Perinatal stress, brain inflammation and risk of autism-Review and proposal

ABSTRACT: BACKGROUND: Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism "susceptibility" genes have been identified, but "environmental" factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. DISCUSSION: We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood-brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with "allergic" or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood-brain-barrier (BBB). A number of papers have reported increased brain expression or CSF levels of proinflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Mutations of the signal-transduction molecule mTOR and its negative regulator Pten have been linked to autism, but also with proliferation and function of mast cells. SUMMARY: Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.     

Intravenous infusion for the treatment of diabetic and ischaemic non-healing pedal ulcers

Diabetic and ischaemic non-healing pedal ulcers have a tendency for chronicity and increased chances of infection, which may threaten the viability of the foot. Systemic administration of therapeutic agents may be insufficient in these cases. We have assessed the role of retrograde venous perfusion (RVP) for the treatment of nine diabetic and 10 ischaemic non-healing pedal ulcers. Agents used were soda bicarbonate, heparin, lignocaine, gentamicin and pentoxiphylline. Five of nine diabetic non-healing ulcers showed complete healing and the remaining four improved. The complete recovery in the cases of diabetic ulcer occurred in 10-24 days (mean 16 days), while ischaemic ulcers took 10-14 days for complete recovery (mean 13.6 days). There was a reduction of rest pain in all 10 patients with ischaemic disease; five patients showed complete healing of ulcers, and the other five improved significantly. In two patients, pre-gangrene changes were reversed. RVP is a useful adjunct to conservative or surgical treatment of non-healing pedal ulcers. Its main impact was in improving ischaemia and promoting healing.     

Functional and phenotypic characterization of human peripheral blood stem cell harvests: a comparative analysis of cells from consecutive collections

A considerable number of patients with malignancies who are treated with high-dose therapy and hematopoietic stem cell transplantation subsequently relapse. Analyses of peripheral blood stem cell (PBSC) harvests obtained from 49 cancer patients showed that the PBSC harvest contained precursors for antitumor effector cells. Ex vivo manipulation of these harvests to maximize the antitumor effector cell activity may provide a new therapeutic approach to decrease or eliminate any minimal residual disease that remains after high-dose therapy. Characterization of PBSC from consecutive collections determined the collections best suited for ex vivo augmentation of antitumor cytotoxic effector cells. We report the results of a functional and phenotypical characterization of PBSC obtained from six consecutive collections from 18 cancer patients receiving granulocyte-macrophage colony-stimulating factor (GM- CSF) for hematopoietic stem/progenitor cell mobilization. The PBSC were evaluated for their cytotoxicity using the 51Cr-release assay. The frequency and subsets of lymphocytes were determined using flow cytometry with appropriate specific marker antibodies and differential cell counts. The content of hematopoietic progenitor cells in each collection was determined using a colony-forming unit granulocyte- macrophage (CFU-GM) culture assay. The frequency of cytotoxic effector cells including lymphokine-activated killer (LAK) cell precursors and lymphocytes was significantly greater (P < .05) in the early collections, whereas the later collections contained significantly (P < .05) more CFU-GM progenitor cells and fewer cytotoxic effector cells. Thus, our results show that PBSC obtained from advanced cancer patients do contain considerable levels of precursor cells for the generation of LAK cell populations. These results suggest that cells from the earlier collections are best suited for ex vivo manipulation to augment the antitumor effects.     

A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome

Antibodies that bind prothrombin without neutralizing its coagulant activity were demonstrated in the plasma of two patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome. The first patient's plasma contained less than 1% prothrombin activity and no detectable prothrombin antigen. The second patient's plasma contained about 6% of both prothrombin activity and antigen. Neither patient's plasma neutralized the prothrombin coagulant activity of normal plasma or of purified prothrombin added in vitro. Nevertheless, double immunodiffusion studies and binding experiments utilizing 125I- prothrombin demonstrated the presence of prothrombin antibodies in each patient's plasma. A Scatchard analysis of the binding data obtained with different concentrations of 125I-prothrombin and the first patient's plasma indicated the presence of a high affinity antibody, apparent Kd approximately 10(-10)M, and a lower affinity antibody, apparent Kd approximately 10(-9)M. Studies utilizing purified cleavage products of prothrombin suggested that the antibodies were directed against an epitope or epitopes located on the carboxyl-terminal, latent thrombin segment of the prothrombin molecule. We postulate that the acquired hypoprothrombinemia in these two patients and in other reported patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome stems from rapid clearance from the circulation of prothrombin antigen-antibody complexes.     

Oral health of Adelaide nursing home residents: longitudinal study

Objective: The Adelaide Dental Study of Nursing Homes aimed to quantify oral disease experience, incidence and increments in Adelaide nursing home residents. Methods: Questionnaires and dental inspections were completed at baseline and at 1‐year for residents from randomly selected Adelaide nursing homes. Results: The residents were very functionally dependent, cognitively impaired and behaviourally difficult older adults with complex oral problems and dental treatment needs. The prevalence of edentulism (total tooth loss) (63%) decreased and more residents were retaining natural teeth. Existing residents had a mean of 10.8 teeth present and new residents had a mean of 12.7 teeth present. Residents’ previous experiences of caries (decay) were high – existing residents had a mean of 1.2 decayed teeth and new residents had a mean of 0.8 decayed teeth. Residents’ caries increments (new decay) over the 1‐year period were high (coronal = 2.5 surfaces; root = 1.0 surfaces), especially in those who had lost weight and who could eat fewer food types. These levels of caries were many times greater than had been reported for community‐dwelling older adults. Large accumulations of plaque, calculus and debris (food) were evident on residents’ natural teeth and dentures, especially those with dementia. Up to 25% of residents owned dentures that were not worn. Residents with dementia gave their carers complex and challenging oral hygiene care problems. Existing and new residents had similar general health and oral health characteristics, with the exceptions that new residents had significantly more filled tooth surfaces, and fewer decayed retained roots. Conclusion: New residents were being admitted to the nursing homes with a compromised oral health status or developed severe oral diseases and conditions within several months of their admittance. Residents’ oral diseases, especially coronal and root caries, rapidly progressed during their stay in residential care.     

Unequal crossing-over: a common basis of single alpha-globin genes in Asians and American blacks with hemoglobin-H disease

The alpha-globin genes of five black Americans, two Chinese, and five Filipinos with HbH disease (an alpha-thalassemia state in which there is a single functional alpha gene) were analyzed by restriction endonuclease techniques. All subjects were found to have one chromosome 16, lacking both alpha genes, and another containing a single alpha gene (--/-alpha). Restriction endonuclease patterns of the DNA obtained from all 12 subjects were identical and compatible with unequal crossing-over as the mechanism of origin of the single alpha gene in these individuals.