Gain and loss of function of P2X7 receptors: Mechanisms, pharmacology and relevance to diabetic neuropathic pain

Background: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. Results: The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. Conclusions: Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population

Variation in the proportion of adults in need of BP-lowering medications by hypertension care guideline in low- and middle-income countries:a cross-sectional study of 1,037,215 individuals from 50 nationally representative surveys

BACKGROUND:Current hypertension guidelines vary substantially in their definition of who should be offered blood pressure–lowering medications. Understanding the effect of guideline choice on the proportion of adults who require treatment is crucial for planning and scaling up hypertension care in low- and middle-income countries. METHODS:We extracted cross-sectional data on age, sex, blood pressure, hypertension treatment and diagnosis status, smoking, and body mass index for adults 30 to 70 years of age from nationally representative surveys in 50 low- and middle-income countries (N = 1 037 215). We aimed to determine the effect of hypertension guideline choice on the proportion of adults in need of blood pressure–lowering medications. We considered 4 hypertension guidelines: the 2017 American College of Cardiology/American Heart Association guideline, the commonly used 140/90 mm Hg threshold, the 2016 World Health Organization HEARTS guideline, and the 2019 UK National Institute for Health and Care Excellence guideline. RESULTS:The proportion of adults in need of blood pressure–lowering medications was highest under the American College of Cardiology/American Heart Association, followed by the 140/90 mm Hg, National Institute for Health and Care Excellence, and World Health Organization guidelines (American College of Cardiology/American Heart Association: women, 27.7% [95% CI, 27.2–28.2], men, 35.0% [95% CI, 34.4–35.7]; 140/90 mm Hg: women, 26.1% [95% CI, 25.5–26.6], men, 31.2% [95% CI, 30.6–31.9]; National Institute for Health and Care Excellence: women, 11.8% [95% CI, 11.4–12.1], men, 15.7% [95% CI, 15.3–16.2]; World Health Organization: women, 9.2% [95% CI, 8.9–9.5], men, 11.0% [95% CI, 10.6–11.4]). Individuals who were unaware that they have hypertension were the primary contributor to differences in the proportion needing treatment under different guideline criteria. Differences in the proportion needing blood pressure–lowering medications were largest in the oldest (65–69 years) age group (American College of Cardiology/American Heart Association: women, 60.2% [95% CI, 58.8–61.6], men, 70.1% [95% CI, 68.8–71.3]; World Health Organization: women, 20.1% [95% CI, 18.8–21.3], men, 24.1.0% [95% CI, 22.3–25.9]). For both women and men and across all guidelines, countries in the European and Eastern Mediterranean regions had the highest proportion of adults in need of blood pressure–lowering medicines, whereas the South and Central Americas had the lowest. CONCLUSIONS:There was substantial variation in the proportion of adults in need of blood pressure–lowering medications depending on which hypertension guideline was used. Given the great implications of this choice for health system capacity, policy makers will need to carefully consider which guideline they should adopt when scaling up hypertension care in their country

Health system performance for people with diabetes in 28 low- and middle-income countries:A cross-sectional study of nationally representative surveys

International audienceThe prevalence of diabetes is increasing rapidly in low- and middle-income countries (LMICs), urgently requiring detailed evidence to guide the response of health systems to this epidemic. In an effort to understand at what step in the diabetes care continuum individuals are lost to care, and how this varies between countries and population groups, this study examined health system performance for diabetes among adults in 28 LMICs using a cascade of care approach

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Measurement of the Spectroscopy of Orbitally Excited B Mesons at LEP

We measure the masses, decay widths and relative production rate of orbitally excited B mesons using 1.25 million hadronic Z decays recorded by the L3 detector. B-meson candidates are inclusively reconstructed and combined with charged pions produced at the primary event vertex. An excess of events above the expected background in the B\pi mass spectrum in the region 5.6-5.8 GeV is interpreted as resulting from the decay B_u,d^** -> B^(*)\pi, where B_u,d^** denotes a mixture of l=1 B-meson states containing a u or a d quark. A fit to the mass spectrum yields the masses and decay widths of the B_1^* and B_2^* spin states, as well as the branching fraction for the combination of l=1 states. In addition, evidence is presented for the existence of an excited B-meson state or mixture of states in the region 5.9-6.0 GeV