Rigid 3D-spiro chromanone as a crux for efficient antimicrobial agents: synthesis, biological and computational evaluation.

The development of new and effective antimicrobial agents with novel chemical skeletons and working mechanisms is highly desirable due to the increased number of resistant microbes. Different new compounds based upon a 3D-spiro chromanone scaffold such as Mannich bases 2 and 3 in addition to azo dye 4 were synthesized. Besides, the condensation reactions of the hydrazide-spiro chromanone 8 with different ketonic reagents led to the synthesis of pyrazoles (9 & 10) and anils (11 & 13). Moreover, the methoxyl substituted spiro chromanone 14 was condensed with different hydrazines and hydrazides to give the corresponding hydrazones 15-18 in up to 85% yields. The condensation of the hydrazone 18 with salicylaldehyde yielded coumarinyl spiro chromanone 19 in an excellent yield, whereas its reaction with benzaldehyde followed by hydrazine afforded aminopyrazole derivative 21 in 82% yield. The antimicrobial evaluation suggested that hydrazide 8 has a substantial activity against different microbes (S. aureus: D = 22 mm, MIC = 1.64 µM; E. coli: D = 19 mm, MIC = 1.64 µM; C. albicans: D = 20 mm, MIC = 6.57 µM). Moreover, promising antimicrobial activities were observed for azo dye 4 (D = 13-19 mm, MIC = 5.95-11.89 µM), hydrazone 17 (D = 17-23 mm, MIC = 1.88-3.75 µM), and aminopyrazole 21 (D = 14-19 mm, MIC = 2.24-8.98 µM). The molecular docking revealed that compounds 4, 8, 17, and 21 had good to high binding affinities with different microbial targets such as penicillin-binding proteins (-7.4 to -9.9 kcal), DNA gyrase (-7.8 to -9.0 kcal), lanosterol 14-alpha demethylase (-8.2 to -11.2 kcal), and exo-beta-1,3-glucanase (-8.2 to -11.9 kcal). The QSAR analysis ascertained a good correlation between the antimicrobial activity of 3D-spiro chromanone derivatives and their structural and/or physicochemical parameters.

Does sedation offer better outcomes than local anaesthesia for thyroid FNA in adult patients?

OBJECTIVE: To examine the potential benefits of sedation in adults undergoing fine needle aspiration (FNA) of thyroid nodules. METHODS: This retrospective study compared the outcomes of sedated and non-sedated FNA patients. RESULTS: A total of 860 patients underwent 1698 FNAs of thyroid nodules. The mean patient age was 52.4±14.4 years, and 80.2% of patients were women. The non-sedated group consisted of 782 patients with 1543 (93.5%) FNA procedures. The sedated group consisted of 66 patients who underwent 107 (6.5%) FNAs. There was no statistical difference between these groups with respect to age, gender, nodule size, nodule vascularity, non-diagnostic sample rate and post FNA hematoma (P > .05). CONCLUSIONS: Performing FNA of thyroid nodules in adult patients under sedation is not associated with a higher diagnostic yield or lower bleeding rate when compared to local anesthesia. Sedation should be judiciously used on only very anxious patients due to the increased overall cost.

Cost-effectiveness of intraoperative nerve monitoring in avoidance of bilateral recurrent laryngeal nerve injury in patients undergoing total thyroidectomy.

BACKGROUND: Intraoperative nerve monitoring (IONM) provides dynamic neural information and is recommended for high-risk thyroid surgery. In this analysis, the cost-effectiveness of IONM in preventing bilateral recurrent laryngeal nerve (RLN) injury was investigated. METHODS: A Markov chain model was constructed based on IONM use. The base-case patient was defined as a 40-year-old woman presenting with a 4·1-cm left-sided papillary thyroid cancer who developed RLN injury with loss of monitoring signal during planned bilateral thyroidectomy. It was hypothesized that, if the surgeon had used IONM, the RLN injury would have been detected and the operation would have been concluded as a thyroid lobectomy to avoid the risk of contralateral RLN injury. Cost in US dollars was converted to euros; probabilities and utility scores were identified from the literature and government resources. Length of follow-up was set as 20 years, and willingness-to-pay (WTP) as €38 000 (US $50 000) per quality-adjusted life-year (QALY). RESULTS: At the end of year 20, the not using IONM strategy accrued €163 995·40 (US $215 783·43) and an effectiveness of 14·15 QALYs, whereas use of the IONM strategy accrued €170 283·68 (US $224 057·48) and an effectiveness of 14·33 QALYs. The incremental cost-effectiveness ratio, comparing use versus no use of IONM, was €35 285·26 (US $46 427·97) per QALY, which is below the proposed WTP, indicating that IONM is the preferred and cost-effective management plan. A Monte Carlo simulation test that considered variability of the main study factors in a hypothetical sample of 10 000 patients showed IONM to be the preferred strategy in 85·8 per cent of the population. CONCLUSION: Use of IONM is cost-effective in patients undergoing bilateral thyroid surgery.

Surgeon volume impact on outcomes and cost of adrenal surgeries.

INTRODUCTION: The number of adrenal surgeries performed in the United Stated is continuing to increase. Identifying factors associated with favorable outcomes can have a major impact on cost-differences. We aim to assess the impact of surgeon volume on both clinical outcomes and cost following adrenal surgery. MATERIALS AND METHODS: A cross-sectional analysis was performed utilizing data from the Nationwide Inpatient Sample, 2003-2009. Surgeon volumes included (adrenalectomies/year): low-volume (1), intermediate-volume (2-6), and high-volume (≥7). RESULTS: A total of 7045 patients were included. Surgeries performed by low-volume surgeons were associated with a higher risk of postoperative complications [OR: 1.66, 95% CI: (1.23, 2.24)]. During the study period, if all operations performed by low-volume surgeons were selectively referred to intermediate-volume surgeons, a 7.7% cost savings would have been incurred. Potential savings were even higher (8.1%) if the operations had been performed by the high-volume surgeons. With the conservative assumption that there are 5000 adrenalectomies per year in the United States, the high-volume surgeons would produce savings of $8.8 million over a span of 14 years. CONCLUSION: A surgeon's expertise is associated with favorable outcomes. Our model estimates that considerable cost savings are attainable with appropriate referrals to high volume endocrine surgeons.

Comparison of inpatient and outpatient thyroidectomy: Demographic and economic disparities.

BACKGROUND: Thyroidectomy is increasingly being performed as an outpatient procedure. In this study, we aim to examine patient characteristics and clinical factors associated with outpatient thyroid surgeries as compared to inpatient procedures. METHODS: A cross-sectional study for the period of 2007-2010. Inpatients and outpatients were selected from the Nationwide Inpatient Sample and State Ambulatory Surgery and Services Databases, respectively. All patients were adults (≥18 years) who underwent thyroidectomy in the States of Florida and New York. RESULTS: A total of 25,267 outpatients, and 8219 inpatients were included. Outpatients were more likely to be female, White, have private insurance, and have one or no comorbidities (p < 0.001 each). Thyroid surgeries performed for thyroid conditions other than malignancy were more common in the outpatient settings (p < 0.05 each). High-volume surgeons were more likely to perform ambulatory thyroidectomy (p < 0.001). Post-outpatient thyroidectomy complications were higher for lower volume surgeons (p < 0.001). Moreover, hospital charges for outpatient surgeries performed by lower volume surgeons were significantly higher compared to high-volume surgeons (p < 0.001). CONCLUSIONS: Racial and economic disparities exist in the utilization of ambulatory thyroidectomy. Experienced surgeons are more likely to provide ambulatory thyroidectomy, and surgeries performed by them are associated with more favorable outcomes and lower hospital charges.

Resection of a catecholamine-elaborating retroperitoneal paraganglioma invading the inferior vena cava.

Paragangliomas are rare tumors originating outside of the adrenal medulla which can be associated with catecholamine secretion or mass effect, one of which typically leads to their discovery. The differences between these tumors and traditional intra-adrenal pheochromocytomas are a subject of recent investigations. Standard of care therapy is medical management and surgical resection of the tumor. When tumors are biochemically active, medical optimization of the autonomic nervous system is a critical component to a safe, definitive resection. Tumors arising in the retroperitoneum present technical challenges for the surgeon as they are often large and difficult to access, making an oncologic resection much more difficult. Lastly, these tumors are mostly benign and rarely invade adjacent structures-an operative finding not always predicted by preoperative imaging-which, if present, adds significant complexity and risk to the resection. A case illustrating these challenges in the management of a biochemically active retroperitoneal paraganglioma invading the inferior vena cava follows.

Initial experience using robot- assisted transaxillary thyroidectomy for Graves' disease.

INTRODUCTION: Graves' disease is the most common form of hyperthyroidism and surgery to remove the thyroid gland is a common treatment option for many of these patients. Interestingly, due to the enlarged gland size, their high vascularity, and the difficulty to control bleeding, many authors feel that Graves' disease remains a contraindication to current endoscopic techniques. We hypothesize that performing robotic subtotal thyroidectomy in Graves' disease settings could overcome the limitations of conventional endoscopic surgeries in the surgical management of this challenging thyroid disease. METHODS: Prospective study in an academic hospital. RESULTS: Sixty-seven patients had robotic transaxillary thyroidectomy within a year. Of these, five cases (7%) were done for Graves' disease. There were three females and two males (mean age, 36 years). There were no conversions to laparoscopic or open surgery. The mean (SD) thyroid volume was 16.6 (3.2) ml. The mean (SD) operative time was 159 (17.8)min and docking time was 81 (20)min. Mean blood loss was 18 mL. All patients were discharged home in 24h. There were no perioperative or postoperative complications. There was no evidence of postoperative vocal cord palsy or paresis. CONCLUSIONS: We showed that robotic transaxillary thyroidectomy is feasible and can be safe and effective in patients with Graves' disease. To our knowledge, this is the first article describing this approach for Graves' disease. These findings, however, warrant additional investigation within future prospective clinical trials.

A targeted parathyroidectomy using guide wire technique in a pregnant patient with primary hyperparathyroidism.

Primary hyperparathyroidism may cause fetal demise in pregnant patients if prompt diagnosis and treatment is not initiated. The paper describes a novel guide wire technique for a targeted parathyroidectomy, which may reduce the risk to mother and fetus and be useful in other related circumstances.

Targeted inhibition of gene expression of pancreatitis-associated proteins exacerbates the severity of acute pancreatitis in rats.

BACKGROUND: Pancreatitis-associated protein (PAP) is a secretory protein not normally expressed in healthy pancreas but highly induced during acute pancreatitis. While PAP has been shown to be anti-bacterial and anti-apoptotic in vitro, its definitive biological function in vivo is not clear. METHODS: To elucidate the function of PAP, antisense oligodeoxyribonucleotides (AS-PAP) targeting all three isoforms of PAP were administered via intrapancreatic injections (5 mg kg day, 2 days) to rats prior to induction of pancreatitis. RESULTS: Severity of pancreatitis and cytokine gene expression in peripheral blood mononuclear cells (PBMC) were evaluated. Administration of AS-PAP, but not the scrambled oligodeoxyribonucleotide (SC-PAP) control, reduced pancreatitis-induced PAP expression by 55.2 +/- 6.4%, 44.0 +/- 8.9%, and 38.9 +/- 10.7% for PAP isoforms I, II, and III, respectively, compared to saline-treated controls (P < 0.05 for all). Inhibition of PAP expression significantly worsened pancreatitis: serum amylase activity, pancreas wet weight (reflecting edema), and serum C-reactive protein levels all increased in AS-PAP-treated animals compared to SC-PAP-treated controls (by 3.5-, 1.7-, and 1.7-fold, respectively; P < 0.05 for all). Histopathologic evaluation of pancreas revealed worsened edema, elevated leukocyte infiltration, and fat necrosis after AS-PAP treatment. Gene expressions of IL-1 microm and IL-4 were significantly higher in PBMC isolated from AS-PAP-treated rats compared to SC-PAP controls. CONCLUSION: This is the first in vivo evidence indicating that PAP mediates significant protection against pancreatic injury. Our data suggest that PAP may exert its protective function by suppressing local pancreatic as well as systemic inflammation during acute pancreatitis.

Cortisol differentially affects memory in young and elderly men.

Nine young and 11 elderly men participated in this placebo-controlled, double-blind, crossover study (0.5 mg/kg cortisol or intravenous placebo). Participants learned a word list before cortisol administration, and delayed recall was then tested. A 2nd word list was learned and recalled after drug administration. In addition, the Paragraph Recall Test and tests measuring working memory (Digit Span), attention (timed cancellation), and response inhibition (Stroop Color and Word Test) were administered at 2 time points after drug administration. Cortisol reduced recall from the word list learned before treatment in both groups but did not influence recall of the list learned after treatment. In contrast, Digit Span performance was decreased by cortisol in young but not elderly participants. The possibility that differential age-associated brain changes might underlie the present results is discussed.

Volumetric analysis of the pre-frontal regions: findings in aging and schizophrenia.

Frontal lobe dysfunction is thought to be involved in schizophrenia and age-associated cognitive decline. Frontal lobe volume changes have been investigated in these conditions using MRI, but results have been inconsistent. Few volumetric MRI protocols exist that divide the pre-frontal cortex into its sub-regions. In the present article, we describe a new method, which allows assessment of the superior, middle and inferior frontal gyrus, as well as the orbitofrontal and cingulate regions. The method uses multiple planes to help guide the anatomical decisions and combines this with a geometric approach utilizing readily apparent anatomical landmarks. Using this protocol, the frontal lobe volumes in young healthy subjects were contrasted with those of young schizophrenic patients and elderly healthy subjects (nine male subjects per group). The results showed that the method could be reproduced with high reliability (r(icc)> or =0.88-0.99). Schizophrenic as well as old subjects had specific significant reductions in the superior frontal gyrus and orbitofrontal regions compared with the young group. However, old and schizophrenic subjects did not differ from each another. No volume differences were observed in the other three regions assessed. Whether or not these volume reductions reflect a common pathological process remains to be investigated in future studies.

Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET).

Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[(18)F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.

Hippocampal formation glucose metabolism and volume losses in MCI and AD.

We used MRI volume sampling with coregistered and atrophy corrected FDG-PET scans to test three hypotheses: 1) hippocampal formation measures are superior to temporal neocortical measures in the discrimination of normal (NL) and mild cognitive impairment (MCI); 2) neocortical measures are most useful in the separation of Alzheimer disease (AD) from NL or MCI; 3) measures of PET glucose metabolism (MRglu) have greater diagnostic sensitivity than MRI volume. Three groups of age, education, and gender matched NL, MCI, and AD subjects were studied. The results supported the hypotheses: 1) entorhinal cortex MRglu and hippocampal volume were most accurate in classifying NL and MCI; 2) both imaging modalities identified the temporal neocortex as best separating MCI and AD, whereas widespread changes accurately classified NL and AD; 3) In most between group comparisons regional MRglu measures were diagnostically superior to volume measures. These cross-sectional data show that in MCI hippocampal formation changes exist without significant neocortical changes. Neocortical changes best characterize AD. In both MCI and AD, metabolism reductions exceed volume losses.

PA28 subunits of the mouse proteasome: primary structures and chromosomal localization of the genes.

The 20S proteasome is a multi-subunit protease responsible for the production of peptides presented by major histocompatibility complex (MHC) class I molecules. Recent evidence indicates that an interferon-gamma (IFN-gamma)-inducible PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome. In the present study, we determined the primary structures of the mouse PA28 alpha- and beta-subunits. The deduced amino acid sequences of the alpha- and beta-subunits were 49% identical. We also determined the primary structure of the mouse PA28 gamma-subunit (Ki antigen), a protein of unknown function structurally related to the alpha- and beta-subunits. The amino acid sequence identity of the gamma-subunit to the alpha- and beta-subunits was 40% and 32%, respectively. Interspecific backcross mapping showed that the mouse genes coding for the alpha- and beta-subunits (designated Psme1 and Psme2, respectively) are tightly linked and map close to the Atp5g1 locus on chromosome 14. Thus, unlike the LMP2 and LMP7 subunits, the IFN-gamma-inducible subunits of PA28 are encoded outside the MHC. The gene coding for the gamma-subunit (designated Psme3) was mapped to the vicinity of the Brca1 locus on chromosome 11. A computer search of the DNA databases identified a gamma-subunit-like protein in ticks and Caenorhabditis elegans, the organisms with no adaptive immune system. It appears that the IFN-gamma-inducible alpha- and beta-subunits emerged by gene duplication from a gamma-subunit-like precursor.

Isolation of low molecular mass polypeptide complementary DNA clones from primitive vertebrates. Implications for the origin of MHC class I-restricted antigen presentation.

Proteasomes are the multisubunit proteases thought to be involved in the generation of peptides presented by MHC class I molecules. When cells are stimulated with IFN-gamma, two MHC encoded subunits, LMP2 and LMP7, are incorporated into the proteasomal complex, presumably by displacing the housekeeping subunits, designated Y and X, respectively. These changes in the subunit composition appear to facilitate class I-mediated Ag presentation, presumably bu altering the cleavage specificities of the proteasome. Here we show that the cartilaginous fish, the most primitive class of vertebrates in which the MHC has been identified, have both LMP7 and X genes. Interestingly, nurse sharks, a member of the cartilaginous fish, appear to have two LMP7 genes, one encoding a typical LMP7 subunit and the other encoding a less typical one. In contrast, only cDNA clones with residues characteristic of X were identified in hagfishes and lampreys, the two extant members of the jawless fish in which no MHC has been identified. Pairwise amino acid sequence comparison and phylogenetic tree analysis showed that the subunits encoded by these clones were nearly equidistant from LMP7 and X, suggesting that the LMP7 gene might have emerged after the appearance of the jawless fish. Sequence comparison of the LMP7 and X/X-like subunits isolated from various vertebrate species showed that, unlike the X/X-like subunit, the LMP7 subunit displays a striking interspecies sequence variability in the vicinity of its catalytic site.