ABSTRACT
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with precursor B-cell ALL (pB-ALL) accounting for ~ 85% of the cases. Childhood pB-ALL development is influenced by genetic susceptibility and host immune responses. The role of the intestinal microbiome in leukemogenesis is gaining increasing attention since Vicente-Dueñas' seminal work demonstrated that the gut microbiome is distinct in mice genetically predisposed to ALL and that the alteration of this microbiome by antibiotics is able to trigger pB-ALL in Pax5 heterozygous mice in the absence of infectious stimuli. In this review we provide an overview on novel insights on the role of the microbiome in normal and preleukemic hematopoiesis, inflammation, the effect of dysbiosis on hematopoietic stem cells and the emerging importance of the innate immune responses in the conversion from preleukemic to leukemic state in childhood ALL. Since antibiotics, which represent one of the most widely used medical interventions, alter the gut microbial composition and can cause a state of dysbiosis, this raises exciting epidemiological questions regarding the implications for antibiotic use in early life, especially in infants with a a preleukemic "first hit". Sheading light through a rigorous study on this piece of the puzzle may have broad implications for clinical practice.
ABSTRACT
BACKGROUND: The number of live births in Germany has decreased by 46.7 % from 1 261 614 in 1960 to 672 675 in 2006. The causes for this are manifold. This study attempts to address the possible causes for the delay of birth in Germany in an east-west comparison. METHOD: Within the "Kinderwunschstudie" (survey of desired/intended fertility) 5 143 women in childbed have been interviewed between 1998 and 2000. They were asked questions concerning the delay of this particular birth. Only women and their spouses who were born in Germany, respectively, were included into the analysis. Berlin women in childbed were excluded from the analysis due to the problematic east-west classification. The number of analysable cases finally added up to 2 020 cases in East Germany and 2 193 cases in West Germany. RESULTS: 24.4 % of the interviewed women in the East admitted a delay of the last birth compared to 21.2 % of those in the West. There are clear differences concerning the reasons for this delay between the old (west) and the new (east) federal states. 34 % of the east German women agreed that an insecure income situation was the reason for the delayed realisation of the desired pregnancy / birth, whereas it was only 16 % in the west. CONCLUSION: This survey ("Kinderwunschstudie") in fact indicates differences regarding the reasons for a delay of birth between east and west German women (in childbed). However, it also highlights the generally negative influence of the given social and economic conditions on the number of births and underlines the prospects for an ongoing decrease. As a result, society will in future have to face problems of unknown dimensions.
Subject(s)
Birth Intervals , Reproductive Behavior/psychology , Social Change , Social Environment , Surveys and Questionnaires , Adult , Birth Rate , Female , Germany , Health Surveys , Humans , Illegitimacy/psychology , Illegitimacy/statistics & numerical data , Infant, Newborn , Maternal Age , Pregnancy , Reproductive Behavior/statistics & numerical data , Single Parent/psychology , Single Parent/statistics & numerical data , Socioeconomic FactorsABSTRACT
A regioisomeric set of 2-naphthylcarbapenems featuring cationic substituents was synthesized. Optimal placement of the cationic group was found to markedly improve activity against methicillin-resistant staphylococci while maintaining a good spectrum of gram-negative activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Carbapenems/chemical synthesis , Methicillin Resistance , Naphthalenes/chemical synthesis , Staphylococcus/drug effects , Anti-Bacterial Agents/pharmacology , Carbapenems/pharmacology , Dipeptidases/metabolism , Molecular Structure , Naphthalenes/pharmacologyABSTRACT
The synthesis of 1 beta-methylcarbapenems having a ROCH2 substituent at the 2-position is described. Their in vitro antibacterial activity and DHP-I susceptibilities are presented.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Structure-Activity Relationship , beta-LactamsABSTRACT
The labile tert-butyldimethylsilyl esters of the azetidinones 6-8b served as the crucial synthons in the preparation of the potentially useful ylide pyridyl thio esters 18-20. These intermediates were utilized to synthesize a host of title carbapenems 25-30d, 32, and 49-53. The antimicrobial properties and DHP-I susceptibility of these carbapenems were studied with reference to thienamycin.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Anti-Bacterial Agents/chemical synthesis , Chemical Phenomena , Chemistry , Structure-Activity Relationship , Thienamycins/pharmacologyABSTRACT
A versatile stereocontrolled total synthesis of thienamycin starting from L-aspartic acid is reported. Stereocontrol is achieved by potassium tri-sec-butylborohydride reduction of a thermodynamically formed 3 alpha-acetylazetidinone intermediate. The key [3.2.0] bicyclic ring system is prepared by a metal catalyzed carbene insertion reaction.
