Diagnosis and rational treatment of painful diabetic peripheral neuropathy: an interdisciplinary expert consensus

Diabetic peripheral neuropathy is a common chronic complication of diabetes mellitus, significantly impairing well-being, quality of life and functioning of patients. The prevalence of diabetic peripheral neuropathy in the Russian Federation ranges from 0.1% to 67.2% in type 1 and from 0.1 to 42.4% in type 2 diabetes mellitus. However, based on the large-scale epidemiological studies, the true prevalence of diabetic peripheral neuropathy is much higher (50 to 70%), with its painful variant occurring in 16% to 30% of patients. Despite the fact that diabetic peripheral neuropathy remains the most common chronic complication of diabetes mellitus, its diagnosis and therapy leave much to be desired. To optimize diagnostic and treatment approaches to painful diabetic peripheral neuropathy, a group of experts representing the leading Russian professional medical associations has developed clinical guidelines for the diagnosis and rational therapy of patients with painful diabetic peripheral neuropathy. This document presents practical aspects of the clinical diagnosis of painful diabetic peripheral neuropathy and an algorithm for differential diagnosis of pain in the lower extremities in patients with diabetes mellitus. The use of symptomatic analgesics with central action, such as anticonvulsants, antidepressants and opioids, is based on the main aspects of neuropathic pain pathophysiology. The characteristics of each drug class are given, with consideration of evidence on their efficacy, tolerability, and the possibility of combination therapy. The data on the first, second, and third lines of agents is presented in accordance with several international clinical guidelines. The need for a tailored drug choice, taking into account the evidence-based data on their efficacy and safety, concomitant drug therapy, tolerability, cost and preferences of the patient, age of the patient and concomitant disorders, is emphasized

The origins and spread of domestic horses from the Western Eurasian steppes

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: All collapsed and paired-end sequence data for samples sequenced in this study are available in compressed fastq format through the European Nucleotide Archive under accession number PRJEB44430, together with rescaled and trimmed bam sequence alignments against both the nuclear and mitochondrial horse reference genomes. Previously published ancient data used in this study are available under accession numbers PRJEB7537, PRJEB10098, PRJEB10854, PRJEB22390 and PRJEB31613, and detailed in Supplementary Table 1. The genomes of ten modern horses, publicly available, were also accessed as indicated in their corresponding original publications57,61,85-87.NOTE: see the published version available via the DOI in this record for the full list of authorsDomestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 BC. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture

Halides Held by Bifurcated Chalcogen–Hydrogen Bonds. Effect of μ_(S,N–H)Cl Contacts on Dimerization of Cl(carbene)Pd^II Species

The reaction of <i>cis</i>-[PdCl₂(CNCy)₂] (<b>1</b>) with thiazol-2-amines (<b>2</b>–<b>10</b>) leads to the C,N-chelated diaminocarbene-like complexes [PdCl­{<i>C</i>(N­(H)­4,5-R₂-thiazol-2-yl)­NHCy}­(CNCy)] (<b>11</b>–<b>14</b>; 82–91%) in the case of 4,5-R₂-thiazol-2-amines (R, R = H, H (<b>2</b>), Me, Me (<b>3</b>), −(CH₂)₄– (<b>4</b>)) and benzothiazol-2-amine (<b>5</b>) or gives the diaminocarbene species <i>cis</i>-[PdCl₂{C­(N­(H)­Cy)­N­(H)­4-R-thiazol-2-yl}­(CNCy)] (<b>15</b>–<b>19</b>; 73–93%) for the reaction with 4-aryl-substituted thiazol-2-amines (R = Ph (<b>6</b>), 4-MeC₆H₄ (<b>7</b>), 4-FC₆H₄ (<b>8</b>), 4-ClC₆H₄ (<b>9</b>), 3,4-F₂C₆H₃ (<b>10</b>)). Inspection of the single-crystal X-ray diffraction data for <b>15</b>–<b>17</b> and <b>19</b> suggests that the structures of all these species exhibit previously unrecognized bifurcated chalcogen–hydrogen bonding μ_(S,N–H)Cl and also Pd^II···Pd^II metallophilic interactions. These noncovalent interactions collectively connect two symmetrically located molecules of <b>15</b>–<b>17</b> and <b>19</b>, resulting in their solid-state dimerization. The existence of the μ_(S,N–H)Cl system and its strength (6–9 kcal/mol) were additionally verified/estimated by a Hirshfeld surface analysis and DFT calculations combined with a topological analysis of the electron density distribution within the formalism of Bader’s theory (AIM method) and NBO analysis. The observed noncovalent interactions are jointly responsible for the dimerization of <b>15</b>–<b>19</b> not only in the solid phase but also in CHCl₃ solutions, as predicted theoretically by DFT calculations and confirmed experimentally by FTIR, HRESI-MS, ¹H NMR, and diffusion coefficient NMR measurements. Available CCDC data were processed under the new moiety angle, and the observed μ_(S,E–H)Cl systems were classified accordingly to E (E = N, O, C) type atoms

1,3-Dipolar Cycloaddition of Nitrones to Gold(III)-Bound Isocyanides

Treatment of gold­(III)-isocyanides [AuCl₃(CNR¹)] (R¹ = Xyl <b>1</b>, Cy <b>2</b>, Bu^<i>t</i> <b>3</b>) with an equimolar amount of 5,5-dimethyl-1-pyrroline-<i>N</i>-oxide (<b>4</b>) in CH₂Cl₂ at −74 °C leads to the generation of the heterocyclic aminocarbene species [AuCl₃{C­(ON^<i>a</i>CMe₂CH₂CH₂C^<i>b</i>H)N^<i>e</i>R¹}­(N^<i>a</i>–C^<i>b</i>)­(C^<i>b</i>–N^<i>e</i>)] <b>8</b> (for R¹ = Bu^<i>t</i>) or gold­(III) complexes <i>cis</i>-[AuCl₂{N^<i>a</i>(CMe₂CH₂CH₂C^<i>b</i>N^<i>e</i>R¹)­C^<i>d</i>O}­(N^<i>a</i>C^<i>b</i>)­(N^<i>e</i>–C^<i>d</i>)] <b>9</b> and <b>10</b> (for R¹ = Xyl and Cy) in good isolated yields (75–87%). DFT calculations show that deprotonation of the endocyclic CH group in the carbene ligand leads to spontaneous N–O bond cleavage, and acidity of this group is a factor controlling the different chemical behavior of <b>1</b>–<b>3</b> depending on the nature of substituent R¹. The reaction of equimolar amounts of the aldonitrone <i>p</i>-TolCHN⁺(Me)­O^– (<b>5</b>) or the ketonitrones Ph₂CN⁺(R²)­O^– (R² = Ph <b>6</b>, CH₂Ph <b>7</b>) with <b>1</b>–<b>3</b> in CD₂Cl₂ at −70 °C in air (or under N₂) revealed the formation of the carbene complexes [AuCl₃{C­(ONMeC^<i>a</i>H-<i>p</i>-Tol)N^<i>b</i>R¹}­(C^<i>a</i>–N^<i>b</i>)] (R¹ = Cy <b>11</b>, Xyl <b>12</b>, Bu^<i>t</i> <b>13</b>), [AuCl₃{C­(ONPhC^<i>a</i>Ph₂)N^<i>b</i>R¹}­(C^<i>a</i>–N^<i>b</i>)] (R¹ = Cy <b>14</b>, Bu^<i>t</i> <b>15</b>), or [AuCl₃{C­(ON­(CH₂Ph)­C^<i>a</i>Ph₂)N^<i>b</i>R¹}­(C^<i>a</i>–N^<i>b</i>)] (R¹ = Cy <b>16</b>, Xyl <b>17</b>), as studied by ¹H NMR. The reaction of <b>6</b> with <b>1</b> and of <b>7</b> with <b>3</b> did not furnish carbene products. Compounds <b>8</b>–<b>10</b> were characterized by ESI-MS, IR, 1D (¹H, ¹³C­{H}) and 2D (¹H,¹H–COSY, ¹H,¹³C-HSQC, ¹H,¹³C-HMBC) NMR spectroscopic techniques, and, only for <b>8</b>, elemental analyses (C, H, N), while compounds <b>11</b>–<b>17</b> were characterized by 1D (¹H, ¹³C­{H}) and 2D (¹H,¹³C-HSQC) NMR. Structures of compounds <b>8</b>, <b>9</b>, and <b>13</b> were additionally established by single-crystal X-ray diffraction

Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)Pd^II Complexes

The reaction of <i>cis</i>-[PdCl₂(CNXyl)₂] (Xyl = 2,6-Me₂C₆H₃) with various 1,3-thiazol- and 1,3,4-thiadiazol-2-amines in chloroform gives a mixture of two regioisomeric binuclear diaminocarbene complexes. For 1,3-thiazol-2-amines the isomeric ratio depends on the reaction conditions and <i>kinetically</i> (<b>KRs</b>) or <i>thermodynamically</i> (<b>TRs</b>) <i>controlled regioisomers</i> were obtained at room temperature and on heating, respectively. In CHCl₃ solutions, the isomers are subject to reversible isomerization accompanied by the cleavage of Pd–N and C–N bonds in the carbene fragment XylNCN­(R)­Xyl. Results of DFT calculations followed by the topological analysis of the electron density distribution within the formalism of Bader’s theory (AIM method) reveal that in CHCl₃ solution the relative stability of the regioisomers (Δ<i>G</i>_exp = 1.2 kcal/mol; Δ<i>G</i>_calcd = 3.2 kcal/mol) is determined by the energy difference between two types of the intramolecular chalcogen bonds, viz. S···Cl in <b>KRs</b> (2.8–3.0 kcal/mol) and S···N in <b>TRs</b> (4.6–5.3 kcal/mol). In the case of the 1,3,4-thiadiazol-2-amines, the regioisomers are formed in approximately equal amounts and, accordingly, the energy difference between these species is only 0.1 kcal/mol in terms of Δ<i>G</i>_exp (Δ<i>G</i>_calcd = 2.1 kcal/mol). The regioisomers were characterized by elemental analyses (C, H, N), HRESI⁺-MS and FTIR, 1D (¹H, ¹³C­{¹H}) and 2D (¹H,¹H-COSY, ¹H,¹H-NOESY, ¹H,¹³C-HSQC, ¹H,¹³C-HMBC) NMR spectroscopies, and structures of six complexes (three <b>KRs</b> and three <b>TRs</b>) were elucidated by single-crystal X-ray diffraction

Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)Pd^II Complexes

The reaction of <i>cis</i>-[PdCl₂(CNXyl)₂] (Xyl = 2,6-Me₂C₆H₃) with various 1,3-thiazol- and 1,3,4-thiadiazol-2-amines in chloroform gives a mixture of two regioisomeric binuclear diaminocarbene complexes. For 1,3-thiazol-2-amines the isomeric ratio depends on the reaction conditions and <i>kinetically</i> (<b>KRs</b>) or <i>thermodynamically</i> (<b>TRs</b>) <i>controlled regioisomers</i> were obtained at room temperature and on heating, respectively. In CHCl₃ solutions, the isomers are subject to reversible isomerization accompanied by the cleavage of Pd–N and C–N bonds in the carbene fragment XylNCN­(R)­Xyl. Results of DFT calculations followed by the topological analysis of the electron density distribution within the formalism of Bader’s theory (AIM method) reveal that in CHCl₃ solution the relative stability of the regioisomers (Δ<i>G</i>_exp = 1.2 kcal/mol; Δ<i>G</i>_calcd = 3.2 kcal/mol) is determined by the energy difference between two types of the intramolecular chalcogen bonds, viz. S···Cl in <b>KRs</b> (2.8–3.0 kcal/mol) and S···N in <b>TRs</b> (4.6–5.3 kcal/mol). In the case of the 1,3,4-thiadiazol-2-amines, the regioisomers are formed in approximately equal amounts and, accordingly, the energy difference between these species is only 0.1 kcal/mol in terms of Δ<i>G</i>_exp (Δ<i>G</i>_calcd = 2.1 kcal/mol). The regioisomers were characterized by elemental analyses (C, H, N), HRESI⁺-MS and FTIR, 1D (¹H, ¹³C­{¹H}) and 2D (¹H,¹H-COSY, ¹H,¹H-NOESY, ¹H,¹³C-HSQC, ¹H,¹³C-HMBC) NMR spectroscopies, and structures of six complexes (three <b>KRs</b> and three <b>TRs</b>) were elucidated by single-crystal X-ray diffraction

Recent progress in L-H transition studies at JET: Tritium, Helium, Hydrogen and Deuterium

We present an overview of results from a series of L-II transition experiments undertaken at JET since the installation of the ITER-like-wall (JET-ILW), with beryllium wall tiles and a tungsten divertor. Tritium, helium and deuterium plasmas have been investigated. Initial results in tritium show ohmic L-H transitions at low density and the power threshold for the L-H transition (P-LH) is lower in tritium plasmas than in deuterium ones at low densities, while we still lack contrasted data to provide a scaling at high densities. In helium plasmas there is a notable shift of the density at which the power threshold is minimum ((n) over bar (e,min)) to higher values relative to deuterium and hydrogen references. Above (n) over bar (e,min) (He) the L-H power threshold at high densities is similar for D and He plasmas. Transport modelling in slab geometry shows that in helium neoclassical transport competes with interchange-driven transport, unlike in hydrogen isotopes. Measurements of the radial electric field in deuterium plasmas show that E-r shear is not a good indicator of proximity to the L-H transition. Transport analysis of ion heat flux in deuterium plasmas show a non-linearity as density is decreased below (n) over bar (e,min). Lastly, a regression of the JET-ILW deuterium data is compared to the 2008 ITPA scaling law