Sexual Orientation in Twins: Evidence That Human Sexual Identity May Be Determined Five Days Following Fertilization.

Human same-sex sexual attraction has been recorded from the beginning of written history. It remains a controversial topic, but recent theories favor prenatal influences. A paradox is the occurrence of same-sex orientation in twins in that there is a higher level of concordance in monozygous twins compared to that in dizygous twins or non-twin siblings. If sexual orientation was entirely genetically determined monozygous twins would be expected to have identical sexual inclinations. Monozygous twins have twice the incidence of sexual concordance in comparison to dizygous twins but a third of these pairs have different sexual identities. An explanation for this disparity may lie in the time an embryo splits to form two separate fetuses. If splitting occurs early in twin development each twin may develop his or her own sexual identity; splitting occurring later results in twins that have the same sexual dispositions. A possible process for such determination may be in the mitochondria, with universal maternal inheritance of a proportion of normal functioning but alternate mitochondria. Variation in the distribution of these mitochondria in neural precursor cells becomes a mechanism for the development of intrinsic sexual orientation and for the spectrum of human sexual inclinations. The timing of embryonic splitting may be determined from the examination of fetal membranes, and the concept of early fetal sexual orientation is open to support or disproval.

Diagnoses for Charles Darwin's Illness: A Wealth of Inaccurate Differential Diagnoses.

Charles Darwin suffered from a relapsing, debilitating illness for much of his adult life with numerous, differing symptoms. His occasional problems as a student, his seasickness throughout the voyage of the HMS Beagle, and his brief illnesses when ashore in South America and Australia were all early expressions of this illness. Diagnoses for Darwin's illness are as numerous as his symptoms and are equally variable. Many diagnoses reflect the medical fashion of their time; psychological and psychogenic diagnoses once flourished. These diagnoses have recently been comprehensively reviewed in an uncritical and unbiased account. Rather than a repeat review of diagnoses this paper aims to critique and make a critical appraisal of the diagnoses given. As stated, they are not all right. Some are not wrong but are simply incomplete. Pathological mitochondrial DNA (mtDNA) mutations are the cause of a variety of childhood diseases and more recently have been recognized as the cause of some adult-onset conditions with a plethora of presenting symptoms. The diagnosis favored here is that Darwin suffered from such a disorder due in his case to a maternally inherited pathological mtDNA mutation. This proposal should be seen in the context of self-certainty and subject to similar critical appraisal. Diagnosing Darwin may have a unique, correct solution, a solution that would benefit those who suffer from a similar disorder today and who, like Darwin, are misdiagnosed, misunderstood, and inappropriately treated.

Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes/Leigh Overlap Syndrome Due to Variant m.13513G>A in MT-ND5.

Mitochondrial disorders are caused due to variants in genes located on the mitochondrial DNA or the nuclear DNA. Here, we report a case with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh overlap syndrome due to variant m.13513G>A in ND5. A 60-month-old female with a congenital, complex, multisystem phenotype was diagnosed with MELAS/Leigh overlap syndrome due to variant m.13513G>A in ND5. Brainstem involvement resulted in dysphagia, dysarthria, and respiratory failure with recurrent episodes of aspiration, respiratory insufficiency, desaturations, lack of respiratory drive, hypercapnia, and pneumonia. Treatment was symptomatic and included non-invasive ventilation, antibiotics, implantation of a percutaneous endoscopic gastrostomy, anti-seizure drugs, anti-dystonia medication, a cocktail of vitamins and antioxidants, and analgesics. Despite these measures, the outcome was poor as the patient died at the age of 62 months after being discharged to home palliative care. In summary, the m.13513G>A variant can manifest as MELAS/Leigh overlap syndrome with Leigh syndrome dominating. Because of brainstem involvement leading to respiratory dysfunction, dysarthria, and dysphagia, the outcome is poor, despite symptomatic measures.

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) in the 18th Century: Mitochondrial Disorders Are Not of Recent Origin.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was one of the first mitochondrial disorders to be identified and characterized, being described as early as 1984. The clinical manifestations of MELAS vary but stroke-like episodes are a defining feature. Mutations in at least 17 mitochondrial DNA (mtDNA) located genes have been shown to be associated with this disorder. Mary Ann, the youngest child of Josiah and Sarah Wedgwood, was born in August 1778 when Sarah was aged 44 years. Mary Ann was of short stature and was physically and mentally retarded. She suffered from partial and generalized seizures and episodes of cortical blindness. She died at the age of eight years. Descriptions of her illness remain and she is depicted with disabilities as can be seen in a family portrait. Her illness is consistent with MELAS. The illnesses of her elder siblings and of their mother are in keeping with a maternally inherited pathological mtDNA mutation, supporting this diagnosis. Her illness is the key to the remarkable illnesses that affected the Wedgwood family. Through her eldest sibling, Susannah, married to Robert Darwin, the disorder was passed to the next generation, a generation that included Charles Darwin and his elder brother, Erasmus.

Charles Darwin's Mitochondrial Disorder: Possible Neuroendocrine Involvement.

Charles Darwin, the famous naturalist, suffered relapsing, debilitating illness for most of his adult life with a plethora of symptoms. The diagnosis favoured here for this illness is that of an adult-onset mitochondrial disorder due to a maternally inherited, pathological mitochondrial DNA mutation clinically manifesting as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome. This diagnosis accounts for Darwin's primary symptoms; in addition, it accounts for the various unusual illnesses that afflicted his siblings and maternal (Wedgwood) ancestors. Symptoms of Darwin's illness may be related to dysfunction of cells with high energy requirements; this includes cells constituting the cardiac conduction system, cerebral endothelial cells, neurons, neuroepithelial cells of the vestibular apparatus, and, as proposed here, central and peripheral neuroendocrine cells. Although Darwin's episodes of sudden facial flushing, his nocturnal panic attacks, and his severe gastrointestinal symptoms are not readily explained, these symptoms may relate to neuroendocrine dysfunction, either an uncontrolled release of stimulatory hormone or impaired inhibitory control. It is also conceivable that the autonomic system had been involved. A study of Darwin's illness may benefit those who suffer from similar symptoms today.

British Society of Gastroenterology guidelines for oesophageal manometry and oesophageal reflux monitoring.

These guidelines on oesophageal manometry and gastro-oesophageal reflux monitoring supersede those produced in 2006. Since 2006 there have been significant technological advances, in particular, the development of high resolution manometry (HRM) and oesophageal impedance monitoring. The guidelines were developed by a guideline development group of patients and representatives of all the relevant professional groups using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. A systematic literature search was performed and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) tool was used to evaluate the quality of evidence and decide on the strength of the recommendations made. Key strong recommendations are made regarding the benefit of: (i) HRM over standard manometry in the investigation of dysphagia and, in particular, in characterising achalasia, (ii) adjunctive testing with larger volumes of water or solids during HRM, (iii) oesophageal manometry prior to antireflux surgery, (iv) pH/impedance monitoring in patients with reflux symptoms not responding to high dose proton pump inhibitors and (v) pH monitoring in all patients with reflux symptoms responsive to proton pump inhibitors in whom surgery is planned, but combined pH/impedance monitoring in those not responsive to proton pump inhibitors in whom surgery is planned. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG.

British Society of Gastroenterology guidelines for oesophageal manometry and oesophageal reflux monitoring

These guidelines on oesophageal manometry and gastro-oesophageal reflux monitoring supersede those produced in 2006. Since 2006 there have been significant technological advances, in particular, the development of high resolution manometry (HRM) and oesophageal impedance monitoring. The guidelines were developed by a guideline development group of patients and representatives of all the relevant professional groups using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. A systematic literature search was performed and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) tool was used to evaluate the quality of evidence and decide on the strength of the recommendations made. Key strong recommendations are made regarding the benefit of: (i) HRM over standard manometry in the investigation of dysphagia and, in particular, in characterising achalasia, (ii) adjunctive testing with larger volumes of water or solids during HRM, (iii) oesophageal manometry prior to antireflux surgery, (iv) pH/impedance monitoring in patients with reflux symptoms not responding to high dose proton pump inhibitors and (v) pH monitoring in all patients with reflux symptoms responsive to proton pump inhibitors in whom surgery is planned, but combined pH/ impedance monitoring in those not responsive to proton pump inhibitors in whom surgery is planned. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG.

Charles Darwin and the Dentists.

Charles Darwin suffered relapsing, debilitating illness for most of his adult life with many symptoms. His most prominent complaints were episodic nausea, retching and vomiting. As is common in patients with repeated vomiting he developed dental problems, problems that may be dated back to his voyage on the Beagle and his vomiting due to persistent seasickness. Dental problems continued after the voyage and he was one of the first patients to have extractions under chloroform. Watching a dental procedure caused Darwin great distress, much as surgical and obstetric procedures had previously caused him distress with onset of symptoms. Darwin's dental experiences are consistent with the proposed diagnosis of his lifetime illness- patients with similar illnesses today have much the same dental problems. Dentists also helped Darwin with his researches and collection of specimens. In Darwin's day, dentists, like country clergymen, had time to follow other interests. Dentists contributed to Darwin's dental health, to the dental health of his family and to Darwin's work and biological studies. Dentists, in their own right, were also prominent in developing our biological understanding.

Cyclic vomiting syndrome in multisystem mitochondrial disorder.

BACKGROUND: Cyclic vomiting syndrome (CVS) is characterized by recurrent episodes of incapacitating nausea or vomiting accompanied by abdominal pain, interspersed with relatively symptom-free intervals that might last from a few weeks to months. There are a number of indications that CVS could be a manifestation of a mitochondrial disorder (MID). AIM: To illustrate how a MID may present with symptoms typical of CVS. CASE: A 31 year old female diagnosed as having CVS since birth had additional features of short stature, deafness, irritable bowel syndrome, cardiomyopathy with myocardial thickening in the absence of arterial hypertension, hepatopathy with steatosis hepatis, myopathy, and polyarthrosis. Her family history was positive for diabetes, short stature, and migraine with a maternal mode of inheritance, frequently found in patients with MIDs. Frequency of CVS episodes decreased with age but other manifestations of the MID became worse over time. Due to the multisystem nature of the disease and the positive family history, a MID was assumed. CONCLUSIONS: Early-onset CVS often improves in adulthood. CVS may be associated with multisystem disease, suggesting the presence of a MID. CVS should be regarded as a manifestation of a MID if typical clinical manifestations of a MID, which cannot be explained by other causes, are present.

Mitochondrial disorder caused Charles Darwin's cyclic vomiting syndrome.

BACKGROUND: Charles Darwin (CD), "father of modern biology," suffered from multisystem illness from early adulthood. The most disabling manifestation was cyclic vomiting syndrome (CVS). This study aims at finding the possible cause of CVS in CD. METHODS: A literature search using the PubMed database was carried out, and CD's complaints, as reported in his personal writings and those of his relatives, friends, colleagues, biographers, were compared with various manifestations of mitochondrial disorders (MIDs), known to cause CVS, described in the literature. RESULTS: Organ tissues involved in CD's disease were brain, nerves, muscles, vestibular apparatus, heart, gut, and skin. Cerebral manifestations included episodic headache, visual disturbance, episodic memory loss, periodic paralysis, hysterical crying, panic attacks, and episodes of depression. Manifestations of polyneuropathy included numbness, paresthesias, increased sweating, temperature sensitivity, and arterial hypotension. Muscular manifestations included periods of exhaustion, easy fatigability, myalgia, and muscle twitching. Cardiac manifestations included episodes of palpitations and chest pain. Gastrointestinal manifestations were CVS, dental problems, abnormal seasickness, eructation, belching, and flatulence. Dermatological manifestations included painful lips, dermatitis, eczema, and facial edema. Treatments with beneficial effects to his complaints were rest, relaxation, heat, and hydrotherapy. CONCLUSION: CVS in CD was most likely due to a multisystem, nonsyndromic MID. This diagnosis is based upon the multisystem nature of his disease, the fact that CVS is most frequently the manifestation of a MID, the family history, the variable phenotypic expression between affected family members, the fact that symptoms were triggered by stress, and that only few symptoms could not be explained by a MID.

Charles Darwin's mitochondria.

Charles Darwin's long-term illness has been the subject of much speculation. His numerous symptoms have led to conclusions that his illness was essentially psychogenic in nature. These diagnoses have never been fully convincing, however, particularly in regard to the proposed underlying psychological background causes of the illness. Similarly, two proposed somatic causes of illness, Chagas disease and arsenic poisoning, lack credibility and appear inconsistent with the lifetime history of the illness. Other physical explanations are simply too incomplete to explain the range of symptoms. Here, a very different sort of explanation will be offered. We now know that mitochondrial mutations producing impaired mitochondrial function may result in a wide range of differing symptoms, including symptoms thought to be primarily psychological. Examination of Darwin's maternal family history supports the contention that his illness was mitochondrial in nature; his mother and one maternal uncle had strange illnesses and the youngest maternal sibling died of an infirmity with symptoms characteristic of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), a condition rooted in mitochondrial dysfunction. Darwin's own symptoms are described here and are in accord with the hypothesis that he had the mtDNA mutation commonly associated with the MELAS syndrome.

Climate and landscape factors associated with Buruli ulcer incidence in Victoria, Australia.

BACKGROUND: Buruli ulcer (BU), caused by Mycobacterium ulcerans (M. ulcerans), is a necrotizing skin disease found in more than 30 countries worldwide. BU incidence is highest in West Africa; however, cases have substantially increased in coastal regions of southern Australia over the past 30 years. Although the mode of transmission remains uncertain, the spatial pattern of BU emergence in recent years seems to suggest that there is an environmental niche for M. ulcerans and BU prevalence. METHODOLOGY/PRINCIPAL FINDINGS: Network analysis was applied to BU cases in Victoria, Australia, from 1981-2008. Results revealed a non-random spatio-temporal pattern at the regional scale as well as a stable and efficient BU disease network, indicating that deterministic factors influence the occurrence of this disease. Monthly BU incidence reported by locality was analyzed with landscape and climate data using a multilevel Poisson regression approach. The results suggest the highest BU risk areas occur at low elevations with forested land cover, similar to previous studies of BU risk in West Africa. Additionally, climate conditions as far as 1.5 years in advance appear to impact disease incidence. Warmer and wetter conditions 18-19 months prior to case emergence, followed by a dry period approximately 5 months prior to case emergence seem to favor the occurrence of BU. CONCLUSIONS/SIGNIFICANCE: The BU network structure in Victoria, Australia, suggests external environmental factors favor M. ulcerans transmission and, therefore, BU incidence. A unique combination of environmental conditions, including land cover type, temperature and a wet-dry sequence, may produce habitat characteristics that support M. ulcerans transmission and BU prevalence. These findings imply that future BU research efforts on transmission mechanisms should focus on potential vectors/reservoirs found in those environmental niches. Further, this study is the first to quantitatively estimate environmental lag times associated with BU outbreaks, providing insights for future transmission investigations.

Deep-diving dinosaurs.

Dysbaric bone necrosis demonstrated in ichthyosaurs may be the result of prolonged deep diving rather than rapid ascent to escape predators. The bone lesions show structural and anatomical similarity to those that may occur in human divers and in the deep diving sperm whale, Physeter macrocephalus.

Mediator subunit 12 is required for neutrophil development in zebrafish.

Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact between the general RNA polymerase II transcriptional machinery and enhancer bound regulatory factors. We have identified a new zebrafish med12 allele, syr, with a single missense mutation causing a valine to aspartic acid change at position 1046. Syr shows defects in hematopoiesis, which predominantly affect the myeloid lineage. Syr has identified a hematopoietic cell-specific requirement for Med12, suggesting a new role for this transcriptional regulator.

mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish.

Macrophages and neutrophils play important roles during the innate immune response, phagocytosing invading microbes and delivering antimicrobial compounds to the site of injury. Functional analyses of the cellular innate immune response in zebrafish infection/inflammation models have been aided by transgenic lines with fluorophore-marked neutrophils. However, it has not been possible to study macrophage behaviors and neutrophil/macrophage interactions in vivo directly because there has been no macrophage-only reporter line. To remove this roadblock, a macrophage-specific marker was identified (mpeg1) and its promoter used in mpeg1-driven transgenes. mpeg1-driven transgenes are expressed in macrophage-lineage cells that do not express neutrophil-marking transgenes. Using these lines, the different dynamic behaviors of neutrophils and macrophages after wounding were compared side-by-side in compound transgenics. Macrophage/neutrophil interactions, such as phagocytosis of senescent neutrophils, were readily observed in real time. These zebrafish transgenes provide a new resource that will contribute to the fields of inflammation, infection, and leukocyte biology.