Global, Regional, and National Levels and Trends in Burden of Oral Conditions from 1990 to 2017: A Systematic Analysis for the Global Burden of Disease 2017 Study.

Government and nongovernmental organizations need national and global estimates on the descriptive epidemiology of common oral conditions for policy planning and evaluation. The aim of this component of the Global Burden of Disease study was to produce estimates on prevalence, incidence, and years lived with disability for oral conditions from 1990 to 2017 by sex, age, and countries. In addition, this study reports the global socioeconomic pattern in burden of oral conditions by the standard World Bank classification of economies as well as the Global Burden of Disease Socio-demographic Index. The findings show that oral conditions remain a substantial population health challenge. Globally, there were 3.5 billion cases (95% uncertainty interval [95% UI], 3.2 to 3.7 billion) of oral conditions, of which 2.3 billion (95% UI, 2.1 to 2.5 billion) had untreated caries in permanent teeth, 796 million (95% UI, 671 to 930 million) had severe periodontitis, 532 million (95% UI, 443 to 622 million) had untreated caries in deciduous teeth, 267 million (95% UI, 235 to 300 million) had total tooth loss, and 139 million (95% UI, 133 to 146 million) had other oral conditions in 2017. Several patterns emerged when the World Bank's classification of economies and the Socio-demographic Index were used as indicators of economic development. In general, more economically developed countries have the lowest burden of untreated dental caries and severe periodontitis and the highest burden of total tooth loss. The findings offer an opportunity for policy makers to identify successful oral health strategies and strengthen them; introduce and monitor different approaches where oral diseases are increasing; plan integration of oral health in the agenda for prevention of noncommunicable diseases; and estimate the cost of providing universal coverage for dental care.

Laparoscopic living donor right nephrectomy: Assessment of outcome and association of BMI to length of right renal vein. / Nefrectomía laparoscópica derecha de donante vivo: evaluación del resultado y asociación del IMC con la longitud de la vena renal derecha.

AIMS: The aim of this study was to describe outcomes of laparoscopic living donor right nephrectomy (LLDRN) and study factors affecting the length of right renal vein from the donors. MATERIAL AND METHODS: This study was conducted in 60 donors (48 males and 12 females) from January 2016 to December 2017. We performed a retrospective review of consecutive patients who underwent transperitoneal right laparoscopic living donor nephrectomy at our unit. RESULTS: LLDRN was successfully performed in all subjects by the same surgeons. Among 60 cases, 47 donors had single renal artery and vein, 2 cases had one artery and 2 veins, and 5 donors had 2 arteries and one vein, and the rest had 2-3 arteries with 1-3 veins. Operative time was 142.60±33.73min. Warm ischemic time was 2.64±0.76min. The mean hospital stay was 6.69±0.63 days. The median length of right renal vein was 1.92±0.41cm. All transplanted kidneys showed immediate function. No graft losses were recorded. Almost no gender differences were found in study variables except BMI and warm ischemic time, that was higher BMI but shorter warm ischemic time in female versus male donors. Further analysis showed a negative correlation between BMI and right renal vein (r=-0.282, P<0.05), but a positive correlation between operative time and estimate blood loss (r=0.37, P<0.01). CONCLUSIONS: LLDRN is a feasible safe procedure, less traumatic approach, and provides good outcomes kidney for recipients. Notably, in the study group the higher BMI was associated with resulting more difficult LLDRN and kidney transplantation.

Individualized treatment of NSCLC: from research to clinical practice.

The exact clinical significance of EGFR mutation status in NSCLC at the time of initial diagnosis remains disputable. The gene expression module in NSCLC for chemotherapy outcome prediction needs to be developed. We analyzed 56 patients with NSCLC received chemotherapy either with (n=20) or without EGFR-TKIs (n=36) between 2008 and 2012 in China. EGFR mutation test and gene expression profiling were performed in samples obtained before medication treatment by liquidchip platform. Significant association (P = 0.028) was seen between EGFR mutation status before first-line chemotherapy and EGFR-TKIs treatment outcomes, which even can be found from the status before second- or third-line treatment. A14-gene expression profiling had been studied. Patients with low mRNA expression of ERCC1 or TYMS preferred higher DCR to cisplatin and pemetrexed than those with high expression (P = 0.39 and P= 0.11). Highly co-expression of TUBB3 and STMN1 gene has associated with the resistance to antimicrotubule drugs (P = 0.03). Our data suggest the EGFR mutations status, even at the time of initial diagnosis, is predictive of outcomes of TKIs treatment after chemotherapy. The mRNA expression profiling investigated in this study has a predictive value in NSCLC treatment, but further research with expanded samples is still required.

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients.

Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSP-mediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 x 10(7) to 3.0 x 10(12) viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 x 10(12) VP and transient grade IV thrombocytopenia at the dose of 3.0 x 10(12) VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4(+) and CD8(+) T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens.

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.

Analysis of in situ NK cell responses during viral infection.

NK cells are required for early control of murine CMV (MCMV) infection, but the distribution of murine NK cells in situ has not been clearly defined. We tested the reactivity of all available NK cell receptor-specific mAbs by immunohistochemistry. Only one mAb, 4D11 (anti-Ly-49G2), was reactive with C57BL/6 tissue sections. mAb 4D11-reactive cells expressed the nuclear morphology and flow cytometric profile of NK cells. In lymphoid organs, NK cells were distributed primarily in the splenic red pulp, between adjacent lobes in lymph node and randomly in the cortex and medulla of the thymus. No NK cells were detected in normal liver sections. Two days following MCMV infection, most splenic NK cells were associated with the lymphoid follicles and marginal zone. By day 3 following infection, the number of liver NK cells had increased significantly and the cells were detected within inflammatory foci. These changes were independent of IL-12, IFN-gamma, and TNF-alpha, as assessed in mice with targeted mutations. Concurrent immunostaining for NK cells and viral Ags revealed close association of NK cells and MCMV-infected cells in the spleen and liver. Similar results were obtained in CD1(-/-) and recombination activation gene-1(-/-) mice lacking NK T or T and B cells, respectively, indicating specificity of staining for NK cells. Thus, following MCMV infection, NK cells accumulate at sites of viral replication in an IL-12-, IFN-gamma-, and TNF-alpha-independent manner.

Specific and nonspecific NK cell activation during virus infection.

The natural killer (NK) cell activation receptor Ly49H is required for resistance to murine cytomegalovirus (MCMV). We show here that NK cell proliferation and production of interferon-gamma (IFN-gamma) was not dependent on Ly49H expression during early MCMV infection. During a later phase of infection, however, Ly49H+ NK cells selectively proliferated and this expansion was blocked by anti-Ly49H administration. With vaccinia virus infection, neither the early nor late phase of NK cell proliferation was selective for Ly49H+ NK cells. These findings indicated that Ly49H+ NK cells were specifically activated by MCMV and that MCMV infection was characterized by nonspecific and specific phases of NK cell activation in vivo.

Synthesis of 14,15-dehydroerythromycin A ketolides: effects of the 13-substituent on erythromycin tautomerism.

A ketolide was prepared from 14,15-dehydroerythromycin A by two different routes. The first approach involving oxidation of the 3-OH of 3-descladinosyl-14,15-dehydroerythromycin A 2'-O-acetate gave unexpectedly high levels of 3,11-double oxidation. This may be due to greater formation of the 9,12-hemiketal in 14,15-dehydroerythromycin A and concomitant exposure of the 11-OH group for oxidation. NMR studies of 14,15-dehydroerythromycin A support this hypothesis, revealing a 9:1 ratio of 9-ketone to 9,12-hemiketal in CDCl3 and a 1:1 ratio in CD3OD as contrasted with the corresponding tautomer ratios of 30:1 in CDCl3, and 6: 1 in CD3OD with erythromycin A. Alteration of the 13-substituent on the erythronolide A ring from ethyl to vinyl thus favors formation of the 9,12-hemiketal. A second route to the ketolides was developed based on these findings, in which the 11-OH is eliminated prior to oxidation of the 3-OH.

Synthesis of 2-fluoro-6-O-propargyl-11,12-carbamate ketolides. A novel class of antibiotics.

A novel class of 2-fluoro-6-O-propargyl-11,12-carbamate ketolide derivatives of erythromycin has been synthesized for antibacterial SAR studies. Replacement of the C2-hydrogen by a fluorine atom allows the synthesis of 6-O-propargylic ketones and electron-deficient 6-O-propargylic aromatic derivatives by preventing intramolecular C2-enolate Michael cyclization.

Inducible expression of the gp49B inhibitory receptor on NK cells.

Murine NK cells express inhibitory receptors belonging to the C-type lectin-like (Ly-49, CD94/NKG2) and Ig superfamily-related (gp49) receptors. The murine gp49B receptor displays structural homology with human killer inhibitory receptors, and was previously identified to be a receptor on mast cells and activated NK cells. The gp49B receptor is highly related to gp49A, a receptor with unknown function. In this study, using a novel mAb produced against soluble gp49B molecules that cross-reacts with gp49A, we examined the cellular distribution and function of these receptors. gp49 is constitutively expressed on cells of the myeloid lineage throughout development, as well as on mature cells. Importantly, gp49 is not expressed on spleen- and liver-derived lymphocytes, including NK cells, but its expression is induced in vitro on NK cells following IL-2 stimulation, or in vivo by infection with murine CMV. Molecular studies revealed that both the immunoreceptor tyrosine-based inhibitory motif-containing gp49B as well as immunoreceptor tyrosine-based inhibitory motif-less gp49A receptors are up-regulated on NK cells following murine CMV infection. When co-cross-linked with NK1.1, gp49B can inhibit NK1.1-mediated cytokine release by NK cells. Taken together, these studies demonstrate that the expression of gp49B on NK cells is regulated, providing the first example of an in vivo activation-induced NK cell inhibitory receptor, in contrast to the constitutively expressed Ly49 family.

Synthesis and antibacterial activity of novel 6-O-substituted erythromycin A derivatives.

A series of novel 6-O-substituted erythromycin A derivatives has been synthesized. Good in vitro antibacterial activity has been demonstrated for analogues incorporating a variety of structural features. The methodology disclosed is expected to find application in the design of future macrolide antibiotics that target the prevalent bacterial resistance problem.

Recent progress in novel macrolides, quinolones, and 2-pyridones to overcome bacterial resistance.

Macrolides, such as clarithromycin and azithromycin, having good activity against pathogens such as Legionella, Chlamydia, Campylobacter spp, Branhamella spp, Pasteurella multocida and streptococci, have gained wide acceptance for the treatment of both upper and lower respiratory tracts, as well as cutaneous infections. Emergence of bacterial resistance, particularly in gram-positive bacteria, has been observed. Macrolide-resistant Streptococcus pneumoniae and S. pyogenes are found in France and many other countries, resulting in failure of therapy for pneumonia, pharyngitis, and skin infection. RU 004, HMR 3647, and TE 802 were reported to be active against these resistant strains. Research at Abbott produced several macrolide derivatives in the anhydrolide, tricyclic and tetracyclic ketolides as well as 6-O-alkyl ketolides series having potent activity against macrolide resistant S. pyogenes and S. pneumoniae. Research on streptogramins to overcome bacterial resistance in gram-positive bacteria has produced interesting compounds. Another class of antibacterial agent called quinolones is useful for the treatment of bacterial infections of respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Ciprofloxacin, the market leader, however, has low potency against anaerobes. Bacterial resistance ( such as Pseudomonas aeruginosa and methicillin- resistant Staphylococcus aureus ) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesized to address these drawbacks. The new quinolones currently under development are characterized by enhanced activities against streptococci, staphylococci, enterococci, and anaerobes. This presentation reviews the current research in the identification of agents to overcome the macrolide and quinolone resistance.

Recent developments in macrolides and ketolides.

Emergence of bacterial resistance to macrolide antibiotics, particularly in Gram-positive bacteria, has been observed. Novel macrolides having C-4" carbamate functional groups and ketolides, the 3-keto derivatives of macrolides, have been found to have activities against macrolide-resistant strains. Several potential non-antibacterial activities of macrolides have been reported, such as inhibition of cytokine production, neutrophil attachment to human bronchial epithelial cells and vesicular transport.

Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: consequences of structural modification at the C-8 position.

The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MRSA. Preliminary studies indicated that oxoquinolizines possess distinct activity and toxicity profiles as compared with their parent quinolones. In order to develop a potent antibacterial agent with the desired spectrum of activity, good tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of oxoquinolizines with various substituents at the C-8 position. Most compounds tested in this study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S. aureus. While maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over ABT-719 as indicated by the mouse protection test. As an example, the oral ED(50) values for the cis-3-amino-4-methylpiperidine analogue 3ss against S. aureus NCTC 10649M, S. pneumoniae ATCC 6303, and E. coli JUHL were 0. 8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and 8.3 mg/kg for ABT-719. The current study revealed that the steric and electronic environment, conformation, and absolute stereochemistry of the C-8 group are very important to the antibacterial profiles. Structural modifications of the C-8 group provide a useful means to improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles. Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum of activity, such as analogues that are selective against respiratory pathogens.

Anhydrolide macrolides. 1. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbamate erythromycin A analogues.

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as improved activity compared to erythromycin A against the inducibly MLS (macrolide, lincosamide, and streptogramin B)-resistant organisms. Structure-activity studies revealed that arylalkyl carbamates with two and four carbon atoms between the aromatic moiety and carbamate nitrogen have the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacterial activity against the constitutively resistant S.aureus A-5278, S. pneumoniae5979, and S.pyogenes 930. However, despite potent in vitro activity, these analogues showed only moderate in vivo activity in mouse protection studies.

Anhydrolide macrolides. 2. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbazate erythromycin A analogues.

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcuspneumoniae ATCC6303. These compounds were also very active against some organisms that show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649). The compounds generally showed poor activity against organisms with constitutive MLS resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were more active than clarithromycin against S. pneumoniae ATCC6303.

Synthesis and structure-activity relationships of 2-pyridones: II. 8-(Fluoro-substituted pyrrolidinyl)-2-pyridones as antibacterial agents.

The 8-position side chain of 2-pyridones is believed to be involved in the binding with bacterial DNA gyrase to form the ternary complex, making them very important for the activity of 2-pyridones. A series of 2-pyridones having fluoro-substituted amines at the 8-position has been synthesized and their antibacterial activities and parmacokinetic properties are reported.