Cell cycle checkpoints and DNA repair preserve the stability of the human genome

Summary Chemical carcinogenesis in the regenerating rat liver is cell-cycle-dependent. Proliferating hepatocytes were maximally susceptible to initiation by a single dose of benzo[a]pyrene diolepoxide I when at the G1/S border. Hepatocytes in early G1 or late S/G2/M were less susceptible and non-proliferating G0 hepatocytes were resistant to initiation. Radiation clastogenesis in proliferating human fibroblasts also is cell-cycle-dependent. Ultraviolet radiation (UV) induced maximal frequencies of chromosomal aberrations in synchronized cells that were at the G1/S border. Cells in early G1 or G2 were significantly less sensitive. For both initiation of chemical carcinogenesis and UV-clastogenesis, it appears that replication of damaged DNA is required and DNA repair before replication reduces cellular risk. If DNA repair is protective, cell cycle checkpoints which delay DNA replication and mitosis should augment this protective influence by providing more time for repair. The contribution of cell cycle checkpoint function to DNA repair during cell cycle-dependent clastogenesis was studied using ataxia telangiectasia (AT) fibroblasts. The AT cells displayed a defect in the coupling of DNA damage to checkpoints which control the G1/S and G2/M transitions and the rate of replicon initiation in S phase cells. UV-clastogenesis in AT cells was cell-cycle-dependent with irradiation at the G1/S boundary inducing 3-times more aberrations than treatment in G0 at the time of release into the cell cycle. Thus, DNA excision repair during the pre-replicative G1 phase was protective even in cells with defective checkpoint function. However, following irradiation at the G1/S border, AT cells displayed about 6-fold increased levels of UV-induced chromosome aberrations in comparison to normal human fibroblasts that were treated at this time. These observations indicate that secondary and tertiary DNA lesions that are produced during replication of UV-damaged DNA (replicative gaps and double-strand breaks) also depend on checkpoint function for repair. The replicon initiation and G2-delay checkpoints that operate after initiation of S phase appear to play a major role in protection against UV-clastogenesis.DNA is, in fact, so precious and so fragile that we now know that the cell has evolved a whole variety of repair mechanisms to protect its DNA from assaults by radiation, chemicals, and other hazards. This is exactly the sort of thing that the process of evolution by natural selection would lead us to expect. Francis Crick inWhat Mad Pursuit     

Disturbances of binocular vision in macular heterotopia]

BACKGROUND: Tractive translocation of the macula (secondary macular heterotopia) may result in disturbance of binocular vision. The report of a case shall discuss the sensorial problems of these patients. HISTORY AND SIGNS: We report of a 40-years old male who had decreased visual acuity and loss of binocular vision for several years due to episodes of uveitis with intravitreous hemorrhage and cataract formation. After bilateral vitrectomy and cataract extraction a good visual acuity was restored in both eyes. Postoperatively, the patient monocularly complained about disturbed egocentric localization (tilting of the visual environment, "past-pointing") and metamorphopsia. Binocularly he was confused by doubled vision with tilted images. Both maculae showed a tractive translocation of 15 degrees downward. Measurements of binocular alignment with the tangent screen showed an excyclotropia of 8 degrees and an exotropia of 7 degrees in all directions of gaze. Haploscopic examination with fusion images demonstrated that sensorial fusion was not possible even with perfect ocular alignment due to disturbed relative retinal localization (obligate fixation disparity). THERAPY AND OUTCOME: Initially, full time occlusion of the left eye was required. After improvement of symptoms occlusion therapy was slowly tapered. Within one year the patient had learned to suppress the image of his left eye and reported only minor residual visual disturbances even without occlusion of his left eye. CONCLUSIONS: Secondary translocation of the macula monocularly results in a disturbance of egocentric localization and in metamorphopsia. Binocularly doubled vision with tilted images and a loss of sensorial fusion are seen. With monocular vision, perceptual adapting to the aberration in egocentric localisation is possible within weeks by reallocation of the retinal meridians in the central nervous system. Binocular improvement of symptoms is limited to the learning of suppression. Improvement of binocular symptoms by adaptation of retinal correspondence does not occur.     

Lymphomatoid papulosis: case report of a patient managed with radiation therapy and review of the literature.

Lymphomatoid papulosis is an elusive and very rare skin disorder. It is clinically benign but histologically "atypical," and about 20% of affected patients go on to develop a lymphoreticular malignancy, usually Hodgkin's disease, or mycosis fungoides. A wide variety of treatments to prevent recurrence and improve local control have been suggested, but the results have been poor. We report on a patient with two nonhealing lymphomatoid papulosis lesions treated successfully with electron beam therapy and describe our technique. The need for close follow-up of all patients with this condition cannot be overemphasized.     

Atypical organisation of the auditory cortex in dyslexia as revealed by MEG

Neuroanatomical and -radiological studies have converged to suggest an atypical organisation in the temporal bank of the left-hemispheric Sylvian fissure for dyslexia. Against the background of this finding, we applied high temporal resolution magnetoencephalography (MEG) to investigate functional aspects of the left-hemispheric auditory cortex in 11 right-handed dyslexic children (aged 8–13 years) and nine matched normal subjects (aged 8–14 years). Event-related field components during a passive oddball paradigm with pure tones and consonant–vowel syllables were evaluated. The first major peak of the auditory evoked response, the M80, showed identical topographical distributions in both groups. In contrast, the generating brain structures of the later M210 component were located more anterior to the earlier response in children with dyslexia only. Control children exhibited the expected activation of more posterior source locations of the component that appeared later in the processing stream. Since the group difference in the relative location of the M210 source seemed to be independent of stimulus category, it is concluded that dyslexics and normally literate children differ as to the organisation of their left-hemispheric auditory cortex.     

Ätiologie und Pathogenese des Zervixkarzinoms

Epidemiological studies have confirmed that human papillomaviruses (HPV) play a causal role in cervical carcinogenesis. Cervical cancer is considered to be the rare consequence of a persistent infection with so called high-risk (HR)-HPV types. The most common HR-HPV types are HPV16, 18, 31, 33 and 45, the DNA of which can be detected in about 80% of cervical cancers. A constitutive strong expression of the viral oncogenes E6 and E7 is a decisive step for the transformation to malignancy. These proteins deregulate cell proliferation and induce genetic instability, promoting the accumulation of mutations which are crucial for the acquisition of phenotypic properties such as invasive growth, angiogenesis and metastasis. Several cofactors which support HPV infection or prevent its elimination, as well as factors which act independently of HPV, also contribute to carcinogenesis.     

Respiratory syncytial virus genotypes and disease severity among children in hospital

OBJECTIVES: To determine the spectrum of N and G genotypes of respiratory syncytial virus (RSV) causing respiratory tract infection and whether particular genotypes are associated with severity of infection. PATIENTS AND METHODS: Nasopharyngeal aspirates (NPAs) were obtained from 114 infants with acute respiratory tract infection due to RSV over two seasons. Viral mRNA was extracted from NPAs or cultured virus, reverse transcribed, and the cDNA amplified by the polymerase chain reaction using primers directed to parts of the N and G gene respectively. Amplicons were separately digested with four different restriction endonucleases for each gene. The fragments were separated by agarose gel, electrophoresis, and the electrophoretic patterns used to assign the various genotypes. Disease severity was assessed as very mild (upper respiratory tract signs only), mild (coryza and signs of lower respiratory tract infection), moderate (requiring nasogastric or intravenous fluids), and severe (requiring oxygen or ventilation). RESULTS: Five of the six known N genotypes were detected, but NP4 and NP2 were found most frequently. There was no association between N genotype and disease severity. Six G (SHL) genotypes were detected. Significantly (p = 0.04) more of the infants infected with the SHL2 genotype had severe or moderate disease. CONCLUSIONS: During the seasonal peaks of RSV respiratory tract infection at least 10 different RSV genotypes cocirculated. While there is no association between N genotypes and disease severity, infection with the SHL2 G genotype appears to result in moderate to severe disease.