Locally regularized spatiotemporal modeling and model comparison for functional MRI

In this work we treat fMRI data analysis as a spatiotemporal system identification problem and address issues of model formulation, estimation, and model comparison. We present a new model that includes a physiologically based hemodynamic response and an empirically derived low-frequency noise model. We introduce an estimation method employing spatial regularization that improves the precision of spatially varying noise estimates. We call the algorithm locally regularized spatiotemporal (LRST) modeling. We develop a new model selection criterion and compare our model to the SPM-GLM method. Our findings suggest that our method offers a better approach to identifying appropriate statistical models for fMRI studies.     

Penetrating Missile Injuries During the Iraqi Insurgency

INTRODUCTION

Since the invasion of Iraq in 2003, the conflict has evolved from asymmetric warfare to a counter-insurgency operation. This study investigates the pattern of wounding and types of injuries seen in casualties of hostile action presenting to a British military field hospital during the present conflict.

PATIENTS AND METHODS

Data were prospectively collected on 100 consecutive patients either injured or killed from hostile action from January 2006 who presented to the sole coalition field hospital in southern Iraq.

RESULTS

Eighty-two casualties presented with penetrating missile injuries from hostile action. Three subsequently died of wounds (3.7%). Forty-six (56.1%) casualties had their initial surgery performed by British military surgeons. Twenty casualties (24.4%) sustained gunshot wounds, 62 (75.6%) suffered injuries from fragmentation weapons. These 82 casualties were injured in 55 incidents (mean, 1.49 casualties; range 1–6 casualties) and sustained a total 236 wounds (mean, 2.88 wounds) affecting a mean 2.4 body regions per patient. Improvised explosive devices were responsible for a mean 2.31 casualties (range, 1–4 casualties) per incident.

CONCLUSIONS

The current insurgency in Iraq illustrates the likely evolution of modern, low-intensity, urban conflict. Improvised explosive devices employed against both military and civilian targets have become a major cause of injury. With the current global threat from terrorist bombings, both military and civilian surgeons should be aware of the spectrum and emergent management of the injuries caused by these weapons.     

Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.     

A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects

Prospective, double-blind, randomized trials comparing atypical antipsychotic drugs (APDs) to typical APDs, such as haloperidol, indicate that atypical APDs provide a modest benefit to cognitive function in schizophrenia. However, the validity of this inference has been contested by suggestions that the cognitive improvements observed with atypical APDs reflect practice effects associated with repeated testing on the same neuropsychological instruments, or an avoidance of a deleterious effect of haloperidol on cognitive function that might be dose related. These alternate hypotheses were assessed by meta-analyses that 1) examined the relationship between cognitive change and dose of haloperidol within the control arms of prospective atypical vs. typical APD clinical trials; and 2) compared the magnitude of change observed within the haloperidol arms of these studies to estimated practice effects for several commonly used neuropsychological measures. The results indicate that overall cognitive performance improves while on haloperidol. Studies that used a low dose of haloperidol (<10 mg) did not yield larger effect sizes for overall cognitive function or specific neuropsychological measures than studies that used a high dose (>10 mg), although doses greater than 24 mg appear to have deleterious effects. For two of the six neuropsychological tests examined (digit symbol substitution and verbal fluency) the magnitude of change observed was significantly less than practice effects. The results indicate that although haloperidol may cause deleterious effects at very high doses, or in specific cognitive domains, these effects are not likely to explain the broader range of cognitive improvements observed with atypical APDs.     

Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats

Background and purpose:

Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro- and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin-resistant JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease.

Experimental approach:

Obese male rats were treated with irbesartan (30 mg·kg⁻¹·day⁻¹, incorporated into chow) from 12 to 25 weeks of age.

Key results:

Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels (∼50%). Fasting plasma triglycerides were marginally reduced (∼25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%).

Conclusions and implications:

Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.     

Huntington''s disease: pathogenesis, diagnosis and treatment.

This review of the clinical features of Huntington's disease incorporates recent developments in pathophysiology, preclinical diagnosis and treatment. Although the mechanism initiating and guiding the cell destruction in this illness is currently unknown, the excitatory neurotoxin and the energy metabolism models may provide a valuable direction for future research. Similarly, although the precise relation between the neuroanatomical damage in Huntington's disease and the functional disability is not clear, applications of recently developed neural connection models have implicated a number of important brain-behavior associations. Preclinical diagnostic procedures have evolved through successive iterations that have each contributed to increased reliability. New functional brain imaging techniques are sure to add to this promising domain in the future. Preclinical diagnosis has been stimulated by the recent isolation of the Huntington's gene which has also rekindled awareness of the importance of informed genetic counselling and the inherent ethical dilemmas in genetic testing. Treatment approaches to Huntington's disease have been confined to palliative care with secondary symptom management and psychotherapeutic support. Experimental therapeutic strategies for the illness itself have had a rather disappointing record to date. Further developments in NMDA antagonism and neural cell grafting may provide some hope for the future.     

IRON DEFICIENCY ANAEMIA IN GENERAL PRACTICE: PRESENTATIONS AND INVESTIGATIONS

Twenty-six patients over the age of 50 years with proven iron deficiency anaemia were identified, investigated and followed up in general practice over a five-year period. The anaemia was symptomatic in 50% of patients but only 20% had symptoms related to the gut. Faecal occult blood testing was positive in five patients only and negative tests occurred in three patients with significant disease, including one caecal carcinoma. All patients agreed to oesophagogastroduodenoscopy (OGD) and fibreoptic sigmoidoscopy carried out on the same occasion. In eight patients, significant abnormalities were found on OGD and in two patients on sigmoidoscopy. Four patients declined barium enema examinations, two of whom had significant OGD abnormalities. Barium enema examination of the other 22 patients showed polyposis of the colon and a caecal carcinoma and initially missed one carcinoma of the caecum which was found subsequently. The likelihood of finding significant disease in iron-deficient patients over 50 years of age is high and should be assumed to be due to blood loss into the gut. Investigation by OGD, sigmoidoscopy and barium enema in the first instance seems warranted and is a condition that can be safely managed by the GP. (Br J Clin Pract 1997; 51(2) : 78-80)     

Guinea pig MSEL-neurophysin. Sequence comparison of eight mammalian MSEL-neurophysins

The amino acid sequence of guinea pig MSEL-neurophysin has been determined using tryptic peptides derived from the performic acid-oxidized protein and staphylococcal proteinase peptides obtained from the reduced-carboxamidomethylated neur-ophysin. Guinea pig MSEL-neurophysin consists of a 93-residue polypeptide chain that shows 12 substitutions and 2 deletions when compared to bovine MSEL-neurophysin. It displays the highest number of variations among known mammalian MSEL-neurophysins. These variations are mainly found in the C-terminal region (residues 88–93). Moreover guinea pig MSEL-neurophysin, like rat homologous protein, exhibits substitutions in positions 2, 5, 29 and 81 and lacks an arginine in the penultimate position. Comparison between eight mammalian MSEL-neurophysins reveals a highly conserved region (residues 1 to 88) and a hypervariable region (residues 89 to 93/95). On the other hand the eight species examined are endowed with arginine vasopressin except pig, which has a lysine vasopressin. In the vasopressin-MSEL-neurophysin precursor, the hormonal moiety and the MSEL region of neurophysin (residues 1–9) are encoded by a common exon in ox, rat and man; it can be concluded that this exon is evolutionarily conservative in contrast to the one encoding the C-terminal region of MSEL-neurophysin.     

Erythropoietin kinetics in rats: generation and clearance

Detailed studies to analyze the early events of erythropoietin (Ep) secretion and clearance were performed in a rat model using a double antibody radioimmunoassay. Ep clearance was determined following intravenous injection of 1 mL of Ep-rich plasma, 1,080 mU/mL, obtained from phlebotomized rats. Analysis revealed a disappearance curve that conformed to a two-compartment model with an alpha half-life t1/2 of 3.6 minutes and a beta t1/2 of 86 minutes. The volume of distribution was similar to the calculated plasma volume. In anephric animals, there was no change in the plasma clearance rate or the volume of distribution. Rapid Ep secretion was elicited by a single 15 mL/kg phlebotomy (hematocrit decrement 45% to 30%), so that levels reached 20 to 30 times baseline (524 +/- 76 v 24 +/- 7 mU/mL) at five hours, whereas they plateaued for at least 33 hours. The increase in the rate of secretion was geometric, from 9.9 mU/h baseline secretion to 429 mU/h. These data identify a very sensitive and rapidly responsive system for Ep modulation in the rat.