The Drosophila Medea gene is required downstream of dpp and encodes a functional homolog of human Smad4

The Transforming Growth Factor-beta superfamily member decapentaplegic (dpp) acts as an extracellular morphogen to pattern the embryonic ectoderm of the Drosophila embryo. To identify components of the dpp signaling pathway, we screened for mutations that act as dominant maternal enhancers of a weak allele of the dpp target gene zerkn?llt. In this screen, we recovered new alleles of the Mothers against dpp (Mad) and Medea genes. Phenotypic analysis of the new Medea mutations indicates that Medea, like Mad, is required for both embryonic and imaginal disc patterning. Genetic analysis suggests that Medea may have two independently mutable functions in patterning the embryonic ectoderm. Complete elimination of maternal and zygotic Medea activity in the early embryo results in a ventralized phenotype identical to that of null dpp mutants, indicating that Medea is required for all dpp-dependent signaling in embryonic dorsal-ventral patterning. Injection of mRNAs encoding DPP or a constitutively activated form of the DPP receptor, Thick veins, into embryos lacking all Medea activity failed to induce formation of any dorsal cell fates, demonstrating that Medea acts downstream of the thick veins receptor. We cloned Medea and found that it encodes a protein with striking sequence similarity to human SMAD4. Moreover, injection of human SMAD4 mRNA into embryos lacking all Medea activity conferred phenotypic rescue of the dorsal-ventral pattern, demonstrating conservation of function between the two gene products.     

The past, present, and future of the prevention of lung cancer

The article relates details of the history of research into the causal association of cigarette smoking and lung cancer on the basis of multidisciplinary studies that have explored the epidemiology, biology, chemistry, and biochemistry of tobacco carcinogenesis and research in behavioral sciences and health education that has sought to address one of our nation's foremost public health problems. Recalling past and present challenges and achievements in all of these areas, the author then outlines his vision for addressing this health problem in the future. This is laid out for various segments of the research community and for society as a whole, i.e., Cancer Centers and hospitals, epidemiologists, laboratory scientists, legislators, educators and behavioral scientists, and the media. It is proposed that for the current policy initiatives in tobacco-related cancer control to succeed, there needs to be a focus on preventing the initiation of tobacco use among children and adolescents. All segments of society can help to achieve this goal. In the nation's research planning, there needs to be a proper balance between basic and applied research, including research on and application of preventive principles, because cancer need not be an inevitable consequence of aging but is largely preventable.     

Runt determines cell fates in the Drosophila embryonic CNS

BACKGROUND AND PURPOSE: Our purpose was to evaluate the ability of transcranial color-coded Doppler sonography (TCCD) to 1) identify Guglielmi detachable coils (GDCs) within intracranial aneurysms, 2) show endovascular aneurysmal occlusion and patency of parent and branch arteries, 3) determine the flow velocities within parent arteries and major branches before and after treatment, and 4) assess persistence of aneurysmal occlusion. METHODS: The sonographic appearance of GDCs was established experimentally by TCCD (2 to 2.5 MHz), which was then performed in 40 patients with 43 aneurysms occluded by GDCs. The patency of parent arteries and major branches was assessed qualitatively and compared with the immediate posttherapeutic angiographic appearance in every patient. Flow velocities were selectively measured and compared before and after treatment in 21 parent arteries and 24 major branches. Follow-up TCCD studies performed in 26 patients were compared with angiographic (16 cases) and MR angiographic (10 cases) findings for signs of recanalization of the treated aneurysms. RESULTS: The GDCs were identified experimentally and in the patients as hyperechoic structures of the size and shape, and in the location of, the treated aneurysm in 41 of 43 cases. TCCD in accordance with angiography showed a lack of flow in 42 aneurysms and the presence of flow signal in one large aneurysm. Patency of the parent artery was shown in 40 aneurysms and in all branches. Follow-up TCCD showed the coils unchanged in 23 of 26 cases. In three large aneurysms, TCCD indicated recanalization and reappearance of a flow signal separate from the parent artery. CONCLUSION: TCCD is a reliable, noninvasive means to assess parent artery and major branch patency and to reveal a lack of hemodynamic compromise in the vicinity of aneurysms after endovascular therapy. On follow-up examinations, TCCD was able to detect signs of aneurysmal recanalization.     

Tendon interposition in a juxta-epiphyseal fracture of the proximal phalanx

PURPOSE: To report the clinicopathologic features of intraocular osseous production in association with proliferative vitreoretinopathy. METHOD: The clinical and histopathologic features of two patients with proliferative vitreoretinopathy and intraocular bone formation are reviewed. RESULTS: Preretinal osseous tissue incorporated in the proliferative vitreoretinopathy was surgically removed in one patient, and osseous tissue was present in the proliferative vitreoretinopathy in the enucleated eye of the other patient. CONCLUSIONS: Bone formation, presumably from metaplastic retinal pigment epithelium, may be present in proliferative vitreoretinopathy tissue. The intraocular bone is present internal rather than external to the neurosensory retina.     

New beginnings: the National Blood Data Resource Center

A case of pulmonary Mycobacterium avium (M. avium) disease associated with idiopathic CD4+ T lymphocytopenia is reported. A rapidly growing pulmonary nodule was detected on a chest roentgenogram in a young man. Bronchoscopic examination revealed M. avium infection. Hematological studies showed a low CD4+ cell count in the absence of any identifiable immunodeficiency, including human immunodeficiency virus (HIV) infection. With the combination of chemotherapy and surgery, he had a good clinical outcome. Idiopathic CD4+ T lymphocytopenia should be considered in patients with unexplained opportunistic infection.     

Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.     

Mucosal immunity to herpes simplex virus type 2 infection in the mouse vagina is impaired by in vivo depletion of T lymphocytes

Intravaginal (IVAG) inoculation of wild-type herpes simplex virus type 2 (HSV-2) in mice causes epithelial infection followed by lethal neurological illness, while IVAG inoculation of attenuated HSV-2 causes epithelial infection followed by development of protective immunity against subsequent IVAG challenge with wild-type virus. The role of T cells in this immunity was studied by in vivo depletion of these cells with monoclonal antibodies. Three groups of mice were used for each experiment: nonimmune/challenged mice, immune/challenged mice, and immune depleted mice [immune mice depleted of a T-cell subset(s) shortly before challenge with HSV-2]. Mice were assessed for epithelial infection 24 h after challenge, virus protein in the vaginal lumen 3 days after challenge, and neurological illness 8 to 14 days after challenge. Monoclonal antibodies to CD4, CD8, or Thy-1 markedly reduced T cells in blood, spleen, and vagina, but major histocompatibility complex class II antigens were still partially upregulated in the vaginal epithelium after virus challenge, indicating that virus-specific memory T-cell function was not entirely eliminated from the vagina. Nevertheless, immune mice depleted of CD4+ and CD8+ T cells, Thy-1+ T cells, or CD8+ T cells alone had greater viral infection in the vaginal epithelium than nondepleted immune mice, indicating that T cells contribute to immunity against vaginal HSV-2 infection. All immune depleted mice retained substantial immunity to epithelial infection and were immune to neurological illness, suggesting that other immune mechanisms such as virus-specific antibody may also contribute to immunity.     

Effects of pulsed ultrasound on the frog heart: III. The radiation force mechanism

Earlier studies have shown that a single, millisecond duration pulse of ultrasound delivered to the frog heart in vivo during systole can produce a reduction in the developed aortic pressure, while a pulse delivered during diastole can produce a premature ventricular contraction. The threshold for these effects is 5-10 MPa with a 5-ms pulse. Since cardiac tissues respond to mechanical stimulation, the objective of this study was to investigate acoustic radiation force as a possible mechanism for the observed effects of ultrasound on the frog heart. In two experiments, the radiation force exerted on the heart was varied by varying the ultrasonic frequency and the acoustic beam width. Results of these studies indicated that the rate of occurrence of the reduced aortic pressure effect was directly correlated with the magnitude of the radiation force exerted on the heart. A third experiment tested the radiation force mechanism directly by placing an acoustic reflector on the frog heart. The acoustic reflector maximized the radiation force delivered to the heart, but eliminated direct interaction of the ultrasound with the heart and experimentally eliminated heating and cavitation as mechanisms of action. The reduced aortic pressure effect was observed with the reflector on the heart, indicating that radiation force is capable of producing this effect. No premature ventricular contractions were observed with the acoustic reflector over the heart, suggesting that another property of the exposure may be responsible for this bioeffect.