CGRP) and glutamate thus modulating cutaneous inflammation and wound healing. We analysed the published data on BTX off label applications on scars and keloids retrieved from PubMed.

Botulin Toxin Use in Rosacea and Facial Flushing Treatment.

Botulinum toxin (BTX) is a neurotoxin derived from the Clostridium botulinum bacterium that inhibits the release of acetylcholine at the neuromuscular junction level whose effects has been used for many years to treat a variety of muscular/neuromuscular conditions and more recently also for cosmetic use. BTX has experimented in some dermatological conditions, which include Rosacea and facial flushing treatment with good results. The complex mechanism underlying those results is not completely understood but was proposed a release inhibition of acetylcholine from peripheral autonomic nerves of the cutaneous vasodilatory system combined with the blockade substance P and calcitonin gene-related peptide (CGRP) thus modulating blood vessel dilatation. We analysed the published data on BTX off label applications rosacea and flushing retrieved from PubMed.

New System Delivering Microwaves Energy for Inducing Subcutaneous Fat Reduction: In - Vivo Histological and Ultrastructural Evidence.

BACKGROUND: Recently, it has been developed a new technology for the reduction of subcutaneous adipose tissue through a non-invasive treatment by microwaves. The main objective of the present study is to demonstrate the feasibility of utilising a non-invasive, localised microwaves (MW) device to induce thermal modifications into subcutaneous adipose tissue only by a controlled electromagnetic field that heats up fat preferentially. This device is provided with a special handpiece appropriately cooled, directly contacting the cutaneous surface of the body, which provides a calibrated energy transfer by microwaves. AIM: In this paper, microscopic and ultrastructural modifications of subcutaneous adipose tissue induced by microwaves irradiation are evaluated. METHODS: Our experimental plan was designed for collecting biopsy samples, for each skin region treated with a single irradiation session, 1) before treatment (control), 2) immediately after treatment, 3) after 6 hrs, 4) after 1 month, 5) after 2 months. Bioptic samples from each step were processed for light microscopy and transmission electron microscopy. At the same time, each region where biopsies were collected was subjected to ultrasound examination. Recorded images permitted to evaluate the thickness of different layers as epidermis, dermis, hypodermis, connective fasciae, until to muscle layer, and related modifications induced by treatment. RESULTS: In every biopsy collected at different time-steps, epidermis and superficial dermis appeared not modified compared to control. Differently, already in the short-term biopsies, in the deep dermis and superficial hypodermis, fibrillar connective tissue appeared modified, showing reduction and fragmentation of interlobular collagen septa. The most important adipose tissue modifications were detectable following 1 month from treatment, with a significant reduction of subcutaneous fat, participating both the lysis of many adipocytes and the related phagocytic action of monocytes/macrophages on residuals of compromised structures of adipocytes. In the samples collected two months following treatment, the remnants of adipose tissue appeared normal, and macrophages were completely absent. CONCLUSIONS: Ultrasound, microscopic and ultrastructural evidence are supporting significant effectiveness of the new device treatment in the reduction of subcutaneous fat. In this paper, the possible mechanisms involved in the activation of the monocytes/macrophages system responsible for the removal of adipocytes residuals have also been discussed.

Gut Microbiota and the Alteration of Immune Balance in Skin Diseases: From Nutraceuticals to Fecal Transplantation.

The P.N.E.I. (Psycho-Neuro-Endocrine-Immunology) approach is represented by the interdisciplinary concept of bidirectional cross-talk between the psycho-neuro-endocrine and immune systems, which can influence the immune response. The well-known Gut-Brain Axis and the Gut-Skin Axis can be merged in a bigger network- the Gut-Brain-Skin Axis, with complex regulation by cytokines, neuro-peptides, neuro-hormones and another messenger (signalling) molecules and maybe the most important modulator of the Gut-Brain-Skin Axis/ the gut microbiota. The role of gut bacterial homeostasis is very important, and the homeostatic imbalance of the immune response may be a relevant etiologic/pathophysiologic factor for extra-intestinal and intestinal inflammatory, allergic and autoimmune diseases. The Low Dose Cytokines Medicine (LDM) is an innovative therapeutic approach. It is based on the most advanced knowledge in molecular biology and low dose pharmacology with the primary outcome. The SKA (Sequential Kinetic Activation) technology, codified and standardised by GUNA S.p.a. -Italy- makes the low doses of signalling molecules able to be active even below the minimum dose classically considered as effective and the significative efficacy of orally administered low-dose signalling molecules is the most representative aspect of LDM. The Physiologic Nutraceuticals and the Low Dose Medicine are two of the most promising approaches for the treatment of skin diseases based on the rebalance of the immune response and the recovery of gut dysbiosis.

New Trends in Cutaneous Melanoma Surgery.

The main surgical treatment for melanoma consists in wide surgical excision of the primary lesion and the sentinel node but in recent times management of melanoma is rapidly evolving with the introduction of new systemic therapies, like BRAF inhibitors, MEK inhibitors and antibodies anti-PD-1 that show good results in controlling even advanced stages of the disease. This review aims to present data for the optimal surgical management of patients with malignant melanoma.

The Effects of Magnesium - Melatonin - Vit B Complex Supplementation in Treatment of Insomnia.

Insomnia means difficulty in falling asleep and/or stays asleep. Insomnia commonly leads to daytime sleepiness, lethargy, and a general feeling of being unwell. The most common treatment of insomnia includes GABAA receptor positive allosteric modulators or Melatonin agonists. Our study aimed to evaluate the efficacy of Magnesium- melatonin-vitamin B complex supplement in the treatment of insomnia. The study included 60 patients diagnosed with insomnia. The patients were randomly divided into study group (N = 30), and control group (N = 30), and study group was treated with Magnesium-melatonin-vitamin B complex (one dose contains 175 mg liposomal magnesium oxide, 10 mg Vit B6, 16 µg vit B12, melatonin 1 mg, Extrafolate-S 600 µg) once a day 1 hour before sleep, during the 3 months. The severity of insomnia symptoms was measured by self-reported Athens insomnia scale (AIS), with a cut-off score by Soldatos (AIS score ≥ 6). Mean AIS score at zero points was 14.93 ± 3.778 in the study group and 14.37 ± 4.081 in the control group (p = 0.476), indicating the compatibility of the groups, and both scores correspond to mild to moderate insomnia. Mean AIS score after 3 months of the Magnesium- melatonin- vitamin B complex supplementation was 10.50 ± 4.21 corresponding to mild insomnia, while median AIS score in the control group was 15.13 ± 3.76 which is referred to moderate insomnia, and difference among groups was significant (p = 0.000). Our founding's indicating that 3 months of the Magnesium- melatonin-vitamin B complex supplementation has a beneficial effect in the treatment of insomnia regardless of cause.

In Ovo Sexing of Chicken Eggs by Virus Spectroscopy.

Recently, some new methods for sexing of chicken eggs by fluorescence and Raman spectroscopy through the shell membrane have been proposed. On the other hand, in another investigation, a new virus medical imaging has been suggested. In this research, summing over these considerations, a new technique for sexing of chicken eggs by virus spectroscopy through the shell membrane is proposed. It is shown that viruses outside the shell of egg can communicate with materials inside it and determine the gender of chick embryo and it's evolutions.

DNA Waves and Their Applications in Biology.

AIM: In this research, we show that DNA waves have many applications in biology. DNA is formed by the joining of quantum particles like electrons and charged atoms. DNA has different motions during transcription, translation, and replication, in which the charged particles move, accelerate, and emit waves. Thus, DNA could emit quantum waves. METHODS: Two methods are proposed to observe the effect of DNA waves. The first proposed method measures DNA waves emitted by bacteria suspended in the milk. The vessel of milk is placed in the interior of an inductor. One side of the vessel is connected to a generator and another side to a scope. By sending a current to the inductor, an input electromagnetic field is produced. Bacteria interact with the input field, change it and produce new output signals. Using the scope, the output signals are observed and compared with the input signals. The number of DNA waves produced also depends on temperature. RESULTS: At lower temperatures, bacterial replication is less, and fewer DNA waves are produced. Conversely, more bacteria are generated at higher temperatures, and more DNA waves are produced. The second proposed method acquires and images of DNA signals of chick embryos. In this method, a circuit is constructed that consists of a graphene or metal tube, generator, inductor, scope, DNA in the interior of eggs and DNA exterior to the eggs. Magnetic waves pass the interior and exterior DNA as well as the graphene. The DNA is excited and the exciting interior/exterior DNA exchanges waves. Some of these waves interact with electrons in the graphene tube, and a current is generated. Properties of the chick embryo DNA can be explored by analysing changes in the waves that emerge from the eggs. CONCLUSION: It is concluded that DNA waves could be used extensively in imaging and provide for us the exact information about evolutions of DNAs interior of biological systems.