Genetic and evolutional mechanisms explain associated malformations--a 'G-E-M' concept

During the process of evolution, segmented structures like heart and kidneys appeared earlier than vertebral column. Single piece notochord was transformed into segmented vertebral column. Ribs followed the segmented vertebral column but preceded the fore limbs in evolution. Segmentation is the underlying principle of the body plan even in annelids and arthropods. In these animals apart from vertebral column; segmentation is obvious in other structures like kidneys and heart. Somewhere on the temporal axis of evolution--vertebral column, heart and kidneys have evolved together; and have shared the genetic control of embryological morphogenesis. Mutations or micro-evolution in homeotic--Hox--genes led to macro evolution and a sudden change in morphology, when six-legged insects diverged from crustacean-like arthropod ancestors with multiple limbs. The control of embryonic morphology has been highly conserved in evolution between vertebrates and invertebrates and Hox genes occupy a central role in the scheme of molecular control of early morphogenesis. Mutations affecting regulatory genes, including those containing homeobox sequences, have been important. Malformations and association like VACTERL can be rationally explained considering the genetic and evolutional mechanisms controlling morphogenesis.     

Interaction between sleep and the immune response in Drosophila: a role for the NFkappaB relish

STUDY OBJECTIVES: The regulation of sleep is poorly understood. While some molecules, including those involved in inflammatory/immune responses, have been implicated in the control of sleep, their role in this process remains unclear. The Drosophila model for sleep provides a powerful system to identify and test the role of sleep-relevant molecules. DESIGN: We conducted an unbiased screen for molecular candidates involved in sleep regulation by analyzing genome-wide changes in gene expression associated with sleep deprivation in Drosophila. To further examine a role of immune-related genes identified in the screen, we performed molecular assays, analysis of sleep behavior in relevant mutant and transgenic flies, and quantitative analysis of the immune response following sleep deprivation. RESULTS: A major class of genes that increased expression with sleep deprivation was that involved in the immune response. We found that immune genes were also upregulated during baseline conditions in the cyc01 sleep mutant. Since the expression of an NFkappaB, Relish, a central player in the inflammatory response, was increased with all manipulations that reduced sleep, we focused on this gene. Flies deficient in, but not lacking, Relish expression exhibited reduced levels of nighttime sleep, supporting a role for Relish in the control of sleep. This mutant phenotype was rescued by expression of a Relish transgene in fat bodies, which are the major site of inflammatory responses in Drosophila. Finally, sleep deprivation also affected the immune response, such that flies deprived of sleep for several hours were more resistant to bacterial infection than those flies not deprived of sleep. CONCLUSION: These results demonstrate a conserved interaction between sleep and the immune system. Genetic manipulation of an immune component alters sleep, and likewise, acute sleep deprivation alters the immune response.     

The antivascular action of physiotherapy ultrasound on a murine tumor: role of a microbubble contrast agent

This study investigated whether a microbubble-containing ultrasound contrast agent had a role in the antivascular action of physiotherapy ultrasound on tumor neovasculature. Ultrasound images (B-mode and contrast-enhanced power Doppler [0.02 mL Definity]) were made of 22 murine melanomas (K1735²²). The tumor was insonated (I_SATA = 1.7 W cm^–2, 1 MHz, continuous output) for 3 min and the power Doppler observations of the pre- and postinsonation tumor vascularities were analyzed. Significant reductions (p = 0.005 for analyses of color-weighted fractional area) in vascularity occurred when a contrast-enhanced power Doppler study occurred before insonation. Vascularity was unchanged in tumors without a pretherapy Doppler study. Histologic studies revealed tissue structural changes that correlated with the ultrasound findings. The underlying etiology of the interaction between the physiotherapy ultrasound beam, the microbubble-containing contrast agent and the tumor neovasculature is unknown. It was concluded that contrast agents play an important role in the antivascular effects induced by physiotherapy ultrasound. (E-mail: sehgalc@uphs.upenn.edu)     

Predicting PSA response of prostate cancer to radiation therapy with Doppler sonography

OBJECTIVE: We report a prospective investigation of the correlation between pretreatment Doppler vascular density (DVD) of the entire prostate gland and subsequent prostate-specific antigen (PSA) response following external beam radiation therapy, for patients with low- or intermediate-risk prostate cancer. This report updates a previous report (Sehgal et al., Acad Radiol 2003;10:366) with longer patient follow-up and additional quantitative and clinically relevant end points. METHODS: Before radiation therapy, we imaged 12 patients with transrectal Doppler sonography and measured the mean DVD of the prostate for each. For analysis, patients were separated into 3 groups by low, intermediate, and high DVD. The mean DVD for each group was linearly correlated with mean values for time above a PSA threshold of 1.0 ng/ml, post-therapy plateau PSA, and nadir PSA. RESULTS: We previously observed that pretreatment mean DVD had a strong inverse correlation with initial rate of post-therapy decline in PSA. With substantially longer follow-up on the same cohort of patients (median, 52 months), we now observe that pretreatment mean DVD also correlates with post-therapy nadir PSA (R = 0.94) and with time above a PSA threshold of 1.0 ng/mL (R = 0.99). CONCLUSION: The results of the current study are consistent with our earlier suggestion that pretreatment measurement of DVD of the entire prostate gland may be a clinically useful prognostic indicator in early prostate cancer treated with radiation. However, additional data from larger numbers of patients are needed to draw firm conclusions.     

Correlation between culture of Mycobacterium tuberculosis and IgG antibody to Mycobacterium tuberculosis antigen-5 in the cerebrospinal fluid of patients with tuberculous meningitis

A retrospective study was made of the correlation between culture of Mycobacterium tuberculosis and detection of IgG antibody to M. tuberculosis antigen-5 in cerebrospinal fluid (CSF) by means of an enzyme linked immunosorbent assay (ELISA). Mycobacterium tuberculosis was cultured from the CSF in 14 of 70 patients with a clinical diagnosis of tuberculous meningitis (TBM). IgG antibody to M. tuberculosis antigen-5 was demonstrated in significant titres (80–640) in all 14 culture-positive patients. Thus, positive correlation was observed between culture of M. tuberculosis and detection of IgG antibody in the CSF. As a result of this observation, the CSF from 56 culture-negative patients with a clinical diagnosis TBM was specifically investigated for the detection of IgG antibody to M. tuberculosis antigen-5 and the findings were correlated with those of culture-positive patients. The assay was positive in 34 of 56 patients, the antibody titre ranging between 80 and 640. In the CSF of 70 patients with non-tuberculous neurological diseases, the assay was negative at a dilution of 1 in 80. Thus, detection of IgG antibody to M. tuberculosis antigen-5 by indirect ELISA carried 100% specificity and 60·7 % sensitivity for a tuberculous aetiology in culture-negative patients with TBM. The results of this study suggest that indirect ELISA for IgG antibody to M. tuberculosis antigen-5 in CSF holds definite promise in diagnosis of TBM, particularly when repeated cultures of CSF are negative for M. tuberculosis.