Hyperoside attenuates carbon tetrachloride-induced hepatic fibrosis via the poly(ADP-ribose)polymerase-1-high mobility group protein 1 pathway.

Oxidative stress and inflammation have been implicated in hepatic fibrosis. Antioxidant and anti-inflammatory activities are among the pharmacological effects of hyperoside. This study aimed to evaluate the impact of hyperoside on hepatic fibrosis and elucidate the underlying processes that perpetuate this relationship. The findings indicated that hyperoside significantly protects mouse livers against damage, inflammation, and fibrosis. Specifically, attenuation of hepatic fibrosis is associated with lower expression of HMGB1 protein and reduced expression of Toll-like receptor 4, PARP-1, and nuclear factor-kB (NF-κB) p65 mRNA and protein. Furthermore, hyperoside inhibited the cytoplasmic translocation of HMGB1 and nuclear localization of NF-κB p65 in the hepatic tissues of mice. The results of this study indicate that hyperoside may impose a blocking or reversing effect on hepatic fibrosis; additionally, the corresponding hyperoside-dependent mechanism may be linked to PARP-1-HMGB1 pathway regulation.

Clinical efficacy of targeted therapy, immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX), and lipiodol embolization in the treatment of unresectable hepatocarcinoma.

To evaluate the clinical efficacy of targeted therapy and immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX and lipiodol embolization in the treatment of unresectable hepatocellular carcinoma. Patients included in the study were those who received targeted therapy and immunotherapy combined with HAIC of FOLFOX and lipiodol embolization in Zhongshan People's Hospital from December 2020 to June 2021 for unresectable hepatocellular carcinoma. Evaluation indicators included objective response rate (ORR), median progression-free survival (mPFS), median duration of response (mDOR), 1-year overall survival rate (OS), surgical conversion rate, and adverse events. Treatment response was assessed using Response Evaluation Criteria in Solid Tumors (mRECIST and RECIST v1.1). A total of 35 patients were included in this study, 30 of whom completed treatment evaluation. According to mRECIST evaluation criteria, the objective response rate (ORR) was 83.3% (25/30); the complete response (CR) was 60% (18/30); the partial response (PR) was 23.3% (7/30), and stable disease (SD) was 16.7% (5/30). The mDOR was 10.3 months (95% Cl: 8.27-NE), and the mPFS was 13.2 months (95% CI: 10.3-NE); the surgical conversion rate was 30.0% (9/30). The 1-year OS was 96.7%. There were no serious surgical complications and grade 4 or 5 adverse events of targeted therapy, immunotherapy and HAIC. Some patients had grade 3 adverse reactions in gastrointestinal toxicity or hepatotoxicity, and the adverse reactions were improved after corresponding symptomatic treatment. We concluded that HAIC of FOLFOX and lipiodol embolization combined with targeted therapy and immunotherapy had a significant curative effect in the treatment of unresectable hepatocellular carcinoma, with no serious adverse reactions and a high rate of surgical conversion rate.

Iclaprim reduces the incidence and severity of Staphylococcus aureus-induced septic arthritis in a murine model.

Staphylococcus aureus is the most common non-gonococcal aetiology of septic arthritis. The efficacy of iclaprim against S. aureus LS-1, a clinical strain identified from a patient with septic arthritis, was studied in MF1 mice to evaluate the activity of iclaprim, which is in clinical development, in preventing joint infections. Iclaprim (2.5-80 mg kg- 1) administered as a single dose via the tail vein reduced the incidence of S. aureus septic arthritis and mortality in an experimental murine model of septic arthritis.

In vitro and in vivo activity of iclaprim, a diaminopyrimidine compound and potential therapeutic alternative against Pneumocystis pneumonia.

Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim-sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. The antimicrobial activity of iclaprim was tested in vitro using an efficient axenic culture system, and in vivo using P. carinii endotracheally inoculated corticosteroid-treated rats. Animals were orally administered iclaprim (5, 25, 50 mg/kg/day), iclaprim/SMX (5/25, 25/125, 50/250 mg/kg/day), TMP (50 mg/kg/day), or TMP/SMX (50/250 mg/kg/day) once a day for ten consecutive days. The in vitro maximum effect (Emax) and the drug concentrations needed to reach 50% of Emax (EC50) were determined, and the slope of the dose-response curve was estimated by the Hill equation (Emax sigmoid model). The iclaprim EC50 value was 20.3 µg/mL. This effect was enhanced when iclaprim was combined with SMX (EC50: 13.2/66 µg/mL) (p = 0.002). The TMP/SMX EC50 value was 51.4/257 µg/mL. In vivo, the iclaprim/SMX combination resulted in 98.1% of inhibition compared to TMP/SMX, which resulted in 86.6% of inhibition (p = 0.048). Thus, overall, the iclaprim/SMX combination was more effective than TMP/SMX both in vitro and in vivo, suggesting that it could be an alternative therapy to the TMP/SMX combination for the treatment of Pneumocystis pneumonia.

Value of C-arm computed tomography in radiofrequency ablation of small lung lesions.

This study aimed to explore the value of C-arm computed tomography (CT) applications in radiofrequency ablation (RFA) of small lung lesions. The puncture success rate, cumulative survival rate, tumor response rate, complications, and radiation dose during C-arm CT-guided RFA of 36 small lung lesions in 34 patients were analyzed. In 35 RFA procedures for 36 small lung lesions, the puncture success rate was 100%. There were 7 cases of complications, including 4 cases of pneumothorax (puncture suction or closed chest drainage was not required) and 3 cases of hemoptysis. The cumulative survival rate in the 34 patients after RFA was 100% at 6 months, 69.0% at 1 year, and 60.0% at 2 years. In assessments of 36 foci imaged during the follow-up period, the total response rates at 1 month, 3 months, and 6 months were 77.8% (28/36), 69.7% (23/33), and 61.3% (19/31), respectively. The mean cumulative dose and average effective dose during surgery were 120.1 ± 61.4 mGy and 3.5 ± 1.7 mSv, respectively. The application of C-arm CT to RFA of small lung lesions could provide abundant information to the surgeon and increase the lesion puncture success rate and is considered to be a promising image-guided technology.

Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: BILR 355 is a second generation non-nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti-HIV-1 activities and favourable human pharmacokinetic properties after co-administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter-mediated pathway. These two drugs are likely to be given together to HIV-infected patients. The objective of this study was to investigate any steady-state pharmacokinetic interactions between RTV-boosted BILR 355 and 3TC/zidovudine (ZDV). METHODS: This was a randomized, open label, prospective study. In group A, 39 healthy subjects were given 3TC/ZDV (150 mg/300 mg) twice daily (b.i.d.) for 7 days, and then BILR 355 and RTV (BILR 355/r, 150 mg/100 mg) were co-administered with this regimen for an additional 7 days. Intensive blood samples were taken on days 7 and 14 for pharmacokinetic assessments. In group B, 12 healthy subjects were given BILR 355/r (150 mg/100 mg) b.i.d. for 7 days. The pharmacokinetic data from group B were pooled with data from group B subjects in other similar studies performed in parallel (BILR 355 alone group in BILR 355 drug-drug interaction studies with tipranavir, lopinavir/RTV, and emtricitabine/tenofovir DF; BILR 355 regimen was the same). RESULTS AND DISCUSSION: After co-administration with BILR 355/r, the AUC(12,ss) and C(max,ss) of 3TC increased by 45% and 24%, respectively; the elimination half-life (t(1/2) ,ss) of 3TC was significantly increased. However, the pharmacokinetics of ZDV was unchanged. Co-administration with 3TC/ZDV resulted in a 22% decrease in AUC(12,ss) and a 20% decrease in C(max,ss) for BILR 355. The observed increase in exposure and prolongation of t(1/2,ss) of 3TC is potentially related to inhibition of OCT-mediated urinary excretion of 3TC. WHAT IS NEW AND CONCLUSION: Concomitant administration of BILR 355 with 3TC/ZDV resulted in a modest decrease in exposure to BILR 355 and a 45% increase in exposure to 3TC.

Use of the Zung depression scale in patients with traumatic brain injury: 1 year post-injury.

OBJECTIVE: The purpose of this study was to examine if the physical disabilities of patients with traumatic brain injury (TBI) would influence the assessment of depression when using the Zung depression scale. METHOD: Patients with TBI (n=59) were assessed 1 year after injury for depression by both a psychiatrist and the use of the Zung depression scale. RESULTS: By psychiatric evaluation, seven of 17 (41%) patients with severe TBI and one of 20 (5%) of the patients with moderate TBI were diagnosed with major depressive disorder. With the Zung depression scale, 10 of 17 (59%) patients with severe TBI met the cut-off (scored >55) for depression, whereas none of the patients with moderate (n=20) or mild (n=22) TBI did. The mean (SD) scores of the somatic scale were 2.91 (0.93), 2.49 (0.92) and 1.25 (0.43) for each group. The mean scores of the affective scale were 2.58 (0.90), 1.85 (0.79) and 1.24 (0.46). For patients with moderate (p<0.05) and severe (p<0.10) TBI, scores on the somatic items exceeded scores on their affective items. No difference in somatic and affective scale scores was noted for the patients with mild TBI. CONCLUSION: The increased endorsement of somatic results may be the somatic difficulties associated with traumatic brain injury.

Thalidomide: dermatological indications, mechanisms of action and side-effects.

Thalidomide was first introduced in the 1950s as a sedative but was quickly removed from the market after it was linked to cases of severe birth defects. However, it has since made a remarkable comeback for the U.S. Food and Drug Administration-approved use in the treatment of erythema nodosum leprosum. Further, it has shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell histiocytosis, aphthous stomatitis, Behçet's syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and uraemic pruritus. This article reviews the history, pharmacology, mechanism of action, clinical uses and adverse effects of thalidomide.

Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin.

The objective of this prospective pilot study was to evaluate the response of HIV-infected patients with asymptomatic syphilis to one of two intensive antibiotic treatment regimens. Thirty-one HIV-infected patients with serum rapid plasma reagin titre > or =1:4 and no clinical findings of syphilis were randomized to receive daily intramuscular injections of ceftriaxone or procaine penicillin (plus oral probenecid) for 15 days; 24 returned for follow-up study. Seven of 10 (70%) procaine penicillin-treated patients and 10 of 14 (71%) ceftriaxone-treated patients had a > or =4-fold decline in RPR (P=0.94); two penicillin-treated and one ceftriaxone-treated patient relapsed. Two patients failed ceftriaxone therapy. Three penicillin-treated, and two ceftriaxone-treated patients were serofast. Serological responses were similar in those patients with and without asymptomatic neurosyphilis. There was no difference in the serologic response to daily treatment with ceftriaxone vs that with procaine penicillin plus probenecid; both treatments were associated with comparatively high rates of serological non-response and relapse.

X-ray crystal structure of proto-oncogene product c-Rel bound to the CD28 response element of IL-2.

BACKGROUND: The proto-oncogene product c-Rel is a Rel/NF-kappaB family transcription factor that plays a critical role in lymphoid cell development and mediates CD28-induced expression of interleukin 2 (IL-2). The CD28 response element (CD28RE) in the IL-2 enhancer is nonameric and similar to the kappaB DNA target sites recognized by p65 homodimers. RESULTS: We have determined and refined the X-ray crystal structure of the c-Rel homodimer complexed to the CD28RE DNA site, 5'-AGAAATTCC-3', to 2.85 A resolution. The c-Rel homodimer binds CD28RE in a mode similar to that observed in the p65/IL-8 kappaB crystallographic complex. Binding studies reveal that the c-Rel homodimer recognizes the CD28RE with higher affinity as compared to other canonical kappaB sequences despite the nonconsensus A:T base pair at the 5' end of the CD28RE. Preferential recognition of the CD28RE by c-Rel results from the direct contacts between the protein and the DNA as well as intrasubunit interactions between the beta(f)-beta(g) loop in the dimerization domain and the DNA-contacting loop L1 of the N-terminal domain. Not only do these loops have different conformations in other Rel/DNA crystallographic complexes, but they also contain two of the five oncogenic point mutations found in v-Rel. CONCLUSIONS: The current structure indicates that a non-DNA-contacting loop in the dimerization domain and the DNA-contacting loop L1 may play critical roles in defining affinity and specificity. Two amino acid changes in these segments may account for the differential DNA binding by v-Rel as compared to that of c-Rel.

Impact of breast-feeding on Giardia lamblia infections in Bilbeis, Egypt.

A total of 152 infants were followed from birth to 1 year of age in a rural community of Egypt to document Giardia lamblia infection and to determine the effect of breast-feeding on enteric infections by this protozoan. Asymptomatic Giardia infections persisted as long as 4 months, with a mean duration of excretion of 7.18 weeks. The incidence of asymptomatic infection was 4.5 episodes per child-year. Exclusively breast-fed infants had lower risk for asymptomatic (odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.45-0.96, P < 0.05) and symptomatic infections (relative risk [RR] = 0.50, 95% CI = 0.27-0.90, P < 0.05). Furthermore, breast-fed infants had fewer clinical manifestations, including mucus in stool (23.8% versus 76.2%, P = 0.08), loss of appetite (17.6% versus 82.3%, P < 0.05), and abdominal tenderness (17% versus 82.9%, P < 0.05) compared with infants who were not exclusively breast-fed. Breast-feeding should be considered as an effective means to prevent Giardia infections and should be encouraged in regions where G. lambia is highly endemic.

Human methadone self-administration: effects of diazepam pretreatment.

The effect of diazepam on methadone self-administration was examined. Five methadone-maintained patients with a history of benzodiazepine abuse were recruited. Patients were stabilized on 80 mg of methadone per day. After stabilization patients participated in methadone self-administration sessions. During each session, 128 presses (fixed ratio 128) of 1 button delivered 10 ml of 0.054 mg/ml methadone solution. The same number of button presses on a 2nd button delivered 10 ml of vehicle. Forty-five min prior to the self-administration session, 0 (placebo), 5, 10, or 20 mg per 70 kg body weight diazepam was administered. Ratings of drug liking, goodness, strength, and high were collected 5, 30, 60, 90, and 150 min after the end of the self-administration session. Diazepam pretreatment significantly decreased the amount of methadone consumed. The 10- and 20-mg diazepam doses significantly increased reports of good, like, strong, and high.

Increased fecal IgE among infants in a rural community of Egypt: an analysis of associated risk factors.

Newborns in rural Bilbeis, Egypt were followed to 1-year of age to document the incidence and risk factors associated with the development of fecal IgE. Factors associated with increased fecal IgE included infants aged 3-6 months (relative risk (RR) = 3.28, 95 per cent confidence intervals (CI) = 1.03-13.60, p < 0.05) and mother being vaccinated antenatally (RR = 2.17, CI - 1.01-4.61, p < 0.05). Decreased fecal IgE was observed with consumption of rice (RR = 0.37, CI = 0.12-0.94, p < 0.05), biscuits (RR = 0.43, CI = 0.15-0.99, p < 0.05), potatoes (RR = 0.39, CI = 0.11-0.98, p < 0.05), and fruits and vegetables (RR = 0.20, CI = 0.02-0.80, p < 0.05). After multivariate adjustment, increased risk was observed with consumption of milk pudding (RR = 7.48, CI = 1.54-36.20, p < 0.05) and wet-nursed infants (RR = 2.77, CI = 1.17-6.54, p < 0.05). Infants who were completely breastfed (RR = 0.13, CI = 0.02-0.68, p < 0.05) and infants' family owning a television set (RR = 0.29, CI = 0.12-0.67, p < 0.05) were less likely to develop fecal IgE. Our findings indicate that prelacteal feeding with certain foods, early supplementation of breastfeeding, and sociodemographic factors are associated with increased fecal IgE.

Emergence of trimethoprim-resistant Escherichia coli in healthy persons in the absence of prophylactic or therapeutic antibiotics during travel to Guadalajara, Mexico.

Thirty-nine healthy US students without diarrheal disease and who had not received prophylactic or therapeutic antibiotics were monitored for emergence of trimethoprim-resistant gram-negative fecal flora for a 3-week period after arrival in Guadalajara, Mexico. During this time period, most students showed no change in total fecal gram-negative bacteria (p > 0.05) but showed an increasing level of trimethoprim (TMP) resistance (p < 0.01) among fecal coliforms. Escherichia coli was the TMP-resistant organism isolated in 18 of 39 (46%) healthy students. These 18 TMP-resistant E. coli were also resistant to ampicillin (44%), azithromycin (11%), chloramphenicol (39%), ciprofloxacin (11%), doxycycline (89%), erythromycin (100%), furazolidone (72%), levofloxacin (17%), trimethoprim-sulfamethoxazole (89%) and trovafloxacin (17%). In the absence of prophylactic and therapeutic antibiotics, increased acquisition of TMP-resistant gram-negative fecal flora in this developing country is probably due to poor sanitary conditions and the recurrent and heavy exposure to antimicrobial-resistant indigenous flora as a result of contaminated food and drink.

Sociodemographic, environmental and clinical risk factors for developing persistent diarrhoea among infants in a rural community of Egypt.

The study documents the incidence of persistent diarrhoea and its sociodemographic, household, environmental and clinical risk factors. One hundred and fifty-two newborns were followed for the first 12 months of life in Bilbeis, Egypt. The household of each participant was surveyed at baseline and was visited twice a week. The study infants experienced persistent diarrhoea at a rate of 0.51 episode/case per year. Development of persistent diarrhoea was associated with water storage in mud-containers (Odds ratio [OR] = 4.36, confidence interval [CI] 1.4-14.8), pump-water supply (OR = 3.5, CI 1.2-10.2), and absence of a latrine in the household (OR = 2.74, CI 1.01-7.38). Detection of faecal IgE (OR = 3.32, CI 1.0-10.9) and high stool frequency (OR = 2.95, CI 1.1-7.8) appeared as important clinical predictors for the onset of persistent diarrhoea. The incidence of persistent diarrhoea among young infants in Bilbeis, Egypt, was high. Sociodemographic, environmental and clinical parameters were important risk factors for the development of persistent diarrhoea.

Major leg wound complications after saphenous vein harvest for coronary revascularization.

BACKGROUND: Major leg wound complications after coronary artery bypass graft procedures are infrequent and few are reported in the literature. We present our experience in treating 23 patients with major leg wound complications after coronary revascularization procedures. METHODS: A retrospective review of 3,525 bypass procedures with saphenous vein grafts performed over a 10-year period was conducted. Ten potential risk factors for those who developed major leg wound complications were analyzed and compared with the entire cohort of patients undergoing similar bypass procedures during the same period. RESULTS: Lower extremity wound complications occurred in 145 patients (4.1%), 23 of whom (0.65%) required additional surgical interventions (62 total). There were 32 wound debridements, 8 skin grafts, 11 vascular procedures, 5 amputations, 3 fasciotomies, 2 free tissue transfers, and 1 fasciocutaneous flap. Of ten variables evaluated by multivariate analysis, female gender, peripheral vascular disease, and postoperative intraaortic balloon pump use were identified as significant independent predictors of major leg wound complications (p < 0.0001). CONCLUSIONS: The causes of major leg wound complications after saphenous vein harvest for coronary artery bypass graft procedures are multifactorial. To minimize these complications, we recommend vascular evaluations before saphenous vein harvest, attention to proper surgical technique, and careful harvest site selection.