Interactions of Aminopropyl–Azithromycin Derivatives,Precursors in the Synthesis of Bioactive Macrozones,with E. coli Ribosome: NMR and Docking Studies

The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. ¹³C and ¹⁵N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.     

Long-term effects of immunosuppressive therapy on lung function in scleroderma patients

The study aims to analyze the effects of induction treatment with cyclophosphamide (CYC) pulse therapy followed by maintenance treatment with other mild immunosuppressive agents on lung function in scleroderma (SSc) patients. Thirty patients with SSc (mean age 52 years, mean disease duration <?2 years) with forced vital capacity (FVC) ≤?80% and/or diffusing capacity of carbon monoxide (DLco) ≤?70% were included. Monthly CYC pulses were given for 6 months (induction treatment), followed by 3-monthly maintenance pulses for the next 18 months, and during the next 5 years patients received other mild immunosupressive therapy brought by the competent rheumatologist. The efficacy was evaluated by comparing FVC% and DLco% after 6, 24, and 84 months from the baseline. All patients completed induction and maintenance treatment with CYC. Three patients were lost to follow-up. The rest of 27 patients, during the next 5 years, received other immunosupressive agents (14 azathioprine, 9 methotrexate, and 4 mycophenolate mofetil). Three patients died in the 4 years of follow-up. By 6, 24, and 84 months, the mean FVC and DLco changes were +?0.47 and +?2.10, +?3.30 and ??2.49, and +?1.53 and ??3.76%, respectively. These changes were not significantly different from the baseline values. CYC does not appear to result in clinically significant improvement of pulmonary function but fulfilled criteria of stable disease. Maintenance treatment with other mild immunosupressive agents preserves the benefits achieved during CYC treatment.     

Bypassing major venous occlusion and duodenal lesions in rats,and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine

AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide(NO) system involvement.METHODS Male Wistar rats underwent superior anterior pancreaticoduodenal vein(SAPDV)-ligation and were treated with a bath at the ligated SAPDV site(BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 m L bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation(filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein(IAPDV) and superior mesenteric vein(SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO-and oxidative stress [malondialdehyde(MDA)]-levels in duodenum.RESULTS Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues.CONCLUSION BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, aneffect related to the NO system and reduction of free radical formation.     

Chronic cognitive sequelae after traumatic brain injury are not related to growth hormone deficiency in adults

Objective: The objective of the study was to asses the possible influence of hypothalamo–pituitary deficiencies, and growth hormone (GH) deficiency in particular, on cognition in adult patients with traumatic brain injury (TBI). TBI is a recently identified risk factor for cognitive deficits and hypopituitarism. Even the patients with favorable outcome after TBI may present with persistent bodily, psychosocial, and cognitive impairments, resembling patients with untreated partial or complete pituitary insufficiency. Design: We performed retrospective and cross‐sectional study of endocrine and cognitive function in TBI in 61 patients (aged 37.7 ± 1.7 years) of both sexes (44 m,17 f), at least 1 year after TBI (3.9 ± 0.6 years). Serum insulin‐like growth factor 1 (IGF‐I), thyroxin, thyroid‐stimulating hormone (TSH), follicle‐stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in men), prolactin, and cortisol were measured, and GH secretion was assessed by growth hormone releasing hormone (GHRH) + growth hormone releasing peptide‐6 (GHRP‐6) test. Cognitive function was assessed by using a standard neuropsychological battery. Results: GH deficiency (GHD) and GH insufficiency (GHI) were found in 20 patients (32.8%). After adjustment for confounders [age, body mass index (BMI), education level, time elapsed from TBI], there were no significant differences in results of neuropsychological tests between patients with TBI with GHD, GHI, and normal GH secretion. There were no correlations of neuropsychological variables with stimulated peak GH secretion or IGF‐I level. Conclusions: GHD persists long after the TBI, independently of trauma severity and age at traumatic event. GH secretion is more sensitive to TBI than other pituitary hormones. No evidence is found for an association of cognitive function impairment and somatotropic axis impairment in adult patients tested more than 1 year after the TBI.     

Internal exposure from building materials exhaling 222Rn and 220Rn as compared to external exposure due to their natural radioactivity content

The main scope of this paper is to point out the importance of introducing radon and thoron exhalation measurements from building materials in the regulating frame. Currently (2009), such a regulation of this kind of exposure is not explicitly included in the Serbian regulating network. To this end, this work reports concentration measurements of ²²⁶Ra, ²³²Th and ⁴⁰K and radon and thoron exhalation rates from building materials used in Serbia. Following detailed analysis, it was noticed that both internal exposures to radon and/or thoron exhaling from building materials may exceed external exposures to their precursors contained therein.     

Effect of Elective Bentall Procedure on Left Ventricular Systolic Function and Functional Status: Long-Term Follow-Up in 90 patients

Because there are so few data on the long-term effects on left ventricular systolic function and functional status in patients who electively undergo Bentall procedures, we established a retrospective study group of 90 consecutive patients. This group consisted of 71 male and 19 female patients (mean age, 54 ± 10 yr) who had undergone the Bentall procedure to correct aortic valve disease and aneurysm of the ascending aorta, from 1997 through 2003 in a single tertiary-care center. We monitored these patients for a mean period of 117 ± 41 months for death, left ventricular ejection fraction and volume indices, and functional capacity as determined by New York Heart Association (NYHA) class.There were no operative deaths. The survival rate was 73.3% during follow-up. There were 10 cardiac and 13 noncardiac deaths, and 1 death of unknown cause. Echocardiography was performed before the index procedure and again after 117 ± 41 months. In surviving patients, statistically significant improvement in left ventricular ejection fraction, in comparison with preoperative values (0.49 ± 0.11 vs 0.41 ± 0.11; P <0.0001), was noted at follow-up. Similarly, we observed statistically significant reductions in left ventricular end-systolic (39.24 ± 28.7 vs 48.77 ± 28.62 mL/m²) and end-diastolic volumes (54.63 ± 6.97 vs 59.17 ± 8.92 mL/m²; both P <0.0001). Most patients (53/66 [80.3%]) progressed from a higher to a lower NYHA class during the follow-up period.The Bentall procedure significantly improved long-term left ventricular systolic function and functional status in surviving patients who underwent operation on a nonemergency basis.     

Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine,aggravated by L-NAME

AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NOsystem. In the 4 d after esophagogastric anastomosis creation, rats received medication(/kg intraperitoneallyonce daily: BPC 157(10 μg, 10 ng), L-NAME(5 mg), or L-arginine(100 mg) alone and/or combined or BPC 157(10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage(sum of the longest diameters, mm), esophagitis(scored 0-5), weak anastomosis(m L H2 O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter(cm H2O), progressive weight loss(g) and mortality. Immediate effect assessed blood vessels disappearance(scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS BPC 157(all regimens) fully counteracted the perilous disease course from the very beginning(i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening(with L-NAME administration) and amelioration(with L-arginine), either L-arginine amelioration prevails(attenuated esophageal and gastric lesions) or they counteract each other(L-NAME + L-arginine); with the addition of BPC 157(L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability(as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening(obtained with L-NAME administration that was counteracted); or amelioration(L-arginine + BPC 157-rats correspond to BPC 157-rats).CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.