Ancient DNA at the edge of the world: Continental immigration and the persistence of Neolithic male lineages in Bronze Age Orkney.

Orkney was a major cultural center during the Neolithic, 3800 to 2500 BC. Farming flourished, permanent stone settlements and chambered tombs were constructed, and long-range contacts were sustained. From ∼3200 BC, the number, density, and extravagance of settlements increased, and new ceremonial monuments and ceramic styles, possibly originating in Orkney, spread across Britain and Ireland. By ∼2800 BC, this phenomenon was waning, although Neolithic traditions persisted to at least 2500 BC. Unlike elsewhere in Britain, there is little material evidence to suggest a Beaker presence, suggesting that Orkney may have developed along an insular trajectory during the second millennium BC. We tested this by comparing new genomic evidence from 22 Bronze Age and 3 Iron Age burials in northwest Orkney with Neolithic burials from across the archipelago. We identified signals of inward migration on a scale unsuspected from the archaeological record: As elsewhere in Bronze Age Britain, much of the population displayed significant genome-wide ancestry deriving ultimately from the Pontic-Caspian Steppe. However, uniquely in northern and central Europe, most of the male lineages were inherited from the local Neolithic. This suggests that some male descendants of Neolithic Orkney may have remained distinct well into the Bronze Age, although there are signs that this had dwindled by the Iron Age. Furthermore, although the majority of mitochondrial DNA lineages evidently arrived afresh with the Bronze Age, we also find evidence for continuity in the female line of descent from Mesolithic Britain into the Bronze Age and even to the present day.

The genomic history of the Iberian Peninsula over the past 8000 years.

We assembled genome-wide data from 271 ancient Iberians, of whom 176 are from the largely unsampled period after 2000 BCE, thereby providing a high-resolution time transect of the Iberian Peninsula. We document high genetic substructure between northwestern and southeastern hunter-gatherers before the spread of farming. We reveal sporadic contacts between Iberia and North Africa by ~2500 BCE and, by ~2000 BCE, the replacement of 40% of Iberia's ancestry and nearly 100% of its Y-chromosomes by people with Steppe ancestry. We show that, in the Iron Age, Steppe ancestry had spread not only into Indo-European-speaking regions but also into non-Indo-European-speaking ones, and we reveal that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia. Additionally, we document how, beginning at least in the Roman period, the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean.

Oral High-Dose Thiamine Improves the Symptoms of Chronic Cluster Headache.

Cluster headache is a rare painful primary disorder occurring in either episodic or chronic patterns. Several authors found that the hypothalamus, the brain region regulating endocrine function and autonomic system, is involved in the pathophysiology of cluster headache. Some authors have found in patients affected by this disease abnormality in glucose metabolism. Considering the role of thiamine in brain function, in energetic metabolism, and in pain modulation, we treated a patient affected by cluster headache with oral high-dose thiamine. We report a 41-year-old man suffering from primary chronic cluster headache since the age of 15 years. The patient began oral therapy with high-dose thiamine in December 2016. Oral thiamine supplementation led to a dramatic improvement of the symptoms. The therapy was effective in reversing all the symptoms of the disease. Our observation suggests that a thiamine deficiency due to enzymatic abnormalities or to dysfunction of the circulation of thiamine in the intracellular space could cause a neuronal selective impairment in the centers that are involved in this disease and could have an important role in the pathogenesis of the symptoms of cluster headache.

Can long-term thiamine treatment improve the clinical outcomes of myotonic dystrophy type 1?

Myotonic dystrophy type 1, also known as Steinert's disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine (vitamin B1) is a cofactor of fundamental enzymes involved in the energetic cell metabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deficiency is critical mainly in the central and peripheral nervous system, as well as in the muscular cells. Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study. We described two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months. We evaluated the patients using the grading of muscle strength according to Medical Research Council (MRC), the Muscular Impairment Rating Scale (MIRS), and the Modified Barthel index. High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology, particularly the muscle strength evaluated with the MRC scale, and the patients' activities of daily living using the Modified Barthel Index. At the end of treatment, the MRC score was 5 in the proximal muscles and 2-4 in the distal muscles (the MRC score before the treatment was 3-4 and 1-3, respectively). The MIRS grade improved by 25% compared to baseline for both patients. In patient #1, the Modified Barthel Index improved by 44%, and in patient #2 by 29%. These findings suggest that clinical outcomes are improved by long-term thiamine treatment.

Thiamine and dystonia 16.

Primary torsion dystonia is a movement disorder characterised by sustained or intermittent involuntary muscle contractions causing abnormal movements, postures or both. In this study, 3 brothers affected by inherited primary dystonia 16 (DYT16) began an oral therapy with high-dose thiamine from November to December 2015. After 3 months, an important improvement of the motor symptoms was observed. Our results support the hypothesis that pathogenesis of the symptoms might be related to a dysfunction in mitochondrial oxidative phosphorylation due to a focal impairment of thiamine-dependent processes. Our results support some authors' hypothesis that dystonia might have a mitochondrial aetiology.

Mapping human dispersals into the Horn of Africa from Arabian Ice Age refugia using mitogenomes.

Rare mitochondrial lineages with relict distributions can sometimes be disproportionately informative about deep events in human prehistory. We have studied one such lineage, haplogroup R0a, which uniquely is most frequent in Arabia and the Horn of Africa, but is distributed much more widely, from Europe to India. We conclude that: (1) the lineage ancestral to R0a is more ancient than previously thought, with a relict distribution across the Mediterranean/Southwest Asia; (2) R0a has a much deeper presence in Arabia than previously thought, highlighting the role of at least one Pleistocene glacial refugium, perhaps on the Red Sea plains; (3) the main episode of dispersal into Eastern Africa, at least concerning maternal lineages, was at the end of the Late Glacial, due to major expansions from one or more refugia in Arabia; (4) there was likely a minor Late Glacial/early postglacial dispersal from Arabia through the Levant and into Europe, possibly alongside other lineages from a Levantine refugium; and (5) the presence of R0a in Southwest Arabia in the Holocene at the nexus of a trading network that developed after ~3 ka between Africa and the Indian Ocean led to some gene flow even further afield, into Iran, Pakistan and India.

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study.

OBJECTIVES: To investigate the potential clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in Parkinson disease (PD). DESIGN: Observational open-label pilot study. SETTING: Outpatient neurologic rehabilitation clinic. PATIENTS AND METHODS: Starting in June 2012, we have recruited 50 patients with PD (33 men and 17 women; mean age, 70.4 ± 12.9 years; mean disease duration, 7.3 ± 6.7 years). All the patients were assessed at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fatigue Severity Scale (FSS) and began treatment with 100 mg of thiamine administered intramuscularly twice a week, without any change to personal therapy. All the patients were re-evaluated after 1 month and then every 3 months during treatment. RESULTS: Thiamine treatment led to significant improvement of motor and nonmotor symptoms: mean UPDRS scores (parts I-IV) improved from 38.55 ± 15.24 to 18.16 ± 15.08 (p = 2.4 × 10(-14), t test for paired data) within 3 months and remained stable over time; motor UPDRS part III score improved from 22.01 ± 8.57 to 9.92 ± 8.66 (p = 3.1 × 10(-22)). Some patients with a milder phenotype had complete clinical recovery. FSS scores, in six patients who had fatigue, improved from 53.00 ± 8.17 to 23.60 ± 7.77 (p < 0.0001, t test for paired data). Follow-up duration ranged from 95 to 831 days (mean, 291.6 ± 207.2 days). CONCLUSIONS: Administration of parenteral high-dose thiamine was effective in reversing PD motor and nonmotor symptoms. The clinical improvement was stable over time in all the patients. From our clinical evidence, we hypothesize that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration. Thiamine could have both restorative and neuroprotective action in PD.

High-dose thiamine improves fatigue after stroke: a report of three cases.

BACKGROUND AND OBJECTIVES: A previous study on fatigue and related disorders in inflammatory bowel disease, patients improved after therapy with high-dose thiamine. Chronic fatigue that accompanies inflammatory and autoimmune diseases could be the clinical manifestation of a mild thiamine deficiency, probably due to a dysfunction of intracellular transport or enzymatic abnormalities. Fatigue is a common symptom after stroke. Some studies show a severe functional effect of this symptom, as well as a high mortality rate. Necrotic cell death after cerebral ischemia triggers the activation of the immune system, followed by an inflammatory response. It is likely that fatigue related to stroke could benefit from high-dose thiamine. Consequently, the authors began treating poststroke patients with oral or parenteral high-dose thiamine. DESIGN: Case study. MATERIALS AND METHODS: Three patients with stroke who also experienced fatigue were recruited. Severity of the fatigue was assessed by using the Fatigue Severity Scale. Blood free thiamine and thiamine pyrophosphate levels were within the healthy reference range in all the patients. Oral or parenteral therapy with high-dose thiamine was started. RESULTS: The therapy led to an appreciable improvement of fatigue. CONCLUSION: This observation suggests that poststroke fatigue and related disorders could be the manifestation of mild thiamine deficiency due to a dysfunction of intracellular transport of thiamine or to structural enzymatic abnormalities.

Thiamine and Hashimoto's thyroiditis: a report of three cases.

OBJECTIVES: In a previous study on fatigue and related disorders in inflammatory bowel disease (IBD), we observed that IBD patients improved after treatment with high-dose thiamine. We hypothesized that the chronic fatigue accompanying inflammatory and autoimmune diseases is the clinical manifestation of a mild thiamine deficiency that is probably due to a dysfunction of the intracellular transport or to enzymatic abnormalities. Hashimoto's thyroiditis is both a common automimmune disease and cause of hypothyroidism. Although levothyroxine, a thyroid hormone, is the treatment of choice for hypothyroidism, a significant number of patients on thyroid hormone replacement therapy report not feeling well despite having thyroid function tests within the healthy range. Based on our hypothesis, we started treating the fatigue in patients affected by Hashimoto's thyroiditis and taking a thyroid hormone with thiamine. This is a report of the outcomes of three cases in which the fatigue component reported by patients with Hashimoto's thyroiditis was treated with thiamine. DESIGN: Three patients on thyroid hormone replacement because of Hashimoto's thyroiditis were treated for the fatigue component of the disease from May to July 2011. Fatigue was measured using the Fatigue Severity Scale. Free thiamine in the serum and thiamine pyrophosphate in red cells were tested before and after the therapy. All three patients received oral (600 mg/day) or parenteral (100 mg/ml every four days) doses of thiamine. RESULTS: Treatment with thiamine led to partial or complete regression of the fatigue within a few hours or days. CONCLUSION: As the administration of thiamine led to a partial or complete regression of the fatigue and related disorders, it is reasonable to infer that the administration of large quantities of thiamine restores thiamine-dependent processes. The mild thiamine deficiency suggested by fatigue and related disorders may be due a dysfunction of the intracellular transport of thiamine or to enzymatic abnormalities most likely related to the autoimmune process of the disease.

A substantial prehistoric European ancestry amongst Ashkenazi maternal lineages.

The origins of Ashkenazi Jews remain highly controversial. Like Judaism, mitochondrial DNA is passed along the maternal line. Its variation in the Ashkenazim is highly distinctive, with four major and numerous minor founders. However, due to their rarity in the general population, these founders have been difficult to trace to a source. Here we show that all four major founders, ~40% of Ashkenazi mtDNA variation, have ancestry in prehistoric Europe, rather than the Near East or Caucasus. Furthermore, most of the remaining minor founders share a similar deep European ancestry. Thus the great majority of Ashkenazi maternal lineages were not brought from the Levant, as commonly supposed, nor recruited in the Caucasus, as sometimes suggested, but assimilated within Europe. These results point to a significant role for the conversion of women in the formation of Ashkenazi communities, and provide the foundation for a detailed reconstruction of Ashkenazi genealogical history.

High-dose thiamine as initial treatment for Parkinson's disease.

Parkinson's disease (PD) is a systemic disease with motor and non-motor deficits. We recruited three patients with newly diagnosed PD. They were not under anti-Parkinson's therapy. Plasmatic thiamine was within healthy reference range. We performed the Unified Parkinson's Disease Rating Scale (UPDRS) and started a parenteral therapy with high doses of thiamine. The therapy led to a considerable improvement in the motor part of the UPDRS ranging from 31.3% to 77.3%. From this clinical observation, it is reasonable to infer that a focal, severe thiamine deficiency due to a dysfunction of thiamine metabolism could cause a selective neuronal damage in the centres that are typically hit in this disease. Injection of high doses of thiamine was effective in reversing the symptoms, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations.

High dose thiamine improves fatigue in multiple sclerosis.

The majority of the patients with multiple sclerosis (MS) experience fatigue. Some observations indicate that fatigue and related manifestations concomitant with MS could be associated with an intracellular mild thiamine deficiency. We recruited 15 patients with MS who also experience fatigue and assessed the severity of the fatigue using the Fatigue Severity Scale. Although blood thiamine and thiamine pyrophosphate levels were within normal limit in all the patients, high-dose thiamine therapy administered orally or parenterally led to an appreciable improvement of the fatigue. The absence of apparent decrease in blood thiamine despite the presence of symptoms referable to a mild thiamine deficiency suggests that these patients may have a dysfunction of the mechanisms of intracellular transport or structural enzymatic abnormalities. The administration of large quantities of thiamine was effective in reversing the fatigue in MS, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations.

High-dose thiamine improves the symptoms of fibromyalgia.

Living with fibromyalgia means living with chronic pain, fatigue, sleep disorders and other associated key symptoms. To date, pharmacotherapy generally produces modest benefits. Some observations indicate that the large majority of symptoms of fibromyalgia could be the clinical manifestation of a mild thiamine deficiency due to a dysfunction of the active transport of thiamine from the blood to the mitochondria or to enzymatic abnormalities. Between June and July 2011, we recruited three female patients affected by fibromyalgia. We proceeded with the study of the patients' history, a physical examination, an evaluation of chronic widespread pain using the Visual Numeric Scale and an evaluation of the fatigue using the Fatigue Severity Scale were also performed. The levels of thiamine and thiamine pyrophosphate in the blood were determined. After the therapy with high doses of thiamine, in the patients, there was an appreciable improvement of the symptoms.

High-dose thiamine improves the symptoms of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder characterised by progressive gait and limb ataxia, dysarthria, areflexia, loss of position sense and a progressive motor weakness of central origin. Some observations indicate that all symptoms of FRDA ataxia could be the manifestation of a thiamine deficiency because of enzymatic abnormalities. Two patients with FRDA were under rehabilitative treatment from February 2012 to February 2013. The scale for assessment and rating of ataxia was performed. The patient began an intramuscular therapy with 100 mg of thiamine every 3-5 days. Injection of high-dose thiamine was effective in reversing the motor failure. From this clinical observation, it is reasonable to infer that a thiamine deficiency due to enzymatic abnormalities could cause a selective neuronal damage in the centres that are typically affected by this disease.

Thiamine and fatigue in inflammatory bowel diseases: an open-label pilot study.

OBJECTIVES: To demonstrate that fatigue and other disorders related to ulcerative colitis and Crohn's disease are the manifestation of an intracellular mild thiamine deficiency and not due to malabsorbtion, augmented requirements, or nutritional factors, and that this dysfunction is curable with high doses of thiamine administered orally or parenterally. DESIGN: In this pilot study, we treated fatigue in eight patients with ulcerative colitis and four patients affected by Crohn's disease from January to April 2011. The patients were recruited through general practitioners' surveys and among personnel and affiliated personnel of the clinic Villa Immacolata. Fatigue was measured using the chronic fatigue syndrome scale, and the determination of thiamine and thiamine pyrophosphate levels in the blood was carried out through blood tests. The levels of thiamine and thiamine pyrophosphate in the blood were normal. All patients were assigned to receive high doses of thiamine orally. Depending upon the body weight of each patient, dosage ranged from 600 mg/day (60 kg) to 1,500 mg/day (90 kg). The chronic fatigue syndrome scale as well as thiamine and thiamine pyrophosphate levels in the blood were measured 20 days after the beginning of the therapy. RESULTS: Ten patients out of twelve showed complete regression of fatigue, while the remaining two patients showed nearly complete regression of fatigue compared to the chronic fatigue syndrome scale scores before therapy. CONCLUSIONS: The absence of blood thiamine deficiency and the efficacy of high-dose thiamine in our patients suggest that fatigue is the manifestation of a thiamine deficiency, likely due to a dysfunction of the active transport of thiamine inside the cells, or due to structural enzymatic abnormalities. The administration of large quantities of thiamine increases the concentration in the blood to levels in which the passive transport restores the normal glucose metabolism in all cells and leads to a complete regression of fatigue.

Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass.

It is known that L-arginine treatment can ameliorate endothelial dysfunction and insulin sensitivity in type 2 diabetes mellitus patients, but little is known on L-arginine effects on these variables in nondiabetic patients with stable cardiovascular disease (coronary artery disease). We evaluated the effects of long-term oral L-arginine treatment on endothelial dysfunction, inflammation, adipokine levels, glucose tolerance, and insulin sensitivity in these patients. Sixty-four patients with cardiovascular disease previously submitted to an aortocoronary bypass and not known for type 2 diabetes mellitus had an oral glucose load to define their glucose tolerance. Thirty-two patients with nondiabetic response were eligible to receive, in a double-blind randomized parallel order, L-arginine (6.4 g/d) or placebo for 6 months. An evaluation of insulin sensitivity index during the oral glucose load, markers of systemic nitric oxide bioavailability and inflammation, and blood flow was performed before and at the end of the treatment in both groups. Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P < .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P < .01), L-arginine to asymmetric dimethylarginine ratio (P < .0001), and reactive hyperemia (P < .05). Finally, L-arginine increased insulin sensitivity index (P < .05) and adiponectin (P < .01) and decreased interleukin-6 and monocyte chemoattractant protein-1 levels. In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.

Distinctive Paleo-Indian migration routes from Beringia marked by two rare mtDNA haplogroups.

BACKGROUND: It is widely accepted that the ancestors of Native Americans arrived in the New World via Beringia approximately 10 to 30 thousand years ago (kya). However, the arrival time(s), number of expansion events, and migration routes into the Western Hemisphere remain controversial because linguistic, archaeological, and genetic evidence have not yet provided coherent answers. Notably, most of the genetic evidence has been acquired from the analysis of the common pan-American mitochondrial DNA (mtDNA) haplogroups. In this study, we have instead identified and analyzed mtDNAs belonging to two rare Native American haplogroups named D4h3 and X2a. RESULTS: Phylogeographic analyses at the highest level of molecular resolution (69 entire mitochondrial genomes) reveal that two almost concomitant paths of migration from Beringia led to the Paleo-Indian dispersal approximately 15-17 kya. Haplogroup D4h3 spread into the Americas along the Pacific coast, whereas X2a entered through the ice-free corridor between the Laurentide and Cordilleran ice sheets. The examination of an additional 276 entire mtDNA sequences provides similar entry times for all common Native American haplogroups, thus indicating at least a dual origin for Paleo- Indians. CONCLUSIONS: A dual origin for the first Americans is a striking novelty from the genetic point of view, and it makes plausible a scenario positing that within a rather short period of time, there may have been several entries into the Americas from a dynamically changing Beringian source. Moreover, this implies that most probably more than one language family was carried along with the Paleo-Indians.