Clinical features and outcomes of calciphylaxis in Chinese patients with chronic kidney disease.

AIM: Calciphylaxis is a rare disease, predominantly in chronic kidney disease (CKD), characterized by high morbidity and mortality. Data from the Chinese population have been an invaluable resource for a better understanding of natural history, optimal treatments and outcomes of calciphylaxis. METHODS: A retrospective study was conducted in 51 Chinese patients diagnosed with calciphylaxis at Zhong Da Hospital affiliated to Southeast University from December 2015 to September 2020. RESULTS: Between 2015 and 2020, 51 cases of calciphylaxis were registered in The China Calciphylaxis Registry (http://www.calciphylaxis.com.cn), which was developed by Zhong Da Hospital. The mean age of the cohort was 52.02 ± 14.09 years, and 37.3% were female. Forty-three patients (84.3%) were on haemodialysis, with a median dialysis vintage of 88 months. Eighteen patients (35.3%) had a resolution of calciphylaxis and 20 patients (39.2%) died. Patients in later stages had higher overall mortality than those in earlier stages. Delay from skin lesions onset to diagnosis and calciphylaxis-related infections were risk factors in both early and overall mortality. Additionally, dialysis vintage and infections were significant risk factors in calciphylaxis-specific mortality. Among therapeutic strategies, only the use of sodium thiosulfate (STS) ≥3 courses (14 injections) was significantly associated with decreased hazard of death in both early and overall mortality. CONCLUSION: For Chinese patients with calciphylaxis, delay from skin lesions onset to diagnosis and infections secondary to wounds are risk factors for the prognosis of patients with calciphylaxis. Additionally, patients in earlier stages have better survival and early continuous use of STS is highly suggested.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects.

AIMS: This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. METHODS: A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. RESULTS: The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. CONCLUSION: HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.

Effect of clonidine on colonic motility in rats.

Clonidine, an alpha(2)-adrenoceptor agonist, has been reported to inhibit gastric and small intestinal motility in rats. Whether clonidine also inhibits colonic motility is still not clear. The aim of this study was to examine the effect of clonidine on colonic motility and its possible site of action in adult Wistar rats. Colonic motilities in anesthetized rats in vivo or motilities of the isolated colon of rats in vitro were recorded. Clonidine was administered intravenously (i.v.) and intracerebroventricularly (i.c.v.) in vivo while bath administration was used in in vitro study. Clonidine i.v. or i.c.v. significantly inhibited colonic motility. This inhibitory effect was antagonized by pre-administration of yohimbine, an alpha(2)-adrenoceptor antagonist, but not by pre-administration of prazosin, an alpha(1)-adrenoceptor antagonist. Also, we have unpublished data indicating that the sympathectomy antagonized the inhibitory effect of systemically administered clonidine. A significant depression of colonic motility on the isolated colon was induced by bath administration of noradrenaline, while no such inhibition was seen by clonidine. The results of the present study suggested that clonidine inhibits colonic motility in rats through activation of central alpha(2)-adrenergic receptor.

Electrophysiology of optic nerve input to suprachiasmatic nucleus neurons in rats and degus.

Neurons in the mammalian suprachiasmatic nucleus (SCN), the principal pacemaker of the circadian system, receive direct retinal input. Some SCN neurons respond to retinal illumination or optic nerve stimulation with changes in firing rates. In nocturnal rodents, retinal illumination increases firing rates of a large majority and decreases firing rates of a minority of responsive neurons. In two species of diurnal rodent, these proportions are altered or even reversed. Since retinal input to the SCN has been reported to involve release of the excitatory neurotransmitter glutamate, the mechanism mediating suppressions is unknown. We studied responses of neurons in SCN slices from diurnal degus and nocturnal rats to optic nerve stimulation. To test whether suppressions are mediated indirectly by release of the inhibitory neurotransmitter GABA from SCN neurons that are first activated by glutamate release, we attempted to block suppressions by adding to the bath either APV, an antagonist for excitatory glutamate receptors, or bicuculline, a GABA(A) receptor antagonist. If glutamate is the only neurotransmitter released by optic nerves in the SCN, APV should prevent both activations and suppressions in response to optic nerve stimulation. We found that APV had little effect on suppressions although it effectively blocked activations. Bicuculline blocked most suppressions. These findings are inconsistent with a model in which the retina provides only excitatory glutamate input to the SCN via NMDA receptors. Since some retinal fibers in adult mammals contain GABA, it is possible that the retinal innervation of the SCN includes both glutamate- and GABA-containing axons.