Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-α-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.
2-Aminoadipic Acid ; toxicity ; Animals ; Anti-Inflammatory Agents ; therapeutic use ; Astrocytes ; pathology ; Carbenoxolone ; pharmacology ; Caspase 6 ; deficiency ; metabolism ; Connexin 43 ; metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors ; pharmacology ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Male ; Mice ; Mice, Transgenic ; Microglia ; pathology ; Minocycline ; therapeutic use ; Neuralgia ; chemically induced ; drug therapy ; pathology ; Pain Measurement ; Phenylurea Compounds ; pharmacology ; Sex Characteristics ; Spinal Cord ; pathology ; Time Factors

Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
Animals ; Humans ; Pain ; metabolism ; Pruritus ; metabolism ; Transient Receptor Potential Channels ; metabolism

Because of tumor compression,blockage,and anti-tumor treatment,patients with head and neck cancer or esophagus cancer often have many adverse reactions,such as dysphagia,loss of appetite,taste disappeared and so on,leading to malnutrition and weight loss,which requires nutritional support treatment.Percutaneous endoscopic gastrostomy(PEG) is a simple technology widely used in clinic which has less complications can improve patients'nutritional status and quality of life.However,the phenomenon of fistula metastasis is easy to be neglected due to lower incidence.the pathogenesis of fistula metastasis is unclear.The occurrence of complications can be reduced by preoperative radiotherapy and chemotherapy,overtubes,povidone iodine and a good fistula care.Surgery,interstitial brachytherapy and radiofrequency ablation therapy may be effective.This article will review the pathogenesis,prevention and prognosis of tumor metastasis after percutaneous endoscopic gastrostomy.

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors. The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors. Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy. The drug resistance associated with some of the entry inhibitors will also be discussed.
Anti-HIV Agents ; chemistry ; pharmacology ; therapeutic use ; CCR5 Receptor Antagonists ; CD4 Antigens ; drug effects ; Cyclohexanes ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; HIV Envelope Protein gp120 ; pharmacology ; HIV Envelope Protein gp41 ; pharmacology ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Peptide Fragments ; pharmacology ; therapeutic use ; Receptors, CCR5 ; physiology ; Receptors, CXCR4 ; antagonists & inhibitors ; Receptors, Chemokine ; drug effects ; Triazoles ; pharmacology ; therapeutic use

Background: Controlling the coronavirus disease 2019 (COVID-19) epidemic requires information beyond new and cumulative cases.This study aims to conduct an in-depth analysis by geographic strata: Wuhan City (hereafter referred to as Wuhan) only,Hubei Province (hereafter referred to as Hubei) excluding Wuhan,and China excluding Hubei.Methods: Daily cumulative confirmed COVID-19 cases between December 8,2019 (the date of symptom onset based on patients' recall during the investigation),and March 1,2020,from official sources and published studies were analyzed.The second derivative model was used for information extraction.Data analysis was conducted separately for the three strata.Results: A total of 80 026 diagnosed COVID-19 cases were reported during the first 85 days of the epidemic,with 49 315 cases from Wuhan,17 788 from Hubei excluding Wuhan,and 12 923 from China excluding Hubei.Analytical results indicate that the COVID-19 epidemic consists of an Acceleration,a Deceleration,and a Stabilization Phase in all three geographic strata,plus a Silent Attack Phase for Wuhan only.Given the reported incubation period of 14 days,effects of the massive anti-epidemic actions were revealed by both the Acceleration and Deceleration Phases.The Acceleration Phase signaled the effect of the intervention to detect the infected;the Deceleration Phase signaled the declines in new infections after the infected were detected,treated and quarantined.Conclusion: Findings of the study provide new evidence to better monitor the epidemic,evaluate its response to intervention,and predict the trend long.In addition to re-evaluating the control of the COVID-19 epidemic in China,this study provided a model for monitoring outbreaks of COVID-19 in different countries across the world.

The voltage-gated Na channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Biotin ; metabolism ; Cells, Cultured ; Disease Models, Animal ; Female ; Ganglia, Spinal ; cytology ; HEK293 Cells ; Humans ; Hybridomas ; chemistry ; Hyperalgesia ; drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; NAV1.5 Voltage-Gated Sodium Channel ; metabolism ; NAV1.7 Voltage-Gated Sodium Channel ; chemistry ; immunology ; metabolism ; Neuralgia ; drug therapy ; metabolism ; Protein Binding ; drug effects ; Recombinant Proteins ; biosynthesis ; therapeutic use ; Sensory Receptor Cells ; drug effects ; physiology

Infant social, emotional and neurological development is shaped by the mother-child dyad. Dysfunction in this bond, as well as maternal mental health problems, can negatively impact child development. The family physician is well-placed to spot dysfunction in the mother-child dyad and screen for postnatal depression during well-child visits. If any issues are identified, the family physician can provide support and help the mother-child dyad to access community resources and specialist psychiatric services.

Objective:To evaluate the difference of dosimetry between three-dimensional and two-dimensional plans based on CT images of occult perforation in brachytherapy of cervical cancer, aiming to provide clinical reference.Methods:A total of 817 patients with cervical cancer received simple intrauterine (intrauterine tandem plus vaginal colpostats) three-dimensional brachytherapy in Chongqing University Cancer Hospital from January 2019 to December 2020 were retrospectively reviewed. Among them, 16 patients had occul uterine perforation. Based on Oncentra Brachy Therapy plan system, the single prescription dose was 6Gy. Three-dimensional (3D group) and two-dimensional (2D group) plans were designed on the perforated CT images The target volume, conformal index (CI), conformal index coformity index (COIN) and organs-at-risk (OAR) D 2cm 3 parameters were used to assess the plans between two groups. Results:The incidence of pccult uterine perforation was 1.96%(16/817) during brachytherapy for cervical cancer. The volume of prescription dose curve in the 3D group was (40.74±14.98) cm 3, significantly smaller compared with (91.46±19.71) cm 3 in the 2D group ( P<0.05), whereas the volume of the high-risk clinical target area wrapped by prescription dose curve did not significantly differ between two groups ( P>0.05). The CI and COIN in the 3D group were 0.79±0.10 and 0.72±0.96, significantly higher compared with 0.38±0.09 and 0.37±0.18 in the 2D group (both P<0.05). The D 2cm 3 of bladder, rectum, sigmoid colon, small intestine in the 3D group were (306.06±77.57) cGy, (252.27±72.60) cGy, (127.25±62.84) cGy and (228.79±94.90) cGy, significantly lower than (548.03±164.21) cGy, (411.16±118.74) cGy, (227.45±94.48) cGy and (450.95±157.96) cGy in the 2D group (all P<0.05). Conclusions:Application of image guidance in brachytherapy of cervical cancer is helpful to detect occult uterine perforation. When occult uterine perforation occurs, the use of three-dimensional plan can basically meet the clinical needs, which is significantly better than the two-dimensional plan.

Objective:To analyze the household smoking behavior of smokers in rural Taizhou City of Zhejiang Province， and to provide the basis for the intervention measures to reduce children's second-hand smoke （SHS） exposure. Methods:The investigation started in May 2018. A total of 418 smoking families in Luqiao and Linhai were included. Field face-to-face questionnaire survey was conducted and cotinine level in children's urine was measured. Kernel density estimation was used for curve fitting. The results were analyzed by Wilcoxon rank sum test and chi square test. Results:The age distribution of smokers in the family was bimodal. The younger smoker group was mainly the parents. The older group was mainly the other relatives such as grandfather. The age started smoking in the parent group was younger than that in relative group， but the average number of cigarettes smoked per day in relative group was higher than that in parent group （P<0.05）. The parent group had higher proportion than the relative group in having family smoking regulations or agreeing not to smoke in the room in the presence of children （P<0.001）.The proportion of the parent group who has heard about third hand smoke and electronic cigarette was higher than that of the relative group （P<0.001）.The detection rates of cotinine in urine of children were 91.05% and 86.96% in parent group and relative group， respectively. The urine cotinine level of the children in the parent group was higher than that in the grandfather group （P=0.049）. Conclusion:Children are more exposed to SHS when the smoker in the household are parents. In order to reduce children's SHS exposure， we should pay more attention to educate the parents with a family based tobacco control program.