Clinically approved small-molecule drugs for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a persistent autoimmune ailment that is typified by the development of pannus, proliferation of synovial lining cells, microvascular neogenesis, infiltration of interstitial inflammatory cells, and destruction of cartilage and bone tissue. The disease not only imposes physical pain and economic burden on patients, but also results in a significant decline in their quality of life, rendering it a leading cause of disability. General treatment and drugs are commonly employed to alleviate the condition and symptoms of RA. Cyclooxygenase (COX), janus kinase (JAK), glucocorticoid receptor (GR) et al. have been identified as the main therapeutic targets for RA. This article provides a comprehensive review of the clinical applications and synthetic routes of 26 representative drugs for the treatment of RA, with the aim of facilitating the discovery of more effective new drugs for the treatment of this debilitating disease.

Recent advance of small-molecule drugs for clinical treatment of multiple myeloma.

Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study.

BACKGROUND: Uremic pruritus (UP) is a common and frustrating symptom in patients receiving hemodialysis (HD). The majority of patients have mild to moderate itching of the skin, and a small percentage have severe itching, which seriously affects their quality of life and survival rate. However, little is known about factors that influence the intensity of itching in patients. METHODS: A cross-sectional study on uremic pruritus in male and female patients receiving HD was conducted in September 2019. This study included 148 eligible patients who received HD at the Blood Purification Center of Xinchang County People's Hospital, Zhejiang Province, China from March 2019 to June 2019. We collected general data consisted of age, sex, body mass index (BMI), place of residence, educational level, diabetes mellitus status and duration of HD; as well as clinical, biochemical indicators, including serum calcium (Ca), serum phosphorus (P), serum albumin (ALB), haemoglobin (Hb), serum intact parathyroid hormone (iPTH), pre-dialysis serum urea nitrogen (BUN), normalized protein catabolic rate (nPCR), urea nitrogen clearance index (KT/V), ferritin (FER) and pre-dialysis serum creatinine (sCR). We also assayed the inflammatory cytokine serum high sensitivity C-reactive protein (hs-CRP). The Five-Dimensional Itching Scale (5DIS) was used to evaluate the degree of skin itching (none, mild, moderate, or severe). We used multiple logistic regression to analyze influencing factors on the degree of skin itching in patients with UP. RESULTS: Of the 148 patients, 60 had uremic pruritus (incidence rate, 40.54%). These included 22 cases of mild skin itching (14.86%), 30 of moderate skin itching (20.27%), and 8 of severe skin itching (5.41%). Compared with uremia patients without skin pruritus, patients with UP had higher levels of iPTH, Hb, BUN, nPCR, and hs-CRP. The composition ratio showed significant differences between urban and rural patients with different degrees of skin itching (P = 0.017); moreover, the difference of iPTH and hs-CRP levels were statistically significant (P = 0.009 and < 0.001, respectively). Using no itching as a reference, multiple logistic regression analysis showed that as hs-CRP level increased, the patient's risks of mild skin itching (odds ratio [OR] = 1.740; 95% confidence interval [CI], 1.061-2.854; P = 0.028), moderate skin itching (OR = 2.8838 95% CI, 1.744-4.718; P < 0.001), and severe skin itching (OR = 9.440; 95% CI, 3.547-25.124; P < 0.001) all increased as well. Compared with urban residents, rural residents have a higher risk of moderate itching (OR = 3.869; 95% CI, 1.099-13.622; P = 0.035). CONCLUSION: Levels of hs-CRP were associated with the intensity of skin itching in patients with UP. Higher hs-CRP levels were closely related to severe skin itching. The relationship between the intensity of skin itching and the environment in maintenance hemodialysis patients needs further clarification.

[Effects of forest gap size and light intensity on herbaceous plants in Pinus koraiensis-dominated broadleaved mixed forest].

1 m x 1 m fixed quadrats were parallelly arranged with a space of 2 m in each of six forest gaps in Pinus koraiensis-dominated broadleaved mixed forest, taking the gap center as the starting point and along east-west and south-north directions. In each quadrat, the coverage and abundance of herbaceous plants at different height levels were investigated by estimation method in June and September 2011, and the matrix characteristics within the quadrats were recorded. Canopy analyzer was used to take fish-eye photos in the selected overcast days in each month from June to September, 2011, and the relative light intensity was calculated by using Gap Light Analyzer 2.0 software. The differences in the relative light intensity and herbaceous plants coverage and richness between different gaps as well as the correlations between the coverage of each species and the direct light, diffuse light, and matrix were analyzed. The results showed that in opening areas and under canopy, the relative light intensity in large gaps was higher than that in small gaps, and the variation ranges of diffuse light and direct light from gap center to gap edge were bigger in large gaps than in small gaps. The direct light reaching at the ground both in large gaps and in small gaps was higher in the north than in the south direction. In the Z1, Z2, Z3, and Z4 zones, both the coverage and the richness of herbaceous plants were larger in large gaps than in small gaps, and the differences of species richness between large and small gaps reached significant level. The coverage of the majority of the herbaceous plants had significant correlations with diffuse light and matrix, and only the coverage of a few herbaceous plants was correlated with direct light.

[Effects of gap size on the spatial heterogeneity of soil water in Pinus koraiensis-dominated broad-leaved mixed forest].

In August-October 2011, the soil water content (SWC) at different depths in different sized gaps in Pinus koraiensis-dominated broad-leaved mixed forest of Xiaoxing' an Mountains, Northeast China was continuously measured by grid nesting method and time domain reflectometry (TDR), and the spatial heterogeneity of the SWC was analyzed by the principles and approaches of geostatistics. The SWC was most abundant in medium gap, followed by in large gap and in small gap whereas the maximum difference of SWC was the biggest in large gap, followed by in medium gap, and in small gap. The variation range of the nugget of SWC at different depths in the large, medium, and small gaps was 0.001-0.404, 0.001-0.273, and 0.001-0.261, respectively. The SWC heterogeneity resulted from random part and the total system SWC spatial heterogeneity were decreased in the order of large gap > medium gap > small gap. The spatial distribution pattern of SWC was most complicated in medium gap, while the spatial dependence in the variation of the SWC pattern was the strongest in large gap. High-grade patches (SWC was 50%-60%) occupied the largest area in medium gap, followed by in large gap, and there was no high-grade patch in small gap. As for the SWC at same depths and in same months, its grade distribution was most simple in small gap, but relatively complicated in large and medium gaps. The maximum value of SWC increased with increasing gap size.

[Analysis of hydrogen-production performance in a UASB system at low pH].

This experiment used upflow anaerobic sludge blanket (UASB) with brown sugar water as fermentation substrate and sewage sludge as the initiation sludge of the reaction, which was made into granular sludge by adding activated carbon. Emphasis was placed on assessing the hydrogen production performance of the UASB hydrogen bio-production system in the stable ethanol-type fermentation. Under the conditions that the influent COD was 4000 mg x L(-1), the temperature was (35 +/- 1) degrees C and the hydraulic retention time (HRT) was 8 h, a certain amount of NaHCO3 was added to adjust pH from 3.72 to 3.80, 3.85, 3.94 and 4.04, the hydrogen production rate increased correspondingly from the initial 5.5 L x d(-1) to about 7.0, 8.0, 9.5 and 6.0 L x d(-1), which was improved by 27.27%, 45.45%, 72.73% and 9.09%, respectively. The highest hydrogen production rate and gas yield were observed at pH 3.94. The maximal gas yield was 15.83 L x d(-1), which was 1.75 times as high as the initial production. Meanwhile, the hydrogen production efficiency was 58.05%. This study broke through the lower limit pH value 4.0 in fermentative hydrogen production.

[Effects of forest gap size and uprooted microsite on the microclimate in Pinus koraiensis-dominated broad-leaved mixed forest].

Three representative forest gaps with pit-mound microsites formed by uprooted trees were selected within the 2.55 hm2 plot in a Pinus koraiensis-dominated broad-leaved mixed forest in Xiao Xing'an Mountains of Northeast China. The cleared land and closed stand were set up as the controls, and the PAR, air temperature and relative humidity in the centers of different size gaps and in mound top as well as the total radiation and precipitation in the gap centers were measured between July and September, 2011 by using multichannel automatic meteorological stations. The differences of the microclimate between the gap centers and mound top in different months were compared, and the monthly and diurnal variations of the microclimatic factors in the gap centers and in the mound top under typical weather conditions were analyzed. The results showed that the mean monthly PAR and air temperature in the three gaps of different sizes were in the order of large gap > medium gap > small gap, and the mean monthly relative humidity was in the order of small gap > medium gap > large gap. For the same size gap, the mean monthly PAR and air temperature were higher in the mound top than in the gap center, whereas the mean monthly relative humidity was higher in the gap center than in the mound top. Both the mean monthly total radiation and the mean monthly air temperature in the forest gaps and in the controls were in the order of July > August > September and of cleared land > large gap > medium gap > small gap > closed stand, while the mean monthly relative humidity was in the order of closed stand > small gap > medium gap > large gap > cleared land. The differences in the mean monthly relative humidity between closed stand and various gaps and between closed stand and cleared land reached significant level. The monthly precipitation from July to September decreased in the order of cleared land > large gap > medium gap > small gap > closed stand. Whether in sunny days or in overcast days, the mean daily PAR and air temperature were higher in mound top than in gap center, and the mean daily relative humidity was in opposite. Whether in mound top or in gap center, the mean daily PAR and air temperature were higher in sunny days than in overcast days, while the mean daily relative humidity was higher in overcast days than in sunny days.

Clinical application of full-face, whole, full-thickness skin grafting: a case report.

A considerable portion of burn patients suffers severe full-face burns. Even after they were treated, some severe abnormalities still stay with them such as upper- and lower-eyelid ectropions, upper- and lower-lip ectropions, microstomia and extensive facial scar hyperplasia accompanied with pruritus. Patients suffer a great deal physically, emotionally and socially. Here we conclude our treatment experience of full-face burns with the full-face, whole, full-thickness skin grafting, which has not yet reported in the literature. We transplanted a whole, full-thickness skin graft to cover the wound in the primary operation and then remedied eyelid ectropions and microstomia in the operation that followed. The results of a 4-year-follow-up suggest that the patient has recovered part of facial expression and sensation without any geographic scars. Full-face, whole, full-thickness skin grafting appears to be an effective and relatively simple method for full-face burns that do not respond well to facial composite tissue allotransplantation (CTA).

[Comparison of dental changes between adult and adolescent skeletal class II malocclusion].

OBJECTIVE: To compare occlusual changes after orthodontic treatment between adults' and adolescents' skeletal class II malocclusion with average mandible plane angle. METHODS: In the study, 30 adolescent girls and 30 women who had skeletal class II and Angle class II, division 1 malocclusions were selected. The two groups were matched by sex, treatment period and method. Cephalometric radiographs taken before and after treatment were traced and measured. Student's t-test was used. RESULTS: After treatment upper incisors retracted and erupted in both groups. Upper molars moved forward and downward in the adolescents but only moved forward in the adults. Lower incisors retracted but their inclination remained constant in both groups. More intrusion of lower incisors was shown in the adults. Lower molars showed more forward and upward movement in the adolescents than in the adults. The adults experienced more clockwise rotation of occlusion plane than the adolescents. CONCLUSION: Growth enhances the correction of deepbite in adolescent skeletal class II malocclusion.

Comparison of skeletal changes between female adolescents and adults with hyperdivergent Class II Division 1 malocclusion after orthodontic treatment.

OBJECTIVE: To compare the skeletal changes between female hyperdivergent adolescents and adults with Class II Division 1 malocclusion after orthodontic treatment. METHODS: Thirty adolescent girls and 30 adult women both with hyperdivergent Class II Division 1 malocclusions were selected. The 2 groups were matched by both treatment period and treatment method. Cephalometric radiographs taken before and after treatment were traced and measured. Data were statistically examined. RESULTS: After treatment, SNA decreased significantly in both groups. SNB remained unchanged in the adolescent group, while it decreased in the adult group. ANB decreased significantly only in the adolescent group and remained unchanged in the adult group. Obvious growth was found in the adolescent group. Ar-Gn, Ar-Go, N-Me and S-Go increased significantly in adolescents. In the adult group, N-Me and ANS'-Me increased after treatment, but with less magnitude than those in the adolescent group. All the angular measures (MP-SN, PP-SN, Ar- Go-Gn and N-S-Ba) remained quite stable in both the adolescent and adult groups. CONCLUSION: Although obvious vertical growth was found in the female hyperdivergent adolescent Class II Division 1 group, no clockwise rotation of the mandible and no mandibular catch-up growth were found. Vertical growth of the mandible was helpful in maintaining the MP-SN angle with conventional orthodontic mechanism in the adolescent group.

[A comparison of skeletal changes between adult and adolescent with skeletal class II malocclusions before and after therapy].

OBJECTIVE: To compare skeletal changes after orthodontic treatment between adults and adolescents skeletal class II malocclusions with average mandible plane angle. METHODS: In our study, 30 adolescent girls and 30 adult females who had skeletal class II and Angle class II, division 1 malocclusions were selected. The two groups were matched by gender, treatment period and method. Cephalometric radiographs taken before and after treatment were traced and measured. Student's t-test was used. RESULTS: After treatment, SNA, SNB and ANB decreased in both groups, but no significant difference was found between the two groups. The length of mandible, anterior and posterior facial heights increased significantly in adolescents, but the ratio of lower and total anterior and posterior facial heights remained unchanged and no difference was found between the two groups. CONCLUSION: Although some maxillary and mandibular growths were found in adolescents, the skeletal changes during treatment in skeletal class II malocclusion with average mandible plane showed no difference between adults and adolescents.

[Comorbidities in patients with cerebral palsy and their relationship with neurologic subtypes and Gross Motor Function Classification System levels].

OBJECTIVE: To analyze the comorbidities in patients with cerebral palsy (CP) from two perspectives as neurologic subtype and gross motor functions, and find their correlations. METHODS: Children with cerebral palsy treated in the rehabilitation center from January 2007 to June 2009 received the following examinations: intelligence capacity test, ophthalmologic consultation, language-speech test, brainstem auditory evoked potential and electroencephalogram. They were stratified according to both neurologic subtype and gross motor functions to detect the occurrence of comorbidities. RESULTS: Of all the 354 cases, 166 (46.89%) had mental retardation, 15 (4.24%) auditory limitations, 138 (38.98%) visual disorder, 216 (61.02%) language-speech disorder and 82 (23.16%) epilepsy. The frequency of individual comorbidities were distributed disproportionately between the different neurologic subtypes. Correlation analysis showed that there was a significant correlation between the spastic diplegia and the visual disorder (correlation coefficient = 0.26), between spastic hemiplegia and epilepsy (correlation coefficient = 0.17), between spastic quadriplegia and epilepsy and mental retardation (the correlation coefficient was 0.38 and 0.11, respectively) and between both dyskinetic and mixed children and language-speech disorder (the correlation coefficient was 0.24 and 0.27, respectively). The frequency of individual comorbidities was distributed disproportionately between the different neurologic subtypes and between the different GMFCS levels (P < 0.05), except for the frequency of visual disorders (chi(2) = 1.90, P > 0.05); and with the increase of the GMFCS levels, the burden of the comorbidities were more heavy and the incidence of the comorbidities was higher. Multi-comorbidities were relatively infrequently encountered in those with spastic hemiplegic or spastic diplegic children or patients whose GMFCS levels were I-III, while these entities occurred at a frequent level for those with spastic quadriplegic, dyskinetic, or mixed or children whose GMFCS levels were IV and V, and the differences were significant (P < 0.05). The mean GMFCS levels of children with spastic quadriplegic, dyskinetic or mixed CP were higher than level III, most of them had no ability of ambulation;while the mean GMFCS levels of spastic hemiplegic or spastic diplegic children were below level III, most of them could walk independently. CONCLUSIONS: There are correlations between the occurrence of the comorbidities such as mental retardation, auditory or visual impairments, language-speech disorders, epilepsy and the cerebral palsy subtype and the gross motor function levels. Clinicians should have a full recognition of these comorbidities, and we should have a cooperation between the different subjects to have an overall evaluation and rehabilitation and to improve the prognosis.

Spontaneous symmetry breaking and bifurcations in ground-state fidelity for quantum lattice systems.

Spontaneous symmetry breaking occurs in a system when its Hamiltonian possesses a certain symmetry, whereas the ground-state wave functions do not preserve it. This provides such a scenario that a bifurcation, which breaks the symmetry, occurs when some control parameter crosses its critical value. It is unveiled that the ground-state fidelity per lattice site exhibits such a bifurcation for quantum lattice systems undergoing quantum phase transitions. The significance of this result lies in the fact that the ground-state fidelity per lattice site is universal, in the sense that it is model independent, in contrast to (model-dependent) order parameters. This fundamental quantity may be computed by exploiting the developed tensor network algorithms on infinite-size lattices. We illustrate the scheme in terms of the quantum Ising model in a transverse magnetic field and the spin-1/2 XYX model in an external magnetic field on an infinite-size lattice in one spatial dimension.

[Expression features of P-glycoprotein, glutathione S transferase-pi and inhibitor of apoptosis proteins in lymph node metastases of gastrointestinal carcinomas].

OBJECTIVE: To investigate the expression features of P-glycoprotein (P-gp), glutathione S transferase-pi (GST-pi) and inhibitor of apoptosis proteins like p53, survivin and bcl-2 in lymph node metastases of gastrointestinal carcinomas. METHODS: The expression of P-gp, GST-pi, p53, survivin and bcl-2 were determined by using immunohistochemistry technique in surgical specimens of primary tumor (PT) and lymph node metastases (LNMs) from 54 gastrointestinal cancer patients with metastasis of lymph nodes. The expression difference of 5 multi-drug resistance (MDR)-related factors between LNMs and PT were compared. RESULTS: Significant difference was found in the expression of P-gp and GST-pi between the two groups (both P < 0.05), and expression of p53 and bcl-2 showed positive correlation between LNMs and PT (r = 0.7248, 0.5524; both P < 0.05), respectively. In LNMs, P-gp expression was positively correlated with GST-pi (r = 0.4062, P < 0.05) and survivin (r = 0.6169, P < 0.05), and also GST-pi expression was related positively with survivin (r = 0.4027, P < 0.05). Statistically positive correlations were noted between bcl-2 and P-gp (r = 0.3986, P < 0.05), bcl-2 and survivin (r = 0.2937, P < 0.05), as well as GST-pi and survivin (r = 0.4481, P < 0.01) in PT. Only a positive correlation between GST-pi and survivin expression was simultaneously shown in both LNMs and PT. CONCLUSIONS: There is significant heterogeneity of MDR-related factors expression in LNMs of gastrointestinal carcinomas. Effective adjuvant chemotherapy after operation should target on the metastatic loci of the disease.

[Correlation of expression of P-glycoprotein and inhibitor of apoptosis proteins to chemosensitivity in gastrointestinal carcinoma tissues].

BACKGROUND & OBJECTIVE: P-glycoprotein (P-gp) mediated classical drug resistance and inhibition of the apoptotic pathway are the two mostly investigated mechanisms of multidrug resistance (MDR). Coexpression and interaction of MDR-related factors result in pleiotropic drug resistance in cancer cells. This study was to investigate the correlation of expressions of multiple MDR-related factors, such as P-gp, p53, Survivin or bcl-2, to chemosensitivitity in gastrointestinal carcinomas. METHODS: Eighty-four tissue specimens of gastrointestinal carcinomas were analyzed. Expressions of P-gp, p53, Survivin and bcl-2 were determined by immunohistochemistry (IHC). Drug chemosensitivity of nine drugs to cancer cells were measured by MTT assay. RESULTS: The positive staining of P-gp, p53, Survivin and bcl-2 were detected in 96.4%, 64.3%, 89.3% and 60.7% of all specimens, respectively. The expression of P-gp and bcl-2 (r=0.5072, P<0.05), and the expression of survivin and bcl-2 (r=0.3027, P<0.05) were positively correlated. The inhibition rates of paclitaxel (PTX), oxaliplatin (OXA) or cisplatin (DDP) on cancer cells were significantly lower in the group with strong P-gp expression than that with weak P-gp expression (all P<0.05). The strong expression of p53 was correlated with decreased inhibition rates of PTX and DDP on cancer cells (P<0.05, P<0.01). When the expression of Survivin was increased, the inhibition rates of vincristine (VCR) or DDP on cancer cells were reduced significantly (P<0.05, P<0.01), but the inhibitory effect of OXA was remarkably increased (P<0.01). The inhibition rates of 5-fluorouracil (5-FU), VCR, epirubicin (EADM) and OXA on cancer cells were lower in the group with strong expression of bcl-2 than in that with weak expression of bcl-2 (P<0.05). CONCLUSIONS: The expression of MDR-related factors in gastrointestinal carcinomas is associated with drug resistance of only certain chemotherapy drugs. Multiple factors and mechanisms should be considered when assessing the influence of MDR related factors on drug resistance.

[Oral motor dysfunction, feeding problems and nutritional status in children with cerebral palsy].

OBJECTIVE: This study was undertaken to investigate the clinical features of oral motor dysfunction and feeding problems as well as the nutritional status of children with cerebral palsy (CP). METHODS: Fifty-nine CP children, 39 boys and 20 girls, mean age 31 months (20 to 72 months), were recruited. Their parents were interviewed for high risk factors and feeding history. Each case was assessed for oral motor and feeding problems based on oral motor and feeding skill score; for nutritional status by measurement of weight, height; neurologically for type of cerebral palsy and for developmental age by Gesell's developmental scale. Equal number of age and sex matched controls were included for comparison of nutritional status, oral motor and feeding skill score. RESULTS: Among 59 patients, 51 cases had oral motor dysfunction and 55 cases had feeding problems including all athtosis, spastic tetraplegia, and 16 had spastic diplegia. The scores of both the mean oral motor function and feeding skill of CP children were significantly lower than those of the controls (P < 0.001). Main food of children with cerebral palsy consisted of liquid and semisolid diet. Body weight and height below the 25th percentile were found in 13 cases and 19 cases, respectively. CONCLUSIONS: The majority of the children with cerebral palsy had oral motor dysfunction and feeding problems which appeared in early age and disturbed the growth and nutritional status. Thorough assessment for oral motor function, feeding problems and nutritional status of CP children is indicated in order to start timely rehabilitation and nutritional interventions which can significantly improve their nutritional status and quality of life.