Structural recovery in lesioned adult mammalian spinal cord by x-irradiation of the lesion site.

Mechanical injury to the adult mammalian spinal cord results in permanent morphological disintegration including severance/laceration of brain-cord axons at the lesion site. We report here that some of the structural consequences of injury can be averted by altering the cellular components of the lesion site with x-irradiation. We observed that localized irradiation of the unilaterally transected adult rat spinal cord when delivered during a defined time-window (third week) postinjury prevented cavitation, enabled establishment of structural integrity, and resulted in regrowth of severed corticospinal axons through the lesion site and into the distal stump. In addition, we examined the natural course of degeneration and cavitation at the site of lesion with time after injury, noting that through the third week postinjury recovery processes are in progress and only at the fourth week do the destructive processes take over. Our data suggest that the adult mammalian spinal cord has innate mechanisms required for recovery from injury and that timed intervention in certain cellular events by x-irradiation prevents the onset of degeneration and thus enables structural regenerative processes to proceed unhindered. We postulate that a radiation-sensitive subgroup of cells triggers the delayed degenerative processes. The identity of these intrusive cells and the mechanisms for triggering tissue degeneration are still unknown.

Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice.

We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow- and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-beta-estradiol pellets releasing either 6, 14, or 28 micrograms/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-alpha-estradiol (28 micrograms/day) or tamoxifen (85 micrograms/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-beta-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels.

Differential replication of a single, UV-induced lesion in the leading or lagging strand by a human cell extract: fork uncoupling or gap formation.

We have constructed simian virus 40 minireplicons containing uniquely placed cis,syn-thymine dimers (T <> T) for the analysis of leading- and lagging-strand bypass replication. Assaying for replication in a human cell-free extract through the analysis of full-size labeled product molecules and restriction fragments spanning the T <> T site resulted in the following findings: (i) The primary site of synthesis blockage with T <> T in either the leading or lagging strand was one nucleotide before the lesion. (ii) Replicative bypass of T <> T was detected in both leading and lagging strands. The efficiency of synthesis past T <> T was 22% for leading-strand T <> T and 13% for lagging-strand T <> T. (iii) The lagging-strand T <> T resulted in blocked retrograde synthesis with the replication fork proceeding past the lesion, resulting in daughter molecules containing small gaps (form II' DNA). (iv) With T <> T in the leading-strand template, both the leading and lagging strands were blocked, representing a stalled replication fork. Uncoupling of the concerted synthesis of the two strands of the replication fork was observed, resulting in preferential elongation of the undamaged lagging strand. These data support a model of selective reinitiation downstream from the lesion on lagging strands due to Okazaki synthesis, with no reinitiation close to the damage site on leading strands [Meneghini, R. & Hanawalt, P.C. (1976) Biochim. Biophys. Acta 425, 428-437].

Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion.

Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor beta 3 (TGF-beta 3) are members of the TGF-beta superfamily with high neurotrophic activity on cultured nigral dopamine neurons. We investigated the effects of intracerebral administration of GDNF and TGF-beta 3 on the delayed cell death of the dopamine neurons in the rat substantia nigra following 6-hydroxydopamine lesions of dopaminergic terminals in the striatum. Fluorescent retrograde tracer injections and tyrosine hydroxylase immunocytochemistry demonstrated nigral degeneration with an onset 1 week after lesion, leading to extensive death of nigral neurons 4 weeks postlesion. Administration of recombinant human GDNF for 4 weeks over the substantia nigra at a cumulative dose of 140 micrograms, starting on the day of lesion, completely prevented nigral cell death and atrophy, while a single injection of 10 micrograms 1 week postlesion had a partially protective effect. Continuous administration of TGF-beta 3, starting on the day of lesion surgery, did not affect nigral cell death or atrophy. These findings support the notion that GDNF, but not TGF-beta 3, is a potent neurotrophic factor for nigral dopamine neurons in vivo.

Enteropathogenic Escherichia coli contains a putative type III secretion system necessary for the export of proteins involved in attaching and effacing lesion formation.

Enteropathogenic Escherichia coli (EPEC) causes a characteristic histopathology in intestinal epithelial cells called the attaching and effacing lesion. Although the histopathological lesion is well described the bacterial factors responsible for it are poorly characterized. We have identified four EPEC chromosomal genes whose predicted protein sequences are similar to components of a recently described secretory pathway (type III) responsible for exporting proteins lacking a typical signal sequence. We have designated the genes sepA, sepB, sepC, and sepD (sep, for secretion of E. coli proteins). The predicted Sep polypeptides are similar to the Lcr (low calcium response) and Ysc (yersinia secretion) proteins of Yersinia species and the Mxi (membrane expression of invasion plasmid antigens) and Spa (surface presentation of antigens) regions of Shigella flexneri. Culture supernatants of EPEC strain E2348/69 contain several polypeptides ranging in size from 110 kDa to 19 kDa. Proteins of comparable size were recognized by human convalescent serum from a volunteer experimentally infected with strain E2348/69. A sepB mutant of EPEC secreted only the 110-kDa polypeptide and was defective in the formation of attaching and effacing lesions and protein-tyrosine phosphorylation in tissue culture cells. These phenotypes were restored upon complementation with a plasmid carrying an intact sepB gene. These data suggest that the EPEC Sep proteins are components of a type III secretory apparatus necessary for the export of virulence determinants.

Lesion-induced reorganization in the brainstem is not completely expressed in somatosensory cortex.

Electrophysiological and neuroanatomical methods were used to determine the extent to which neonatal forelimb removal altered the organization of the cuneate nucleus and representations of the fore- and hindlimbs in the primary somatosensory cortex of adult rats. Neonatal forelimb removal resulted in invasion of the cuneate nucleus by sciatic nerve primary afferents and development of cuneothalamic projection neurons with split receptive fields that included both the hindlimb and forelimb stump. Mapping in the primary somatosensory cortex of the neonatally manipulated adult rats demonstrated abnormalities, but the major change observed in the cuneate nucleus was demonstrable at only a few (5%) cortical recording sites in the remaining stump representation and there were none at all in the hindlimb representation. These results suggest that lesion-induced brainstem reorganization may be functionally suppressed at either the thalamic or cortical level.

Better Lesion Creation And Assessment During Catheter Ablation

Permanent destruction of abnormal cardiac tissue responsible for cardiac arrhythmogenesis whilst avoiding collateral tissue injury forms the cornerstone of catheter ablation therapy. As the acceptance and performance of catheter ablation increases worldwide, limitations in current technology are becoming increasingly apparent in the treatment of complex arrhythmias such as atrial fibrillation. This review will discuss the role of new technologies aimed to improve lesion formation with the ultimate goal of improving arrhythmia-free survival of patients undergoing catheter ablation of atrial arrhythmias.

Conservative endodontic management of teeth associated with extensive periapical pathology: report of two cases

Traditionally, long-term calcium hydroxide dressings have been recommended for the conservative management of large periapical lesions. However, calcium hydroxide therapy has some disadvantages such as variability of treatment time, difficulties with patient follow-up and prolonged treatment periods that increase the risk of root canal contamination via microleakage and crown fractures. This paper reports the healing of large periapical lesions following conservative non-surgical treatment with calcium hydroxide dressings.

Genetic analysis of resistance to root-lesion nematode (Pratylenchus thornei) in wheat

The inheritance of resistance to root-lesion nematode was investigated in five synthetic hexaploid wheat lines and two bread wheat lines using a half-diallel design of F-1 and F-2 crosses. The combining ability of resistance genes in the synthetic hexaploid wheat lines was compared with the performance of the bread wheat line 'GS50a', the source of resistance to Pratylenchus thornei used in Australian wheat breeding programmes. Replicated glasshouse trials identified P. thornei resistance as polygenic and additive in gene action. General combining ability (GCA) of the parents was more important than specific combining ability (SCA) effects in the inheritance of P. thornei resistance in both F-1 and F-2 populations. The synthetic hexaploid wheat line 'CPI133872' was identified as the best general combiner, however, all five synthetic hexaploid wheat lines possessed better GCA than 'GS50a'. The synthetic hexaploid wheat lines contain novel sources of P. thornei resistance that will provide alternative and more effective sources of resistance to be utilized in wheat breeding programmes.

A longitudinal controlled study of factors associated with mutans streptococci infection and caries lesion initiation in children 21 to 72 months old

Purpose: The purpose of this longitudinal study was to determine factors associated with mutans streptococci (MS) infection and development of caries lesions in a group of children 21 to 72 months old. Methods: The 63 caries-free children, recruited since birth, were divided into: (1) a study group of 24 children who were colonized with MS; and (2) a control group of 39 children without MS. The children were recalled every 3 months for approximately 24 months, and their social, medical, and dental histories were updated. At each recall, the teeth were checked for presence or absence of plaque, enamel hypoplasia, and caries lesions, and their MS status was assessed using a commercial test kit. Results: MS infection was associated with: (1) visible plaque (P < .01); (2) enamel hypoplasia (P < .05); (3) commencement of tooth-brushing after 12 months of age (P < .05); (4) lack of parental assistance with tooth-brushing (P < .025); and (5) increased hours of child care/school (P < .05). Four children (20%) were colonized at an age range of 21 to 36 months, 9 (45%) at 37 to 48 months, and 7 (35%) at 49 to 72 months (P < .001). Eight children who developed caries lesions: (1) had more hypoplastic teeth (P < .001); (2) ate sugar-containing snacks (P < .05); and (3) did not brush regularly with chlorhexidine gel (P < .01) compared to those who remained free of caries lesions. Conclusions: Lack of oral hygiene, consumption of sugar-containing snacks, and enamel hypoplasia are significant factors for both MS infection and caries lesion initiation.

Deoxycytidine glyoxal:Lesion induction and evidence of repair following vitamin C supplementation in vivo

Oxidative DNA damage is postulated to be involved in carcinogenesis, and as a consequence, dietary antioxidants have received much interest. A recent report indicates that vitamin C facilitates the decomposition of hydroperoxides in vitro, generating reactive aldehydes. We present evidence for the in vivo generation of glyoxal, an established product of lipid peroxidation, glucose/ascorbate autoxidation, or free radical attack of deoxyribose, following supplementation of volunteers with 400 mg/d vitamin C. Utilizing a monoclonal antibody to a deoxycytidine-glyoxal adduct (gdC), we measured DNA lesion levels in peripheral blood mononuclear cells. Supplementation resulted in significant (p = .001) increases in gdC levels at weeks 11, 16, and 21, with corresponding increases in plasma malondialdehyde levels and, coupled with previous findings, is strongly suggestive of a pro-oxidative effect. However, continued supplementation revealed a highly significant (p = .0001) reduction in gdC levels. Simultaneous analysis of cyclobutane thymine dimers revealed no increase upon supplementation but, as with gdC, levels decreased. Although no single mechanism is identified, our data demonstrate a pro-oxidant event in the generation of reactive aldehydes following vitamin C supplementation in vivo. These results are also consistent with our hypothesis for a role of vitamin C in an adaptive/repair response and indicate that nucleotide excision repair specifically may be affected. © 2003 Elsevier Science Inc.