Characterisation of Twelve Newly Synthesised N-(substituted Phenyl)-2-chloroacetamides with QSAR Analysis and Antimicrobial Activity Tests

In this study we screened twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides for antimicrobial potential relying on quantitative structure-activity relationship (QSAR) analysis based on the available cheminformatics prediction models (Molinspiration, SwissADME, PreADMET, and PkcSM) and verified it through standard antimicrobial testing against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans. Our compounds met all the screening criteria of Lipinski’s rule of five (Ro5) as well as Veber’s and Egan’s methods for predicting biological activity. In antimicrobial activity tests, all chloroacetamides were effective against Gram-positive S. aureus and MRSA, less effective against the Gram-negative E. coli, and moderately effective against the yeast C. albicans. Our study confirmed that the biological activity of chloroacetamides varied with the position of substituents bound to the phenyl ring, which explains why some molecules were more effective against Gram-negative than Gram-positive bacteria or C. albicans. Bearing the halogenated p-substituted phenyl ring, N-(4-chlorophenyl), N-(4-fluorophenyl), and N-(3-bromophenyl) chloroacetamides were among the most active thanks to high lipophilicity, which allows them to pass rapidly through the phospholipid bilayer of the cell membrane. They are the most promising compounds for further investigation, particularly against Gram-positive bacteria and pathogenic yeasts.Key Words: N-substituted amides, antimicrobial potential, quantitative analysis of chemical structure and activity relationship     

Breast cancer patients with brain metastases or leptomeningeal disease: 10‐year results of a national cohort with validation of prognostic indexes

Development of brain metastasis (BM) and leptomeningeal (LM) disease in breast cancer (BC) patients indicates poor prognosis and impairs patients’ quality of life. Prognostic survival scores for BM can help predict expected survival in order to choose the most appropriate treatment. The aim of our study was to analyze national data for BC patients treated with radiation therapy for BM/LM disease and validate the applicability of different survival prognostic scores. We retrospectively evaluated medical records of 423 BC patients with BM/LM disease receiving radiation therapy between April 2005 and December 2015. Patients were classified by BC Recursive Partitioning Analysis (B‐RPA), Breast Graded Prognostic Assessment (Breast‐GPA), Modified Breast Graded Prognostic Assessment (MB‐GPA), and Simple Survival score for patients with BM from BC (SS‐BM). Overall survival (OS) was calculated from the development of BM/LM disease to death or last follow‐up date. After a median follow‐up of 7.5 years, the median OS was 6.9 months (95% CI 5.5‐7.8, range 0‐146.4) and 1‐ and 2‐year survival rates were 35% and 17%, respectively. Survival analysis showed significant differences in median OS regarding biologic subtypes (P < 0.0001), as follows: 3.2 (95% Confidence Interval (CI) 2.5‐3.9), 3.9 (95% CI 2.3‐5.6), 7.1 (95% CI 4.3‐9.8), 12.1 (95% CI 8.3‐15.9), and 15.4 (95% CI 8.8‐22.1) months for primary triple‐negative BC (TNBC), Luminal B HER2‐negative, Luminal A, HER2‐enriched, and Luminal B HER2‐positive tumors, respectively. Good Karnofsky Performance Status (KPS), single metastasis, and absence of LM or extracranial disease all demonstrated better OS in univariate and multivariate analysis. All four employed prognostic indexes provided good prognostic value in predicting survival. SS‐BM and MB‐GPA showed the best discriminating ability (Concordance indexes C were 0.768 and 0.738, respectively). This study presents one of the largest single‐institution series validating prognostic scores for BC patients with BM/LM. SS‐BM and MB‐GPA proved to be useful tools in the clinical decision‐making process.     

Fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime

Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure.     

Computer-assisted surgery and computer-assisted telesurgery in otorhinolaryngology

Surgical preparation is enhanced by the availability of computer-generated three-dimensional models that allow surgeons to explore the surgical field in various projections prior to an actual operation. In fact, with adequate computed tomography images, an entire operation can be simulated beforehand so that surgeons can plan the safest and most effective approach and be prepared to avoid or overcome obstacles during the actual procedure. Also, computer technology allows surgeons to conduct remote consultations and to even perform telesurgery--that is, to operate on a patient from a great distance. In this article, we describe our experience with computer-assisted local and remote endoscopic sinus surgery in Croatia.     

Early-senescing human skin fibroblasts do not demonstrate accelerated telomere shortening

Most normal mammalian cell lines demonstrate limited growth capacity due to the gradual accumulation of senescent cells in the culture. Senescent cells appear initially at a low incidence, but with increasing frequency as the culture accumulates more divisions. Because it has been suggested that senescence is regulated by telomere shortening in human cells, we compared the telomere lengths of the subpopulation of senescent cells, present in presenescent cultures, with those of young cells. Senescent cells were separated from young cycling cells by either bromodeoxyuridine (BrdU) incorporation followed by Hoechst dye and light treatment or DiI staining followed by separation on a high-speed cell sorter. Our results demonstrate that telomeres of early-senescing cells are the same length, and must shorten at the same rate, as cycling sister cells in the culture. Therefore, senescent cells in young mass cultures occur as a result of a stochastic, nontelomere-dependent process that we have described: sudden senescence syndrome.     

Structural, immunocytochemical, and mr imaging properties of periventricular crossroads of growing cortical pathways in preterm infants

BACKGROUND AND PURPOSE: Periventricular white matter (WM) areas are widely recognized as predilection sites for complex cellular damage after ischemia/reperfusion or inflammatory injury of the perinatal cerebrum. We analyzed histochemical and MR imaging properties of fiber architectonics and extracellular matrix (ECM) of periventricular areas to disclose the potential significance of topographically specific WM lesions for the neurodevelopmental outcome. METHODS: We combined histochemical methods for demonstration of fibers, axonal guidance molecules, and ECM with T1-weighted MR images on postmortem specimens aged 15 to 36 postovulatory weeks (POW) and T2-weighted MR images on in vivo fetuses aged 14 to 26 POW. RESULTS: The fiber architectonics of the fetal cerebrum display tangential axon strata in frontopolar and occipitopolar regions, whereas the central periventricular region contains crossroads of intersecting callosal (transverse), associative (sagittal), and thalamocortical/corticofugal (radial) fiber bundles. In early preterms, crossroads contain hydrophylic ECM with axonal guidance molecules, and they are easily recognized as hypointensities on T1-weighted MR images or hyperintensities on T2-weighted MR images. After the 28 POW, tangential fetal fiber-architectonic stratification transforms into the corona radiata system; however, the growth of cortical pathways continues in crossroad areas, as indicated by the presence of ECM and their distinct MR imaging signal intensities. CONCLUSIONS: The correlation of MR imaging with histochemical findings demonstrated the presence of periventricular fiber crossroads rich in ECM and axonal guidance molecules. We propose that, in perinatal WM lesions, periventricular WM crossroads represent a hitherto unrecognized and vulnerable cellular and topographic target in which combined damage of association-commissural and projection fibers may explain the complexity of cognitive, sensory, and motor deficit in survivors of periventricular WM lesions.     

Relationship between loss of pedal sensibility, balance, and falls in patients with peripheral neuropathy

: The purpose of this study was to describe the relationship between balance and foot sensibility in a population of patients with impaired lower extremity sensation. The hypothesis was that increasing impairment of sensation correlates with impaired balance. To date, no report has investigated the relationship between loss of balance with the degree of sensibility in the foot in a population with neuropathy. Ten control subjects and 35 patients with sensory abnormalities and balance problems related to a neuropathy were evaluated. The MatScan Measurement System was used to measure their ability to stand still, maintaining their balance with their eyes open and then with their eyes shut. The degree to which the person moves while attempting to stand still is defined as "sway," which was recorded for normal and neuropathy patients. Sensibility of the foot was measured with the Pressure-Specified Sensory Device, which is noninvasive and nonpainful. The 1- and 2-point static touch thresholds are measured for the pulp of the big toe, medial heel, and the dorsum of the foot. Loss of 2- or 1-point sensation was recorded as sensibility score and compared with controls. Statistical analysis of data and their comparisons for the 2 groups was completed. There were 55% females in control and 64% in neuropathy patients, whereas average age was 50 and 62 years, respectively. Neuropathy was the result of diabetes in 64.5%, hypothyroidism in 19.3%, their combination in 13%, and of unknown etiology in the remaining 19% of patients. Controls had significantly lower mean sway than neuropathy patients (22.9 +/- 9% vs. 189.5 +/- 180%, P = 0.006). Likewise, sensibility score for normal and neuropathy patients was also significantly different (31.4 +/- 9% vs. 232.8 +/- 59%, P <0.0001). When compared with the controls, 99% upper limit of confidence, sensibility in the neuropathy group at the hallux pulp was abnormal at a level consistent with axonal loss in 52% and was completely absent in the remaining 48%. Similarly, at the heel, sensibility was normal in 6.5%, abnormal at a level consistent with axonal loss in 71%, and absent in the remaining 22.5%. The correlation coefficient between sway and sensibility score was 0.36. The results of this investigation for the first time document the intuitive relationship between increasing loss of foot sensibility and increasing loss of balance. These measurements can now be used prospectively to evaluate whether restoration of sensation to patients with neuropathy, through peripheral nerve decompression, can improve balance and reduce falls/fractures in this patient population.