A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor.

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents.

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil-azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure-activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil-azole hybrids can be considered as potential cytotoxic agents.

Synthesis of 3-hydroxypyridin-4-one derivatives bearing benzyl hydrazide substitutions towards anti-tyrosinase and free radical scavenging activities.

Tyrosinase is a vital enzyme in the biosynthesis of melanin, which has a significant role in skin protection. Due to the importance of the tyrosinase enzyme in the cosmetics and health industries, studies to design new tyrosinase inhibitors have been expanded. In this study, the design and synthesis of 3-dihydroxypyridine-4-one derivatives containing benzo hydrazide groups with different substitutions were carried out, and their antioxidant and anti-tyrosinase activities were also evaluated. The proposed compounds showed tyrosinase inhibitory effects (IC50) in the 25.29 to 64.13 µM range. Among all compounds, 6i showed potent anti-tyrosinase activity with an IC50 = 25.29 µM. Also, the antioxidant activity of derivatives by using DPPH radical scavenging indicates an EC50 value between 0.039 and 0.389 mM. Molecular docking studies were performed to reveal the position and interactions of 6i as the most potent inhibitor within the tyrosinase active site. The results showed that 6i binds well to the proposed binding site and forms a stable complex with the target protein. Furthermore, the physicochemical profiles of the tested compounds indicated drug-like and bioavailability properties. The kinetic assay revealed that 6i acts as a competitive inhibitor. Also, for the estimation of the reactivity of the best compound (6i), the density functional theory (DFT) was performed at the B3LYP/6-31+G**.

Design, synthesis, computational study and cytotoxic evaluation of some new quinazoline derivatives containing pyrimidine moiety.

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 µM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 µM, 2.3 ± 5.91 µM and 5.65 ± 2.33 µM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.

Barium silicate nanoparticles, an efficient catalyst for one-pot green synthesis of α-benzyl amino coumarin derivatives as potential chemotherapeutic agents.

A new, simple, and efficient method for synthesis of α-benzyl amino coumarin and its derivatives (1-24) is described via a one-pot, three-component condensation of aromatic aldehydes, amine, and 4-hydroxycoumarin under green chemistry conditions: water as a solvent and BaSiO3 nanoparticles as catalyst. BaSiO3 nanoparticles and all synthesized derivatives were characterized by multiple methods including; XRD, NMR, and FE-SEM. This method which gives higher yields, is also less expensive, and more environmentally friendly compared with other methods in the literature. In silico physicochemical and pharmacokinetics analyses were done on all synthesized compounds and indicated that these α-benzyl amino coumarins would be effective scaffolds for the future development of chemotherapeutic agents.

Comparison of Protective Effects of Phenolic Acids on Protein Glycation of BSA Supported by In Vitro and Docking Studies.

Several diabetic complications are associated with forming advanced glycation end products (AGEs). Different chemical and natural compounds are able to prevent the development of these products. In this study, glycosylation was induced as a model by incubating bovine serum albumin (BSA) with glucose. Consequently, BSA was treated with glucose and different concentrations (1.25, 2.5, and 5 µM) of syringic acid, gallic acid, ellagic acid, ferulic acid, paracoumaric acid, and caffeic acid for 4 and 6 weeks. Biochemical experiments comprise measurements of fluorescent AGEs, protein carbonyl contents, total thiol, hemolysis tests, and also malondialdehyde (MDA) levels in RBC. These demonstrated the antiglycating mechanism of these phenolic acids. Most of the phenolic acids used in this study reduced MDA levels and protected thiol residues in protein structures. They also inhibited the formation of fluorescent AGEs and RBC lysis, except gallic acid. Moreover, ferulic acid, paracoumaric acid, and caffeic acid proteins significantly prevent carbonylation. Molecular docking and simulation studies showed that ellagic, caffeic, gallic, and syringic acids could interact with lysine and arginine residues in the active site of BSA and stabilize its structure to inhibit the formation of AGEs. Our results suggest that phenolic acid could be used as a potential phytochemical against protein glycation and related diabetic complications.

6-Bromoquinazoline Derivatives as Potent Anticancer Agents: Synthesis, Cytotoxic Evaluation, and Computational Studies.

A series of 6-bromoquinazoline derivatives (5a-j) were synthesized. Cytotoxic effectiveness of compounds was done against two cancerous cell lines (MCF-7 and SW480) by standard MTT method. Fortunately, all of the compounds showed desirable activity in reducing the viability of the studied cancerous cell lines with IC50 value in the range of 0.53-46.6 µM. Compound 5b with a fluoro substitution at meta position of the phenyl moiety showed stronger activity than cisplatin with IC50 =0.53-1.95 µM. Studies on the hit compound (5b) through apoptosis assay illustrated that it could induce apoptosis in MCF-7 cell lines in dose dependent manner. Molecular docking study was done to investigate the detailed binding modes and interactions with EGFR as a plausible mechanism. The drug- likeness was predicted. To survey the reactivity of compounds, DFT calculation was performed. Taken together, 6-bromoquinazoline derivatives, especially 5b can be considered as hit compounds to rational drug designing as antiproliferative agents.

Novel 1,4 benzothiazine 3-one derivatives as anticonvulsant agents: Design, synthesis, biological evaluation and computational studies.

In this study, two series of novel 1,4-benzothiazine-3-one derivatives with alkyl substitution (series 1: 4a-4f) and aryl substitution (series 2: 4g-4l) were designed and synthesized based on the chemical scaffolds of perampanel, hydantoins, progabide and etifoxine as anti-convulsant agents. The chemical structures of the synthesized compounds were confirmed by FT-IR, 1H NMR and 13C NMR spectroscopy. Anti-convulsant effect of the compounds was examined through intraperitoneal pentylenetetrazol (i.p. PTZ) induced epilepsy mouse models. Compound 4h (4-(4-bromo-benzyl)- 4 H-benzo[b] [1,4] thiazin-3(4 H)-one) demonstrated a promising activity toward chemically-induced seizure experiment. Molecular dynamics simulation on GABA-Aergic receptors as a plausible mechanism were also done to achieve the binding and orientation of compounds in the active site of the target to evaluate the results of docking and experimental studies. The computational results were confirmed the biological activity. DFT study of 4c and 4h was performed on B3LYP/6-311 G** level of theory. Reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, hardness and softness were studied in detail and show that 4h has higher activity than 4c. Also, the frequency calculations were performed on the same level of theory and the results are in line with experimental data. Moreover, in silico ADMET properties were done to establish a relationship between the physiochemical data of the designed compounds and their in-vivo activity. Appropriate plasma protein binding and high blood-brain barrier penetration are the main features of desired in-vivo performance.

Azole Derivatives: Recent Advances as Potent Antibacterial and Antifungal Agents.

BACKGROUND: Azoles are the famous and widespread scaffold in the pharmaceutical industry due to their wide range of activities, high efficacy, good tolerability, and oral availability. Furthermore, azole derivatives have attracted attention as potent antimicrobial agents. INTRODUCTION: The purpose of this review is to provide an overview of pharmacological aspects of the main scaffolds of azoles, including imidazole, benzimidazole, triazole, and tetrazole, which possess antimicrobial activity, reported from 2016 to 2020, as well as all of our publication in this field. In addition, we discuss the relationship between structure and activity and molecular docking studies of the azole derivatives to provide critical features and valuable information for the synthesis of novel azole compounds with desirable biological activities. The presented structures in this review have been tested against several bacteria and fungi, such as E. coli and C. albicans, which have been common in all of these studies. RESULTS: A comparison of the reported MIC for tested compounds showed fluconazole base structures as the most active antifungal agents, and triazole derivatives bearing nitrophenyl and coumarin moieties to have the most dominant antibacterial activity. CONCLUSION: Triazole and imidazole scaffolds are more important for designing antimicrobial compounds than other azole derivatives, like benzimidazole or tetrazole. All the most active compounds were observed to fulfill the Lipinski rule.

Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents.

Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, 1H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 µM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Synthesis, biological evaluation, and computational studies of some novel quinazoline derivatives as anticancer agents.

A series of quinazolinone derivatives (7a-7h) were synthesized as antiproliferative agents. All compounds, were synthesized through three steps method and structurally evaluated by FTIR, 1H-NMR, 13CNMR and Mass spectroscopy. Their cytotoxic activities were assessed using MTT protocol against three humans cancerous (MCF-7, A549 and 5637) and normal (MRC-5) cell lines. In addition, molecular docking and simulation studies of the synthesized compounds were performed to assessment their orientation, interaction mode against EGFR as plausible mechanism of quinazoline compounds as anticancer agents. The synthesized compounds mostly showed moderate activity against the three studied cell lines. They also indicated an appropriate selectivity against tumorigenic and non-tumorigenic cell line. The molecular docking results also confirmed biological activity. Most of the compounds fulfilled Lipinski rule. Collectively, these compounds with further modification can be considered as potent antiproliferative agents.

Efficient synthesis of 1,3-naphtoxazine derivatives using reusable magnetic catalyst (GO-Fe3O4-Ti(IV)): anticonvulsant evaluation and computational studies.

A series of 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines (S1-S11) were synthesized with an eco-friendly and recoverable nanocatalyst (GO-Fe3O4-Ti(IV)) as an efficient magnetic composite. The new nanocatalyst was characterized by FT-IR, XRD and, EDS analysis. A conformable procedure, easy to work up and having a short reaction time with high yields are some advantages of this method. The new catalyst is also thermal-stable, reusable and, environment-friendly. The chemical structures of the synthesized 1,3-oxazine compounds were confirmed by comparing their melting points with those reported in literature. Then, the anticonvulsant activity of these compounds was assessed by the intraperitoneal pentylenetetrazole test (ipPTZ). Compounds S10 and S11 displayed considerable activity against chemically-induced seizure tests. The molecular simulation was also done to achieve their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as an assumptive mechanism of their anticonvulsant action. The result of molecular studies represented strongly matched with biological activity. Molecular docking simulation of the potent compound (S10) and diazepam as the positive control was performed and some critical residues like Thr262, Asn265, Met286, Phe289, and Val290 were identified. Based on the anticonvulsant results and also in silico ADME predictions, S11 can be to become a potential drug candidate as an anticonvulsant agent.

Central sleep apnea in a treatment-resistant migraine patient: a case report.

Introduction: Patients with migraine, who suffer from sleep apnea, whether obstructive or central, might lead to treatment-resistant headaches. In this study, we have reported a 42-year-old man with a confirmed treatment-resistant migraine headaches and hemiplegic attacks, who was referred to our sleep clinic for evaluation of sleep breathing problems. Case Report: The patient had recurrent attacks of migraine headaches with hemiplegic attacks. The patient had headache in the past 15 years that based on ICHD-3 criteria classified as hemiplegic migraine. The severity and recurrences of headache and hemiplegic attacks gradually increased for 1 year, before he referred to our sleep clinic that led to several hospital admissions. He had been evaluated for other causes of headache; it seems that other headache causes have been ruled out. Treatment with medication was not effective to abolish symptoms. He had a history of occasional snoring and his wife had witnessed multiple episodes of apnea and frequent awakening by feeling suffocation at sleep. The patient abused methadone since 2 years ago. Based on the findings in polysomnography, the patient was diagnosed with central sleep apneas. After titration, bi-level positive airway pressurespontaneous timed mode (BiPAP-ST) was prescribed for the patient. In one year of using BiPAPST the central apneas events were controlled, while the frequency of migraine headache decreased remarkably to one attack per month and the hemiplegic attacks resolved without any other change in his medical treatment or methadone use. Discussion: Patients with chronic headaches usually have insufficient sleep, sleep apnea and poor sleep quality, change in sleep architecture can be an introduced trigger for headache, furthermore in opium abusers, symptoms got intensified. Resolve exacerbating factors can reduce headache recurrence and severity. Conclusion: It is important to screen high-risk patients for possible sleep disorders such as apnea, especially in treatment resistant migraine cases. Also, we should assess analgesics or opioids abuses and a complete history for other risk factors of central sleep apnea.

Anticonvulsant activity, molecular modeling and synthesis of spirooxindole-4H-pyran derivatives using a novel reusable organocatalyst.

Fifteen derivatives of spirooxindole-4H-pyran (A1-A15) were subjected to evaluate through intravenous infusion of pentylenetetrazole (PTZ)-induced epilepsy mouse models. Four doses of the compounds (20, 40, 60 and 80 mg/kg) were tested in comparison with diazepam as positive control. The resulted revealed that compounds A3 and A12 were the most active compounds and indicated significant anticonvulsant activity in the PTZ test. The tested compounds were prepared via a multicomponent reaction using graphene oxide (GO) based on the 1-(2-aminoethyl) piperazine as a novel heterogeneous organocatalyst. The prepared catalyst (GO-A.P.) was characterized using some diverse microscopic and spectroscopic procedures as well. The results showed high catalytic activity of the catalyst in the synthesis of spirooxindole-4H-pyran derivatives. The GO-A.P. catalyst was reusable at least for 5 times with no significant decrease in its catalytic action. In silico assessment of physicochemical activity of all compounds also were done which represented appropriate properties. Finally, molecular docking study was performed to achieve their binding affinities as γ-aminobutyric acid-A (GABA-A) receptor agonists as a plausible mechanism of their anticonvulsant action. Binding free energy values of the compounds represented strongly matched with biological activity.

Quinazoline analogues as cytotoxic agents; QSAR, docking, and in silico studies.

BACKGROUND AND PURPOSE: Synthesis and investigation of pharmacological activity of novel compounds are time and money-consuming. However, computational techniques, docking, and in silico studies have facilitated drug discovery research to design pharmacologically effective compounds. EXPERIMENTAL APPROACH: In this study, a series of quinazoline derivatives were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometric methods were conducted to provide relations between structural features and cytotoxic activity of a variety of quinazoline derivatives against breast cancer cell line. An in silico-screening was accomplished and new impressive lead compounds were designed to target the epidermal growth factor receptor (EGFR)-active site based on a new structural pattern. Molecular docking was performed to delve into the interactions, free binding energy, and molecular binding mode of the compounds against the EGFR target. FINDINGS/RESULTS: A comparison between different methods significantly indicated that genetic algorithm-partial least-squares were selected as the best model for quinazoline derivatives. In the current study, constitutional, functional, chemical, resource description framework, 2D autocorrelation, and charge descriptors were considered as significant parameters for the prediction of anticancer activity of quinazoline derivatives. In silico screening was employed to discover new compounds with good potential as anticancer agents and suggested to be synthesized. Also, the binding energy of docking simulation showed desired correlation with QSAR and experimental data. CONCLUSION AND IMPLICATIONS: The results showed good accordance between binding energy and QSAR results. Compounds Q1-Q30 are desired to be synthesized and applied to in vitro evaluation.

Educational video to improve CPAP use in patients with obstructive sleep apnoea at risk for poor adherence: a randomised controlled trial.

BACKGROUND: Suboptimal adherence to CPAP limits its clinical effectiveness in patients with obstructive sleep apnoea (OSA). Although rigorous behavioural interventions improve CPAP adherence, their labour-intensive nature has limited widespread implementation. Moreover, these interventions have not been tested in patients at risk of poor CPAP adherence. Our objective was to determine whether an educational video will improve CPAP adherence in patients at risk of poor CPAP adherence. METHODS: Patients referred by clinicians without sleep medicine expertise to an urban sleep laboratory that serves predominantly minority population were randomised to view an educational video about OSA and CPAP therapy before the polysomnogram, or to usual care. The primary outcome was CPAP adherence during the first 30 days of therapy. Secondary outcomes were show rates to sleep clinic (attended appointment) and 30-day CPAP adherence after the sleep clinic visit date. RESULTS: A total of 212 patients met the eligibility criteria and were randomised to video education (n=99) or to usual care (n=113). There were no differences in CPAP adherence at 30 days (3.3, 95% CI 2.8 to 3.8 hours/day video education; vs 3.5, 95% CI 3.1 to 4.0 hours/day usual care; p=0.44) or during the 30 days after sleep clinic visit. Sleep clinic show rate was 54% in the video education group and 59% in the usual care group (p=0.41). CPAP adherence, however, significantly worsened in patients who did not show up to the sleep clinic. CONCLUSIONS: In patients at risk for poor CPAP adherence, an educational video did not improve CPAP adherence or show rates to sleep clinic compared with usual care. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02553694.

Positive airway pressure improves nocturnal beat-to-beat blood pressure surges in obesity hypoventilation syndrome with obstructive sleep apnea.

Positive airway pressure (PAP) treatment has been shown to have a modest effect on ambulatory blood pressure (BP) in patients with obstructive sleep apnea (OSA). However, there is a paucity of data on the effect of PAP therapy on rapid, yet significant, BP swings during sleep, particularly in obesity hypoventilation syndrome (OHS). The present study hypothesizes that PAP therapy will improve nocturnal BP on the first treatment night (titration PAP) in OHS patients with underlying OSA, and that these improvements will become more significant with 6 wk of PAP therapy. Seventeen adults (7 men, 10 women; age 50.4 ± 10.7 years, BMI 49.3 ± 2.4 kg/m(2)) with OHS and clinically diagnosed OSA participated in three overnight laboratory visits that included polysomnography and beat-to-beat BP monitoring via finger plethysmography. Six weeks of PAP therapy, but not titration PAP, lowered mean nocturnal BP. In contrast, when nocturnal beat-to-beat BPs were aggregated into bins consisting of at least three consecutive cardiac cycles with a >10 mmHg BP surge (i.e., Δ10-20, Δ20-30, Δ30-40, and Δ>40 mmHg), titration, and 6-wk PAP reduced the number of BP surges per hour (time × bin, P < 0.05). PAP adherence over the 6-wk period was significantly correlated to reductions in nocturnal systolic (r = 0.713, P = 0.001) and diastolic (r = 0.497, P = 0.043) BP surges. Despite these PAP-induced improvements in nocturnal beat-to-beat BP surges, 6 wk of PAP therapy did not alter daytime BP. In conclusion, PAP treatment reduces nocturnal beat-to-beat BP surges in OHS patients with underlying OSA, and this improvement in nocturnal BP regulation was greater in patients with higher PAP adherence.

Integrating risk management data in quality improvement initiatives within an academic neurosurgery department.

OBJECT While malpractice litigation has had many negative impacts on health care delivery systems, information extracted from lawsuits could potentially guide toward venues to improve care. The authors present a comprehensive review of lawsuits within a tertiary academic neurosurgical department and report institutional and departmental strategies to mitigate liability by integrating risk management data with quality improvement initiatives. METHODS The Comprehensive Risk Intelligence Tool database was interrogated to extract claims/suits abstracts concerning neurosurgical cases that were closed from January 2008 to December 2012. Variables included demographics of the claimant, type of procedure performed (if any), claim description, insured information, case outcome, clinical summary, contributing factors and subfactors, amount incurred for indemnity and expenses, and independent expert opinion in regard to whether the standard of care was met. RESULTS During the study period, the Department of Neurosurgery received the most lawsuits of all surgical specialties (30 of 172), leading to a total incurred payment of $4,949,867. Of these lawsuits, 21 involved spinal pathologies and 9 cranial pathologies. The largest group of suits was from patients with challenging medical conditions who underwent uneventful surgeries and postoperative courses but filed lawsuits when they did not see the benefits for which they were hoping; 85% of these claims were withdrawn by the plaintiffs. The most commonly cited contributing factors included clinical judgment (20 of 30), technical skill (19 of 30), and communication (6 of 30). CONCLUSIONS While all medical and surgical subspecialties must deal with the issue of malpractice and liability, neurosurgery is most affected both in terms of the number of suits filed as well as monetary amounts awarded. To use the suits as learning tools for the faculty and residents and minimize the associated costs, quality initiatives addressing the most frequent contributing factors should be instituted in care redesign strategies, enabling strategic alignment of quality improvement and risk management efforts.

Multi-wavelength spectrophotometric determination of acidity constant of some newly synthesized Schiff bases and their QSPR study.

The acidity constants of some newly synthesized Schiff base derivatives were determined by hard-model based multivariate data analysis of the spectrophotometric data in the course of pH-metric titration in 50% (v/v) methanol-water binary solvent. The employed data analysis method was also able to extract the pure spectra and pH-dependent concentration profiles of the acid-base species. The molecules that possess different substituents (both electron donating and withdrawing) on the ortho-, meta- and para-positions of one of the phenyl ring showed variable acidity constants ranging from 8.77 to 11.07 whereas the parent molecule had an acidity constant of 10.25. To investigate the quantitative effects of changing of substitution pattern on the acidity constant, a quantitative structure-property relation analysis was conducted using substituent constants and molecular descriptor. Some models with high statistical quality (measured by cross-validation Q(2)) were obtained. It was found that the acidity constant of the studied molecules in the methanol-water mixed solvent not only is affected by electronic features of the solutes but also by the lipophilic interaction between methanol part of solvent and the deprotonated solutes.

X-linked agammaglobulinemia: a survey of 33 Iranian patients.

In order to determine the clinical and laboratory features of X-linked agammaglobulinemia, the records of 33 male patients with XLA were reviewed during 22 years (1980-2002) in the Iranian referral center of primary immunodeficiency disorders. The patients' ages ranged from 20 to 360 months (median 113 months). The median age at the onset of the disease was 8 months and the median age of diagnosis was 48 months, with a median diagnosis delay of 33 months. Almost all of the patients presented common infectious diseases, which were: pneumonia, otitis, diarrhea, sinusitis, and arthritis. During the course of illness, infections in the respiratory tract, gastrointestinal tract, central nervous system, and musculoskeletal system were seen in 93.9%, 75.8%, 33.3%, and 21.2% of XLA patients, respectively. The most common complications of these patients were chronic infections in 75.8% of them, including: chronic otitis media, chronic sinusitis, chronic diarrhea, and bronchiectasis.