[Clinical effects of retrograde anterolateral thigh flaps in repairing anterior knee joint wounds under the concept of precise flap surgery].

Objective: To introduce the methods of retrograde anterolateral thigh flaps in repairing anterior knee joint wounds under the concept of precise flap surgery and to explore the clinical effects. Methods: A retrospective observational study was conducted. From August 2014 to March 2022, 7 patients with anterior knee joint wounds were treated with retrograde anterolateral thigh flap under the guidance of the concept of precise flap surgery in the 920th Hospital of Joint Logistic Support Force of PLA. Among them, 6 were males and 1 was female, aged 36 to 66 years. The sizes of wounds were 7 cm×5 cm to 15 cm×11 cm after debridement. All the patients were performed with computed tomography angiography (CTA), the donor and recipient sites were evaluated according to the precise flap surgery method, and the optimal pedicle, perforator, and pivot of flaps were chosen. The flap sizes were 10 cm×6 cm to 20 cm×9 cm, and all the donor sites of flaps were sutured directly. The consistency of the intraoperative exploration with preoperative CTA was observed. The flap survival and occurrence of complications were observed after surgery. The color, appearance, texture, and occurrence of complications were followed up. At the last follow-up, the blood supply of flaps was evaluated using the blood circulation evaluation indicators of Chinese Medical Association Hand Surgery Branch's trial criteria for digital replantation function evaluation, and the function of knee joint was evaluated using knee joint scoring system of hospital for special surgery. Results: The flap condition of the intraoperative exploration was completely consistent with that of preoperative CTA. The flaps survived completely after surgery in 6 patients, while necrosis at the edge of the flap occurred in 1 patient, which healed after dressing change. All the flaps were hyperperfused after surgery, and the color of the flaps gradually became normal after 1 week. Follow-up of 7 to 44 months showed that the color, appearance, and texture were well in all the patients, while local osteomyelitis at the proximal tibia occurred in 1 patient. At the last follow-up, all the 7 patients had excellent blood circulation; the function score of knee joint was 69 to 91, which was evaluated as excellent in 3 cases, good in 3 cases, and fair in 1 case. Conclusions: The retrograde anterolateral thigh flap has large variations, and the application of precise flap surgery method can accurately understand the variations before surgery, guide the design and cutting of the flaps, thus achieving precise repair of anterior knee joint wounds, with good repair outcome.

Association between IL-1RN gene polymorphisms and susceptibility to ankylosing spondylitis: a large Human Genome Epidemiology review and meta-analysis.

We made a Human Genome Epidemiology review and meta-analysis to examine a possible association between interleukin-1 receptor antagonist (IL-1RN) polymorphisms and susceptibility to ankylosing spondylitis (AS). Studies of IL-1RN polymorphisms and susceptibility to AS were found by searching the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI, and CBM databases. Data were extracted by 2 independent reviewers. The meta-analysis was performed with the Review Manager Version 5.1.6 and STATA Version 12.0 software. The odds ratio (OR) and 95% confidence intervals (95%CI) were calculated based on the extracted data. Thirteen studies with 5391 AS cases and 5239 healthy controls were retrieved. Seven IL-1RN polymorphisms were addressed, including rs30735, rs31017, rs419598, rs315951, rs315952, rs27810, and VNTR. Meta-analysis showed that the rs30735*C allele/carrier, the rs31017*G carrier and the rs315952*T carrier were positively and significantly associated with susceptibility to AS (OR = 1.45, 95%CI = 1.19-1.76; OR = 1.73, 95%CI = 1.34-2.24; OR = 1.30, 95%CI = 1.01-1.69; OR = 1.54, 95%CI = 1.16-2.04). A subgroup analysis based on ethnicity revealed significant positive associations between the rs30735*C allele/carrier and the rs31017*G allele and susceptibility to AS in both Caucasian and Asian populations, while the positive association between the rs315952*T carrier and AS susceptibility was significant only in Asian populations (OR = 1.54, 95%CI = 1.16-2.04). This meta-analysis suggests that IL-1RN polymorphisms are involved in the pathogenesis of AS. The rs30735*C allele/carrier, and the rs31017*G allele may be risk factors for ankylosing spondylitis in Caucasians and Asians, while the rs315952*T carrier is associated with susceptibility to this disease only in Asians.

Indoleamine 2,3-dioxygenase is differentially expressed by different white blood cell populations of rhesus macaques (Macaca mulatta).

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is involved in immune processes such as transplant and fetal rejection, autoimmunity, cancer, and infection; however, its expression in rhesus macaques has not been fully addressed. METHODS: Indoleamine 2,3-dioxygenase mRNA and protein in the white blood cells (WBCs) of Chinese rhesus macaques were examined by RT-PCR, western blotting, real-time RT-PCR, and flow cytometry. RESULTS: Both IDO protein and mRNA could be readily detected in WBCs or peripheral blood mononuclear cells (PBMCs) of normal rhesus macaques. IDO+ cell frequency was the highest among CD14(+) mononuclear cells, followed by CD56(+) cells and DCs. No difference in the frequency of IDO+ cells between CD4(+) and CD8(+) T cells; however, Th17 cells have higher frequency of IDO+ cells than Th1 cells, with Th2 cells the lowest. Toll-like receptor (TLR) stimulation significantly increased IDO protein level in CD14(+) , CD56(+) , CD1c(+) , CD11c(+) , and CD123(+) myeloid cells. CONCLUSION: Rhesus macaques express IDO differentially in their leukocyte subsets and are suitable for IDO-related pathophysiological studies.

Novel major histocompatibility complex class II alleles in a group of Chinese rhesus macaques (Macaca mulatta).

Seven novel MhcMamu-DQB1 alleles were observed in a population of rhesus macaques of Chinese origin.

Applications of population pharmacokinetics in current drug labelling.

BACKGROUND AND OBJECTIVE: The application of population pharmacokinetics (PopPK) appears increasingly in drug labelling. The current study was to examine the use of PopPK in dose recommendation in drug-product labels. METHOD: PopPK information was identified in the data sheets included in the physician desk reference (PDR). Electronic key word searches were conducted in the electronic library of PDR. The use of PopPK in the prescribing information, including the determination of dosing regimen, dosing in special populations and dose-adjustments was summarized and evaluated. The reliability and criteria for integrating the information derived from PopPK studies into the product labelling were discussed. RESULTS AND DISCUSSION: Among more than 2500 items listed in the PDR, 88 listings were found to have PopPK information in the labelling. The information included general data (Gen) on pharmacokinetics (PK) and the effects of gender (sex), age, race, drug-drug interactions (DDI), smoking (Smk), alcohol consumption (Alc), disease state (Dis), renal impairment (Ren) and metabolic status (Met) on the PK parameters (Table). Whether there was an effect (+) or not (-) is also shown. Appendix 1 lists the products included in each category. Searches conducted at different times suggest an increase in both quantity and quality of PopPK data in drug development. PopPK is widely used in paediatric studies and the sample sizes in these studies are sometimes too small. The application of PopPK to protein drugs is increasing rapidly (Appendix 2). Several precautions should be exercised when PopPK is applied to protein drugs. When considering gender effects, different normalization methods for body weight have been used. The number of subjects included in the PopPK analysis should be given and the influence of the imbalance in any covariate should be investigated. PopPK-DDI results are particularly difficult to evaluate unless details about potentially influential factors such as dosing and sampling information for both drug and interacting drugs are given. CONCLUSIONS: The use of PopPK to aid optimal dosing is increasing. Several noticeable problems raised usually avoid the acceptability of PopPK studies. More investigations are needed to inform the development of consensuses on these issues. There is an accelerating shift from PopPK to PopPK/PD. The limitations of such modelling should be recognized.

Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Human liver microsomal metabolism of paclitaxel and drug interactions.

The aim of this study was to investigate the influence of several anticancer drugs and investigational multidrug resistance (MDR) reversing agents on the hepatic metabolism of paclitaxel (Taxol) to its primary metabolites, 6alpha-hydroxypaclitaxel (metabolite, MA) and 3'-p-hydroxypaclitaxel (metabolite, MB). There is significant inter-individual variability associated with the levels of these two metabolites. In many cases, 6alpha-hydroxypaclitaxel has been observed to be the predominant metabolite, in others, 3'-p-hydroxypaclitaxel has been the principal metabolite. The formation of 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel is catalyzed by cytochrome P450 isozymes CYP2C8 and CYP3A4, respectively. A number of factors, including co-administration of drugs and adjuvants, are known to influence the activity of these isozymes. Therefore, the influence of MDR reversing agents, R-verapamil, cyclosporin A (CsA) and tamoxifen and anti-cancer drugs doxorubicin, etoposide (VP-16) and cisplatin on paclitaxel metabolism was assessed employing human liver microsomes in vitro. Paclitaxel (10 microM) was incubated with human liver microsomes (1 mg protein, -0.34 nmol CYP) in the presence of a NADPH generating system at 37 degrees C for 1 h, with and without the presence of interacting drug. Controls included incubations with quercetin and ketoconazole, known inhibitors of 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel formation, respectively. At the end of the incubation period, paclitaxel and the metabolites were extracted in ethyl acetate and analyzed employing an HPLC method. Significant inhibition of paclitaxel conversion to 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel was observed in the presence of R-verapamil, tamoxifen and VP-16 (P 0.005). Doxorubicin significantly inhibited the formation of 3'-p-hydroxypaclitaxel and CsA inhibited the formation of 6alpha-hydroxypaclitaxel (P 0.005). This study demonstrates that co-administration of several of the above listed compounds could lead to significant changes in the pharmacokinetics of paclitaxel.