HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

Childhood B-cell precursor (BCP) ALL is thought to be caused by a delayed immune response to an unidentified postnatal infection. An association between BCP ALL and HLA class II (DR, DQ, DP) alleles could provide further clues to the identity of the infection, since HLA molecules exhibit allotype-restricted binding of infection-derived antigenic peptides. We clustered >30 HLA-DPB1 alleles into six predicted peptide-binding supertypes (DP1, 2, 3, 4, 6, and 8), based on amino acid di-morphisms at positions 11 (G/L), 69 (E/K), and 84 (G/D) of the DPβ1 domain. We found that the DPβ11-69-84 supertype GEG (DP2), was 70% more frequent in BCP ALL (n=687; P<10−4), and 98% more frequent in cases diagnosed between 3 and 6 years (P<10−4), but not <3 or >6 years, than in controls. Only one of 21 possible DPB1 supergenotypes, GEG/GKG (DP2/DP4) was significantly more frequent in BCP ALL (P=0.00004) than controls. These results suggest that susceptibility to BCP ALL is associated with the DP2 supertype, which is predicted to bind peptides with positively charged, nonpolar aromatic residues at the P4 position, and hydrophobic residues at the P1 and P6 positions. Studies of peptide binding by DP2 alleles could help to identify infection(s) carrying these peptides

A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence

Several theories of the underlying mechanisms of Sudden Infant Death Syndrome (SIDS) have been proposed. These theories have born relatively narrow beach-head research programs attracting generous research funding sustained for many years at expense to the public purse. This perspective endeavors to critically examine the evidence and bases of these theories and determine their plausibility; and questions whether or not a safe and reasoned hypothesis lies at their foundation. The Opinion sets specific criteria by asking the following questions: 1. Does the hypothesis take into account the key pathological findings in SIDS? 2. Is the hypothesis congruent with the key epidemiological risk factors? 3. Does it link 1 and 2? Falling short of any one of these answers, by inference, would imply insufficient grounds for a sustainable hypothesis. Some of the hypotheses overlap, for instance, notional respiratory failure may encompass apnea, prone sleep position, and asphyxia which may be seen to be linked to co-sleeping. For the purposes of this paper, each element will be assessed on the above criteria

A Network Model of Local Field Potential Activity in Essential Tremor and the Impact of Deep Brain Stimulation

Essential tremor (ET), a movement disorder characterised by an uncontrollable shaking of the affected body part, is often professed to be the most common movement disorder, affecting up to one percent of adults over 40 years of age. The precise cause of ET is unknown, however pathological oscillations of a network of a number of brain regions are implicated in leading to the disorder. Deep brain stimulation (DBS) is a clinical therapy used to alleviate the symptoms of a number of movement disorders. DBS involves the surgical implantation of electrodes into specific nuclei in the brain. For ET the targeted region is the ventralis intermedius (Vim) nucleus of the thalamus. Though DBS is effective for treating ET, the mechanism through which the therapeutic effect is obtained is not understood. To elucidate the mechanism underlying the pathological network activity and the effect of DBS on such activity, we take a computational modelling approach combined with electrophysiological data. The pathological brain activity was recorded intra-operatively via implanted DBS electrodes, whilst simultaneously recording muscle activity of the affected limbs. We modelled the network hypothesised to underlie ET using the Wilson-Cowan approach. The modelled network exhibited oscillatory behaviour within the tremor frequency range, as did our electrophysiological data. By applying a DBS-like input we suppressed these oscillations. This study shows that the dynamics of the ET network support oscillations at the tremor frequency and the application of a DBS-like input disrupts this activity, which could be one mechanism underlying the therapeutic benefit

Intrathoracic Petechial Hemorrhages in Sudden Infant Death Syndrome and Other Infant Deaths: Time for Re-examination?

The objective of this study was to provide a predictive tool to assist forensic and pediatric pathologists in the diagnosis of sudden unexpected infant death and to discuss the pathogenesis of intrathoracic petechial hemorrhages through a retrospective autopsy report review of 174 sudden infant death syndrome (SIDS) cases (2004 definition) and 67 age-matched comparison deaths. The setting was a qualitative assessment (presence or absence) of macroscopic intrathoracic petechiae in SIDS and age-matched comparison of sudden unexpected deaths that occurred in the late 1980s and early 1990s. Sensitivity, specificity, and positive and negative predictive values for thymic, pleural, and epicardial petechial hemorrhages were developed. Results showed 89.5%, 80%, and 79.9% SIDS (&lt;12 months of age) had thymic, pleural, and epicardial petechiae, respectively, compared with 47.6%, 47.5% and 43.6% in non-SIDS deaths, respectively. Respective odds ratios were: 9.4 (4.5 to 19.9), 4.6 (2.3 to 9.1), 5.3 (2.6 to 10.8). When all 3 intrathoracic organ sites contain macroscopic petechiae, this is 84.9% predictive of SIDS; when all 3 sites have no detectable petechiae this is 93.1% predictive of a non-SIDS diagnosis. Thus, we conclude that careful assessment of intrathoracic petechiae at autopsy is likely to be diagnostically useful in the assessment of sudden unexplained infant death.Paul N. Goldwate