Dysregulated FOXM1 signaling in the regulation of cancer stem cells.

Since the introduction of the cancer stem cell (CSC) paradigm, significant advances have been made in understanding the functional and biological plasticity of these elusive components in malignancies. Endowed with self-renewing abilities and multilineage differentiation potential, CSCs have emerged as cellular drivers of virtually all facets of tumor biology, including metastasis, tumor recurrence/relapse, and drug resistance. The functional and biological characteristics of CSCs, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation are regulated by an array of extracellular factors, signaling pathways, and pluripotent transcriptional factors. Besides the well-characterized regulatory role of transcription factors OCT4, SOX2, NANOG, KLF4, and MYC in CSCs, evidence for the central role of Forkhead box transcription factor FOXM1 in the establishment, maintenance, and functions of CSCs is accumulating. Conventionally identified as a master regulator of the cell cycle, a comprehensive understanding of this molecule has revealed its multifarious oncogenic potential and uncovered its role in angiogenesis, invasion, migration, self-renewal, and drug resistance. This review compiles the large body of literature that has accumulated in recent years that provides evidence for the mechanisms by which FOXM1 expression promotes stemness in glioblastoma, breast, colon, ovarian, lung, hepatic, and pancreatic carcinomas. We have also compiled the data showing the association of stem cell mediators with FOXM1 using TCGA mRNA expression data. Further, the prognostic importance of FOXM1 and other stem cell markers is presented. The delineation of FOXM1-mediated regulation of CSCs can aid in the development of molecularly targeted pharmacological approaches directed at the selective eradication of CSCs in several human malignancies.

Molecular pathogenesis of Cutaneous T cell Lymphoma: Role of chemokines, cytokines, and dysregulated signaling pathways.

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative neoplasms that exhibit a wide spectrum of immune-phenotypical, clinical, and histopathological features. The biology of CTCL is complex and remains elusive. In recent years, the application of next-generation sequencing (NGS) has evolved our understanding of the pathogenetic mechanisms, including genetic aberrations and epigenetic abnormalities that shape the mutational landscape of CTCL and represent one of the important pro-tumorigenic principles in CTCL initiation and progression. Still, identification of the major pathophysiological pathways including genetic and epigenetic components that mediate malignant clonal T cell expansion has not been achieved. This is of prime importance given the role of malignant T cell clones in fostering T helper 2 (Th2)-bias tumor microenvironment and fueling progressive immune dysregulation and tumor cell growth in CTCL patients, manifested by the secretion of Th2-associated cytokines and chemokines. Alterations in malignant cytokine and chemokine expression patterns orchestrate the inflammatory milieu and influence the migration dynamics of malignant clonal T cells. Here, we highlight recent insights about the molecular mechanisms of CTCL pathogenesis, emphasizing the role of cytokines, chemokines, and associated downstream signaling networks in driving immune defects, malignant transformation, and disease progression. In-depth characterization of the CTCL immunophenotype and tumoral microenvironment offers a facile opportunity to expand the therapeutic armamentarium of CTCL, an intractable malignant skin disease with poor prognosis and in dire need of curative treatment approaches.

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance.

The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

Extracellular Vesicle-Mediated Bone Remodeling and Bone Metastasis: Implications in Prostate Cancer.

Bone metastasis is the tendency of certain primary tumors to spawn and dictate secondary neoplasia in the bone. The process of bone metastasis is regulated by the dynamic crosstalk between metastatic cancer cells, cellular components of the bone marrow microenvironment (osteoblasts, osteoclasts, and osteocytes), and the bone matrix. The feed-forward loop mechanisms governs the co-option of homeostatic bone remodeling by cancer cells in bone. Recent developments have highlighted the discovery of extracellular vesicles (EVs) and their diverse roles in distant outgrowths. Several studies have implicated EV-mediated interactions between cancer cells and the bone microenvironment in synergistically promoting pathological skeletal metabolism in the metastatic site. Nevertheless, the potential role that EVs serve in arbitrating intricate sequences of coordinated events within the bone microenvironment remains an emerging field. In this chapter, we review the role of cellular participants and molecular mechanisms in regulating normal bone physiology and explore the progress of current research into bone-derived EVs in directly triggering and coordinating the processes of physiological bone remodeling. In view of the emerging role of EVs in interorgan crosstalk, this review also highlights the multiple systemic pathophysiological processes orchestrated by the EVs to direct organotropism in bone in prostate cancer. Given the deleterious consequences of bone metastasis and its clinical importance, in-depth knowledge of the multifarious role of EVs in distant organ metastasis is expected to open new possibilities for prognostic evaluation and therapeutic intervention for advanced bone metastatic prostate cancer.

Comparison of equipotent doses of Ramosetron, Ondansetron, and sub-hypnotic dose of Propofol for prevention of postoperative nausea and vomiting in laparoscopic cholecystectomy.

Background and Aims: For prevention of Postoperative nausea vomiting (PONV) in laparoscopic surgery, ramosetron is a selective 5-HT3 receptor antagonist with higher receptor affinity and slow dissociation than ondansetron. We compared these 2 drugs with propofol which has also shown antiemetic properties. The aim was to study ondansetron, ramosetron, and propofol with respect to incidence of PONV, its severity and the need for rescue antiemetic along with the side effects. Prospective, randomized, double blind study. Material and Methods: We compared antiemetic properties of ondansetron (4 mg i.v; n = 40) and ramosetron (0.3 mg i.v; n = 40) with propofol (0.5 mg/kg i.v; n = 40) on 120 ASA I/II patients scheduled for laparoscopic cholecystectomy. The side effects associated with study drugs, time to recovery from anesthesia, readiness for PACU discharge and patient satisfaction was also compared. Qualitative data variables are expressed by using frequency and percentage and quantitative data variables are expressed by using mean and SD. Quantitative data variables were compared using ANOVA test and others were compared by post hoc ANOVA Tukey's test. Results: Incidence of vomiting and need for rescue antiemetic was lowest with Ramosetron and highest in Propofol group. Time to recovery was more in Propofol group which was statistically significant. Readiness for PACU discharge was comparable in all the three groups. Conclusion: Subhypnotic dose of propofol requires more rescue antiemetic than Ondansetron and Ramosetron because of its short duration of action. Between Ondansetron and Ramosetron the latter is more effective in PONV prevention.

Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor.

The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.

Clonidine as an adjuvant to ropivacaine-induced supraclavicular brachial plexus block for upper limb surgeries.

BACKGROUND AND AIMS: Ropivacaine is a new amide, long acting, pure S-enantiomer, local anesthetic, with differential blocking effect. The addition of clonidine to local anesthetic improves the quality of peripheral nerve blocks. This study was conducted to evaluate the effect of clonidine on characteristics of ropivacaine-induced supraclavicular brachial plexus block. MATERIAL AND METHODS: A total of 60 adult patients were randomly recruited to two groups of 30 each: Group I: 30 ml 0.75% ropivacaine + 1 ml normal saline. Group II: 30 ml 0.75% ropivacaine + 1 mcg/kg clonidine diluted to 1 ml with normal saline. RESULTS: The onset of sensorimotor block was earlier in Group II (4.36 ± 0.81 min for sensory block and 9.83 ± 1.12 min for motor block) than in Group I (4.84 ± 0.65 min for sensory block and 10.85 ± 0.79 min for motor block). The duration of both sensory and motor block were significantly prolonged by clonidine (P < 0.001). The duration of analgesia was also prolonged in patients receiving clonidine (613.10 ± 51.797 min vs. 878.33 ± 89.955 min). Although incidence of hypotension and bradycardia was higher in Group II when compared to Group I, it was not clinically significant. CONCLUSIONS: Ropivacaine 0.75% is well-tolerated and provides effective surgical anesthesia as well as relief of postoperative pain. Clonidine as an adjuvant to ropivacaine significantly enhances the quality of supraclavicular brachial plexus block by faster onset, prolonged duration of sensory and motor block and improved postoperative analgesia, without associated adverse effects at the dose used.

Sanguinarine Triggers Apoptosis in Cutaneous Squamous Cell Carcinoma Cells through Reactive Oxygen Species-Dependent c-Jun N-Terminal Kinase Signaling Pathway.

BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action. METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (ΔΨm) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids. RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, ΔΨm depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids. CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.

To Compare the Safety and Efficacy of Conscious Sedation with Dexmedetomidine and Propofol Infusion for Endoscopic Discectomy.

OBJECTIVE: Endoscopic discectomy is a minimally invasive, day care spine surgery. Patient comfort is of utmost importance as it is performed under local anaesthesia and in prone position. Propofol and dexmedetomidine are titrable and short-acting and commonly used for conscious sedation. The objectives of the study are to study the effect of dexmedetomidine and propofol infusion on cardiorespiratory parameters and to evaluate the efficacy of dexmedetomidine and propofol infusion for conscious sedation. METHODS: This is a prospective, randomized, patient-blinded study. Sixty adult patients were randomly recruited to 2 groups of 30 each, to receive an infusion of dexmedetomidine or propofol, titrated to bispectral index score 70-80. The intra-operative cardiorespiratory parameters and level of sedation, postoperative visual analogue scale score, time to discharge from post-anaesthesia care unit, and patient satisfaction were monitored. RESULTS: Both groups were comparable with respect to demographic parameters and surgical duration. The heart rate was significantly lower with dexmedetomidine whereas the intraoperative mean arterial pressure was higher with dexmedetomidine. Though the level of intraoperative sedation was higher with propofol, the respiratory parameters were comparable. Postoperative visual analogue scale score was significantly higher with propofol. CONCLUSION: Dexmedetomidine and propofol provide adequate sedation without any cardiorespiratory compromise when used for conscious sedation for minimally invasive spine surgeries performed in prone position. Dexmedetomidine provides an added advantage of postoperative analgesia and better patient satisfaction.

Non-Invasive Biomarkers for Early Lung Cancer Detection.

Worldwide, lung cancer (LC) is the most common cause of cancer death, and any delay in the detection of new and relapsed disease serves as a major factor for a significant proportion of LC morbidity and mortality. Though invasive methods such as tissue biopsy are considered the gold standard for diagnosis and disease monitoring, they have several limitations. Therefore, there is an urgent need to identify and validate non-invasive biomarkers for the early diagnosis, prognosis, and treatment of lung cancer for improved patient management. Despite recent progress in the identification of non-invasive biomarkers, currently, there is a shortage of reliable and accessible biomarkers demonstrating high sensitivity and specificity for LC detection. In this review, we aim to cover the latest developments in the field, including the utility of biomarkers that are currently used in LC screening and diagnosis. We comment on their limitations and summarise the findings and developmental stages of potential molecular contenders such as microRNAs, circulating tumour DNA, and methylation markers. Furthermore, we summarise research challenges in the development of biomarkers used for screening purposes and the potential clinical applications of newly discovered biomarkers.

Pertussis seroprevalence in mother-infant pairs from India: role of maternal immunisation.

OBJECTIVE: To evaluate pertussis antibody status of pregnant women and their newborns, and the impact of antenatal immunisation. DESIGN: Observational study. SETTING: Hospitals in urban western India. PARTICIPANTS: Pregnant women and their newborns. METHODS: Pertussis antibody titres in mothers and their newborns were determined. Vaccinated and unvaccinated mothers and their newborns were compared for baseline characteristics, geometric mean titres (GMTs) and placental transfer ratio of antibodies. Multivariate logistic regression was performed to understand the influence of different factors on protective antibody titres. RESULTS: Of 284 mother-infant pairs, 75 mothers and 73 of their newborns were seropositive for anti-pertussis toxin (PT) IgG antibodies. 94 women were vaccinated in pregnancy; 51 (54.3%) of these mothers and newborns were PT IgG positive, compared with 24 (12.3%) of the women (and 22 newborns) not vaccinated in pregnancy. Women vaccinated in pregnancy and their newborns had higher GMT (30.88 and 32.54 IU/mL), compared with women who were not vaccinated (12.63%, 2.24 IU/mL) and their newborns (11.58%, 2.53 IU/mL). Placental transfer ratios in newborns of mothers vaccinated in pregnancy and those who had childhood immunisation or natural immunity were similar (1.05 and 1.12, respectively). Protective titres of antibodies at birth (>20 IU/mL) were observed in 72.3% vs 21% of newborns of vaccinated and unvaccinated pregnant women, respectively; influenced by mother's vaccination status and seropositivity. CONCLUSION: Protection against pertussis is low in newborns of mothers who are only immunised during childhood. Vaccination early in pregnancy boosts maternal and neonatal immunity.

Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis.

Abnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia remains unclear. NSP-B, a meroterpenoid fungal secondary metabolite, possesses anticancer potential in human leukemic cells lines; however, the underlying mechanism has not been elucidated. The present study aimed to explore the role of NSP-B on FOXM1/BUB1B signaling and the underlying molecular mechanism of apoptosis induction in leukemic cells. We performed gene expression profiling of NSP-B-treated and untreated leukemic cells to search for differentially expressed genes (DEGs). Interestingly BUB1B was found to be significantly downregulated (logFC -2.60, adjusted p = 0.001) in the treated cell line with the highest connectivity score among cancer genes. Analysis of TCGA data revealed overexpression of BUB1B compared to normal in most cancers and overexpression was associated with poor prognosis. BUB1B also showed a highly significant positive correlation with FOXM1 in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an in vitro study model to validate our findings. We found that NSP-B treatment of leukemic cells suppressed the expression of FOXM1 and BUB1B in a dose-dependent manner. In addition, NSP-B also resulted in the downregulation of FOXM1-regulated genes such as Aurora kinase A, Aurora kinase B, CDK4, and CDK6. Suppression of FOXM1 either by siRNA or NSP-B reduced BUB1B expression and enhanced cell survival inhibition and induction of apoptosis. Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target.

Guggulsterone Induces Apoptosis in Multiple Myeloma Cells by Targeting High Mobility Group Box 1 via Janus Activated Kinase/Signal Transducer and Activator of Transcription Pathway.

Multiple myeloma (MM) is a hematological disorder characterized by the abnormal expansion of plasma cells in the bone marrow. Despite great advances over the past three decades in discovering the efficacious therapies for MM, the disease remains incurable for most patients owing to emergence of drug-resistant cancerous cells. Guggulsterone (GS), a phytosteroid, extracted from the gum resin of guggul plant, has displayed various anticancer activities in vitro and in vivo; however, the molecular mechanisms of its anticancer activity have not been evaluated in MM cells. Therefore, in this study, we investigated the anticancer activity of GS in various MM cell lines (U266, MM.1S, and RPMI 8226) and the mechanisms involved. GS treatment of MM cells caused inhibition of cell proliferation and induction of apoptotic cell death as indicated by increased Bax protein expression, activation of caspases, and cleavage of poly (ADP-ribose) polymerase. This was associated with the downregulation of various proliferative and antiapoptotic gene products, including cyclin D, Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein. GS also suppressed the constitutive and interleukin 6-induced activation of STAT3. Interestingly, the inhibition of Janus activated kinase or STAT3 activity by the specific inhibitors or by siRNA knockdown of STAT3 resulted in the downregulation of HMGB1, suggesting an association between GS, STAT3, and HMGB1. Finally, GS potentiated the anticancer effects of bortezomib (BTZ) in MM cells. Herein, we demonstrated that GS could be a potential therapeutic agent for the treatment of MM, possibly alone or in combination with BTZ.

Extracellular vesicles in the development of organ-specific metastasis.

Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most cancer-related mortalities. This process is orchestrated by many complex biological interactions and processes that are mediated by a combination of anatomical, genetic, pathophysiological and biochemical factors. Recently, extracellular vesicles (EVs) are increasingly being demonstrated as critical mediators of bi-directional tumour-host cell interactions, controlling organ-specific infiltration, adaptation and colonization at the secondary site. EVs govern organotropic metastasis by modulating the pre-metastatic microenvironment through upregulation of pro-inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotype-specific differentiation and recruitment of specific stromal cell types. This review discusses EV-mediated metastatic organotropism in visceral (brain, lung, liver, and lymph node) and skeletal (bone) metastasis, and discusses how the pre-metastatic education by EVs transforms the organ into a hospitable, tumour cell-friendly milieu that supports the growth of metastatic cells. Decoding the organ-specific traits of EVs and their functions in organotropic metastasis is essential in accelerating the clinical application of EVs in cancer management.

Evaluation of magnesium as an adjuvant to ropivacaine-induced axillary brachial plexus block: A prospective, randomised, double-blind study.

BACKGROUND AND AIMS: Axillary brachial plexus block is commonly performed for surgeries on the hand and forearm. However, there are very few studies on the use of magnesium sulphate in axillary brachial plexus block and, hence, the study was designed to evaluate magnesium as an adjuvant to ropivacaine-induced axillary block with respect to onset and duration of sensorimotor block and postoperative analgesia. METHODS: Sixty patients of the American Society of Anesthesiologists (ASA) physical status I and II, undergoing surgeries on the hand and forearm were randomly recruited to receive ultrasound-guided axillary block with either 150 mg magnesium sulphate or 1 mL normal saline added to 0.5% ropivacaine. The primary outcome measure was to compare block characteristics including postoperative analgesia and the secondary outcome was to compare the use of rescue analgesia and the side-effect profile. Data were statistically analysed using Statistical Package for Social Sciences (SPSS version 21.0). Categorical variables were compared using the Chi-square test or Fisher's exact probability test; continuous variables compared using unpaired t-test or Mann-Whitney U test. RESULTS: Onset of sensory (9.93 ± 1.31 vs 8.83 ± 1.12 min) as well as motor block (13.37 ± 1.63 vs 11.57 ± 1.30 min) was significantly hastened with addition of magnesium to ropivacaine (p < 0.001) and so was the duration (sensory 386.60 ± 18.26 vs 526.37 ± 27.43, motor 323.73 ± 15.17 vs 436.97 ± 18.99 min) (p < 0.001) and postoperative analgesia (425 ± 21.39 vs 572.83 ± 32.04 min) (p < 0.001) which reflected in decreased requirement of rescue analgesic and total postoperative analgesic dosage. CONCLUSIONS: Magnesium is an effective and safe adjuvant to local anaesthetics and improves all characteristics of axillary brachial plexus block along with postoperative analgesia.

Discovery of Peptide Antibiotics Composed of d-Amino Acids.

A paucity of viable programs and pipelines for the discovery of new antibiotics poses a significant public health threat. The emergence of resistant strains against vancomycin is particularly dangerous in hospital settings. Here, we report the design of enantiomeric targets based on bacterial cell wall biosynthesis precursors that allow for selection and identification of short linear, cyclic and bicyclic peptides that are composed of d-amino acids. These compounds are active against Staphylococcus aureus, Methicillin-resistant S. aureus, and vancomycin-resistant Enterococci that possess moderately high antibacterial activity and furthermore display no toxicity to both human red blood cells and mammalian cells at these concentrations. This 'mirror image phage display' approach yielded templates that can serve as scaffolds for further improvements in activity-based structural modifications. This strategy has the potential to provide a new class of antimicrobials that are metabolically stable and have the promise for oral delivery. The use of this platform combined with traditional medicinal chemistry approaches could rapidly yield large numbers of new therapeutic lead compounds.

Enantioselective H-atom transfer reaction: a strategy to synthesize formaldehyde aldol products.

[reaction: see text] Enantioselective radical alkylation of Baylis-Hillman adducts furnished aldol products in good yield and selectivity. The results illustrate that the selectivity in the hydrogen atom transfer is dependent on the size of the ester substituent, with smaller substituents providing better enantioselectivity.

Enantioselective rhodium enolate protonations. A new methodology for the synthesis of beta2-amino acids.

[reaction: see text] Rhodium-catalyzed conjugate addition of an aryl boronic acid to alpha-methylamino acrylates followed by enantioselective protonation of the oxa-pi-allylrhodium intermediate provides access to aryl-substituted beta(2)-amino acids. The impact of the different variables of the reaction on the levels of enantioselectivity has been assessed.

Comparison of clonidine and dexmedetomidine as adjuncts to intravenous regional anaesthesia.

BACKGROUND AND AIMS: Intravenous regional anaesthesia (IVRA) provides reliable and rapid analgesia with good muscular relaxation of the extremity distal to the tourniquet, but tourniquet pain and absence of post-operative analgesia are major drawbacks. α2 agonists, clonidine and dexmedetomidine are known to potentiate peripheral nerve blocks. The aim of this study was to compare clonidine and dexmedetomidine as adjuvants to IVRA with respect to block characteristics, tourniquet pain and post-operative analgesia. METHODS: A prospective, randomised, double-blind study was conducted on 60 adult patients of American Society of Anesthesiologists physical status grades I and II, in two groups of 30 each, to receive either clonidine 1 µg/kg or dexmedetomidine 1 µg/kg added to 40 ml 0.5% preservative-free lignocaine. Independent samples t-test was used for analysing demographic data, haemodynamic data and block characteristics and Mann-Whitney U-test for skewed data. RESULTS: Sensorimotor block onset was significantly faster and recovery delayed with dexmedetomidine as compared to clonidine. Intra-operative visual analogue scale (VAS) at 10 min, 15 min and 40 min and post-operative VAS at 30 min and 2 h were significantly higher with clonidine. Fentanyl consumption and sedation were comparable. Duration of analgesia was significantly longer with dexmedetomidine. Haemodynamic parameters were comparable. CONCLUSIONS: Dexmedetomidine significantly facilitates onset, prolongs recovery of sensory as well as motor block and also prolongs duration of analgesia as compared to clonidine.   Both decrease tourniquet pain satisfactorily and have comparable intra-operative fentanyl requirement . Patient satisfaction is better with dexmedetomidine.