HIV-1 integrase (IN) is an essential enzyme for retroviral replication. There is no analogue for this enzyme in human cells so that inhibition of IN will not bring strong effect on human body. Thus, HIV-1 IN has become a rational target for therapy of AIDS. This review provides a comprehensive report of alpha, gamma-diketo IN inhibitors discovered in recent years. Compilation of such data will prove to be beneficial in developing QSAR, pharmacophore hypothesis generation and validation, virtual screening and synthesis of compounds with higher activity.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; HIV Integrase ; chemistry ; physiology ; HIV Integrase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; HIV-1 ; drug effects ; Humans ; Keto Acids ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Quantitative Structure-Activity Relationship

OBJECTIVETo evaluate the clinical and radiographic results of extensively porous-coated femoral stem in revision of total hip arthroplasty (THA).

METHODSFrom January 1999 to December 2003, fifteen hips of fifteen cases received revision of THA with extensively porous-coated femoral stem. There were six males and nine females. The average age was 66 years (ranging 58-82 years). The reason for the revision was aseptic loosening in 10 cases, septic loosening in 2, femoral shaft fracture around loose implant in 2, and femoral revision for malposition of the femoral component in 1. All the patients were clinically evaluated using Harris hip score and radiographically evaluated both preoperatively and postoperatively at regular follow-up intervals.

RESULTSNo patients were lost for follow-up. The average length of follow-up was 2.3 years (range, 1-5 years). The average preoperative Harris hip score was 42 points, which was improved to 89 points at latest follow-up. The latest follow-up showed that bone in-growth occurred in fourteen stems and solid fibrous fixation in one. Complications consisted of femoral shaft fracture in two cases (1 undisplaced distal femur fracture and 1 cortical perforation at the tip of the prosthesis), and postoperative dislocation in one. There was no mechanical failure of the stem in this study.

CONCLUSIONSSatisfactory results of short-term clinical and radiographic follow-up have been achieved in using extensively porous-coated femoral stem for revision of THA. It should be noticed that the straight, 203 mm stem should be used with caution in short people.

OBJECTIVETo evaluate the results of total knee arthroplasty (TKA) in patients with posttraumatic degenerative arthritis due to a previous fracture around the knee.

METHODSWe analyzed the results of 15 TKAs, performed from 1997 to 2003, in 15 patients with post-traumatic degenerative arthritis due to a previous fracture around knee. There were 3 women and 12 men with an average age of 58 years (range, 31-76 years). The time from fracture to arthroplasty averaged 8.2 years (range, 2-27 years). Internal fixation had previously been performed in 8 patients resulting in retained hardware. At the time of arthroplasty a femoral fracture malunion was present in two knees. Lateral retinacular release (4 knees), extensor mechanism realignment (1 knee) or medial collateral ligament reconstruction (1 knee) were needed at the time of arthroplasty.

RESULTSFollow-up averaged 35 months (range, 12-73 months). No patient was lost for follow-up. According to the Knee Society Score scale, the mean preoperative knee score was 37 (range, 10-70) and functional score was 41 (range, 0-60). They were improved significantly to a mean of 84 (range, 10-100) and 76 (range, 20-100) points, respectively at the latest follow-up. The mean knee arc of motion were improved from 84 degree preoperation to 94 degree at the latest follow-up. Postoperative manipulation under anesthesia for poor motion was carried out in 4 knees. No knee had aseptic loosening that required subsequent revision. Two knees developed superficial infection and were treated with debridement. It subsequently recovered with the retention of components.

CONCLUSIONSSignificant improvement in function and relief of pain has been achieved in patients with previous fractures undergoing subsequent TKA. However, this procedure is technically demanding and patients are at increased risk for restricted motion and need more care following TKA. This study suggests that the outcome of TKA may be improved further by making special efforts to restore limb alignment, to ensure correct component positioning, and to manage soft tissue balance.

Adult ; Aged ; Arthroplasty, Replacement, Knee ; adverse effects ; Female ; Humans ; Knee Injuries ; complications ; Male ; Middle Aged ; Osteoarthritis ; surgery

OBJECTIVETo assess the value of immunoregulants in improving the prognosis of infants with wheezing.

METHODSForty-three infants with wheezing with given oxygen support, injection or inhalation of glucocorticosteroids or bronchodilatator to relieve the symptoms. Of these infants, 24 received immunoregulant treatment with bronchovaxom at the daily dose of 3.5 mg for 10 days every a month for a treatment course of 3 months. The other 19 infants were managed with budesonide aerosol at 200 microg once or twice daily for 3 months (basic treatment group). All the infants were followed up for 1 year to record the number of wheezing episode and infections. Ten healthy infants were also included in this study as the control group.

RESULTSIn infants with bronchovaxom treatment, 25% reported more than 3 wheezing episodes within the 1-year follow-up, a rate significantly lower than that in the control group (63.2%, Chi(2)=6.344, P<0.05). The episodes of respiratory infection were similar between bronchovaxom group and the healthy control group (t=0.72, P>0.05), but significantly higher in the basic treatment group than in bronchovaxom and the healthy control group (t=3.11 and 3.92, respectively. P<0.05).

CONCLUSIONSBronchovaxom can effectively reduce the recurrence of wheezing and respiratory infections in the infants with wheezing attack to reduce the risks of asthma development.

Asthma ; diagnosis ; drug therapy ; prevention & control ; Bacteria ; Cell Extracts ; administration & dosage ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Immunologic Factors ; therapeutic use ; Infant ; Male ; Prognosis ; Respiratory Sounds ; drug effects

OBJECTIVETo investigate the effect of polysaccharide nucleic acid of BCG (BCG-PSN) injection on immune and pulmonary function in asthmatic children complicated with allergic rhinitis.

METHODSThirty-seven cases were separated at random into two groups, the BCG-PSN group (17 cases) was treated with BCG-PSN plus inhaled glucocortisteriods, and the control group (20 cases) was treated with inhaled glucocortisteriods only. The children in both groups were followed up for 6 months to record their lung function, allergic rhinitis scores, frequency of asthmatic attacks and respiratory infection. The levels of interleukin (IL)-4, interferon-gamma (IFN-g) and plasma total IgE were detected by using double antibody sandwich ELISA at the beginning and the end of treatment.

RESULTSIn comparison with the control group, after treatment, the levels of IFN-g and the ratio of IFN-g/IL4 in the BCG-PSN group significantly increased, whereas the level of IL-4 and the plasma total IgE significantly decreased (P less than 0.05), while those of the control group had no significant change. The lung function of both groups had significant improvement (p less than 0.05). The frequencies of asthmatic attacks in BCG-PSN and control groups were 0.81 +/- 0.20 vs. 1.72 +/- 0.80, and the difference was statistically significant. The frequencies of respiratory tract infection in BCG-PSN and control groups were 1.15 +/- 0.55 vs. 3.21 +/- 0.73, the difference was significant.

CONCLUSIONBCG-PSN may be able to correct the imbalance of Th1/Th2 and improve the lung function of children with asthma complicated with allergic rhinitis, which suggest that the immune adjusting treatment should be emphasized besides anti-inflammation therapy.

Adjuvants, Immunologic ; chemistry ; therapeutic use ; Adolescent ; Asthma ; blood ; complications ; drug therapy ; BCG Vaccine ; chemistry ; therapeutic use ; Child ; Child, Preschool ; Enzyme-Linked Immunosorbent Assay ; methods ; Female ; Humans ; Interferon-gamma ; blood ; Interleukin-4 ; blood ; Male ; Nucleic Acids ; chemistry ; Polysaccharides, Bacterial ; chemistry ; Rhinitis, Allergic, Perennial ; blood ; complications ; drug therapy ; Treatment Outcome

OBJECTIVETo investigate the effects of leukotriene receptor antagonist on the levels of Th1 and Th2 cytokines and the serum cysteinyl leukotrenes (CysLTs) in infants and young children with respiratory syncytial virus (RSV) pneumonia.

METHODSThirty-seven infants and young children with RSV pneumonia were divided into two groups after discharge. The cases in group 1 (n=24) were treated with a leukotriene receptor antagonist, Singulair 4 mg once daily for 12 weeks; the cases in group 2 (n=13) were treated with budesonide aerosol 200 ug once or twice daily for 12 weeks. The serum CysLTs, IFN-gamma and IL-4 were detected with enzyme_linked immunosorbent assays (ELISA) for all the 37 cases, and 10 healthy infants of the same age served as controls.

RESULTSThe serum CysLTs level in the cases with RSV pneumonia was significantly higher than that in controls (P<0.05). There was an imbalance in expression of Th1 and Th2 cytokines (IFN-gamma and IL-4 ) in these cases. Both Singulair and budesonide aerosol could correct the imbalance of Th1 and Th2 cytokines. The serum CysLTs level declined after treatment with Singulair in 24 cases, but no significant change occurred after treatment with budesonide aerosol in the remaining 13 cases.

CONCLUSIONSThe serum CysLTs level in children with RSV pneumonia was higher than that in healthy children, and there was an imbalance of Th1 and Th2 cytokines in these infants, which was similar to those with asthma. Leukotriene receptor antagonist may be effective in preventing children with RSV pneumonia from evolving into asthma.

Child, Preschool ; Cytokines ; blood ; Female ; Humans ; Infant ; Leukotriene Antagonists ; administration & dosage ; pharmacology ; Male ; Pneumonia, Viral ; drug therapy ; immunology ; virology ; Respiratory Syncytial Virus Infections ; drug therapy ; immunology ; virology ; Respiratory Syncytial Viruses ; drug effects ; immunology ; Th1 Cells ; drug effects ; immunology ; Th2 Cells ; drug effects ; immunology

·AIM: To evaluate the effects of foldable capsular vitreous body (FCVB) implantation on the treatment of severe ocular trauma and late silicone oil-dependent eyes due to severe ocular trauma and recurrent retinal detachment. · METHODS: We retrospectively reviewed the four patients (four eyes) with FCVB implantation at our hospital since November 2017. Out of these 4 patients,2 were males and 2 were females, with an average age of 31.5 years and an average intraocular pressure (IOP) of 5.6mmHg pre-operatively. Among those 4 eyes,3 eyes underwent silicone oil tamponade due to severe ocular trauma and the other one was recurrent retinal detachment in silicone oil - filled eye. Standard pars plana vitrectomy (PPV) was performed, and the FCVB was triple folded and implanted in the vitreous cavity of four eyes. The retinal was assessed, as well as visual acuity,IOP, FCVB condition before and after treatment, and applied therapy. ·RESULTS: All of those 4 eyes underwent successfully implantation of FCVB, which remained its proper position. During 1-3mo follow-up, the mean visual acuity was no different compared with pre - operative values.

BACKGROUNDEstrogen might play an important role in type 2 diabetes mellitus pathogenesis. A number of polymorphisms have been reported in the estrogen receptor alpha (ERalpha) gene (also named ESR1), including the XbaI and PvuII restriction enzyme polymorphisms of ESR1, which may be involved in disease pathogenesis. The aim of this study was to determine whether ERX gene polymorphisms are associated with type 2 diabetes mellitus and serum lipid level.

METHODSTwo hundred and ninety-nine patients with type 2 diabetes mellitus were compared with three hundred and forty-one health controls of Guangzhou in China, both were male and postmenopausal female residents at 51 - 70 years. ESR1 genotyping was performed using polymerase chain reaction (PCR) and PvuII and XbaI restriction fragment length polymorphism (PCR-RFLP) analysis.

RESULTSESR1 allelic frequencies of P, p and X, x alleles were 0.408, 0.592; 0.360, 0.640 in the type 2 diabetes mellitus group and 0.318, 0.682; 0.328, 0.672 in the control group, respectively. In case-control study, there was significant difference in PvuII, but not XbaI, allele frequency between the type 2 diabetes mellitus and control groups (P = 0.001 and P = 0.122). When the group was separated into men and women, the difference was significant in women (P < 0.001) but not in men (P = 0.854) with the PvuII genotype, and the effect of PvuII variant on the development of type 2 diabetes mellitus was improved with aging. In addition, PvuII genotype was associated with blood glucose [fasting blood glucose (FBG), postprandial blood glucose (PBG)] and serum lipid [total cholesterol (TC) and low density lipoprotein (LDL)-c] concentration in healthy women.

CONCLUSIONSPvuII polymorphism of ESR1 increases susceptibility to type 2 diabetes mellitus in Chinese Guangzhou women. ESR1 variants may also impact serum lipid metabolism, which might provide a mechanism connecting ESR1 to type 2 diabetes.

Aged ; Blood Glucose ; analysis ; Cholesterol, LDL ; blood ; Diabetes Mellitus, Type 2 ; blood ; genetics ; Estrogen Receptor alpha ; genetics ; Female ; Genotype ; Humans ; Lipids ; blood ; Logistic Models ; Middle Aged ; Polymorphism, Genetic

OBJECTIVETo evaluate the outcomes of total hip arthroplasty (THA) for coxarthrosis due to dysplasia with acetabular reconstruction of an uncemented cup in conjunction with a femoral head autograft.

METHODSA retrospective study was made on 21 hips in 20 patients (18 female and 2 male; average age, 50 years) with developmental hip dysplasia treated by THA with use of an uncemented cup. The acetabular cup was placed at the level of the true acetabulum; all patients required autogenous femoral head grafts due to acetabular deficiency. The average coverage of the acetabular cup by the femoral head autograft was 31% (range, 10% to 45%). Eight hips had less than 25% cup coverage and 13 between 25% and 50%. The average follow-up period was 4.7 years (range, 1-8 years). All patients were evaluated with the use of a modified Harris hip score. Radiographic evaluations were made by preoperative and follow-up.

RESULTSAll autografts were seen to be united to host-bone. No collapse of the autograft and no hip had the evidence of loosening of component seen in all patients. According to the modified Harris hip score, the average hip score increased from 46 at preoperation to 89 at the final review. Preoperative leg-length discrepancy was greater than 2 cm seen in all except 1 patient with bilateral hip dysplasia. After surgery, only 2 of 20 patients still had a leg-length discrepancy greater than 1 cm. Three hips showed minor resorption in the lateral portion of the graft which was not supporting the cup. Three hips developed grade 1 Brooker heterotopic ossification and one had grade 2.

CONCLUSIONSTHA with an uncemented cup in conjunction with a femoral head autograft for coxarthrosis due to dysplasia could obtain favorable results. This method could provide reliable acetabular fixation and appeared to restore acetabular bone stock in patients with developmental hip dysplasia when the coverage of the cementless cup by the graft does not exceed 50%.

Adult ; Aged ; Arthroplasty, Replacement, Hip ; methods ; Bone Cements ; Bone Transplantation ; methods ; Female ; Femur Head ; surgery ; Hip Dislocation, Congenital ; complications ; surgery ; Humans ; Male ; Middle Aged ; Osteoarthritis, Hip ; etiology ; surgery ; Retrospective Studies ; Transplantation, Autologous

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.