Takayasu Arteritis Presenting as Severe Ascending Aortic Arch Dilation and Aortic Regurgitation in a 10‐Year‐Old Female

Takayasu arteritis (TA) is a large‐vessel arteritis affecting the aorta and its major branches. It is a rare disease in children less than 10 years old, and its diagnosis is frequently delayed, likely because of TA's rarity and nonspecific symptoms early in the disease. Females are affected disproportionately, with a female to male ratio of 8.5 to 1. Recently, the European League against Rheumatism published an international consensus statement for making the diagnosis of childhood TA. Criteria include angiographic abnormalities of the aorta and/or its branches, pulse deficit or claudication, blood pressure discrepancy, bruits, hypertension, and elevated acute phase reactants. We described a 10‐year‐old female with severe TA of the ascending aorta and who presented with classic signs and symptoms of this rare disease.     

Genomic microdeletions associated with epilepsy: not a contraindication to resective surgery

Purpose: Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain, will affect surgical outcome. Methods: A reevaluation was undertaken of clinical presurgical data, histopathology of surgical specimen, and postsurgical outcome in patients with mesial temporal lobe epilepsy (MTLE) who have had surgical treatment for their drug‐resistant seizures, and who have been found to have particular genomic microdeletions. Key Findings: Three thousand eight hundred twelve patients with epilepsy were genotyped and had a genome‐wide screen to identify copy number variation. Ten patients with MTLE, who had resective epilepsy surgery, were found to have 16p13.11 microdeletions or other microdeletions >1 Mb. On histopathology, eight had classical hippocampal sclerosis (HS), one had nonspecific findings, and one had a hamartoma. Median postsurgical follow‐up time was 48 months (range 10–156 months). All patients with HS were seizure‐free after surgery, International League Against Epilepsy (ILAE) outcome class 1, at last follow‐up; the patient with nonspecific pathology had recurrence of infrequent seizures after 7 years of seizure freedom. The patient with a hamartoma never became seizure‐free. Significance: Large microdeletions can be found in patients with “typical” MTLE. In this small series, patients with MTLE who meet criteria for resective surgery and harbor large microdeletions, at least those we have detected, can have a good postsurgical outcome. Our findings add to the spectrum of causal heterogeneity of MTLE + HS.     

Determinants of individual variation in intracellular accumulation of anti-HIV nucleoside analog metabolites

Individual variation in response to antiretroviral therapy is well-known, but it is not clear if demographic characteristics such as gender, age, and ethnicity are responsible for the variation. To optimize anti-HIV therapy and guide antiretroviral drug discovery, determinants that cause variable responses to therapy need to be evaluated. We investigated the determinants of intracellular concentrations of nucleoside analogs using peripheral blood mononuclear cells from 40 healthy donors. We observed individual differences in the concentrations of the intracellular nucleoside analogs; the mean concentrations of the triphosphate metabolite of ethynylstavudine (4'-Ed4T), zidovudine (AZT), and lamivudine (3TC) were 0.71 pmol/10(6) cells (minimum and maximum, 0.10 and 3.00 pmol/10(6) cells, respectively), 0.88 pmol/10(6) cells (minimum and maximum, 0.10 and 15.18 pmol/10(6) cells, respectively), and 1.70 pmol/10(6) cells (minimum and maximum, 0.20 and 7.73 pmol/10(6) cells, respectively). Gender and ethnicity had no effect on the concentration of 4'-Ed4T and 3TC metabolites. There was a trend for moderation of the concentrations of AZT metabolites by gender (P = 0.17 for gender·metabolite concentration). We observed variability in the activity and expression of cellular kinases. There was no statistically significant correlation between thymidine kinase 1 (TK-1) activity or expression and thymidine analog metabolite concentrations. The correlation between the activity of deoxycytidine kinase (dCK) and the 3TC monophosphate metabolite concentration showed a trend toward significance (P = 0.1). We observed an inverse correlation between the multidrug-resistant protein 2 (MRP2) expression index and the concentrations of AZT monophosphate, AZT triphosphate, and total AZT metabolites. Our findings suggest that the observed variation in clinical response to nucleoside analogs may be due partly to the individual differences in the intracellular concentrations, which in turn may be affected by the cellular kinases involved in the phosphorylation pathway and ATP-binding cassette (ABC) transport proteins.     

Severe adverse reactions to dental local anaesthetics: systemic reactions

Background: Occasionally, patients suffer systemic adverse effects from injections of local anaesthetic solutions. This may range from minor transient vasovagal attacks to life‐threatening collapse. Methods: The suspected adverse reactions reported to the Office of Product Review of the Therapeutic Goods Administration (TGA) were analysed in detail. Results: There was a high incidence (70%) of adverse reactions associated with prilocaine, which is much greater than its market share (less than 20%). There is a tendency to consider all systemic adverse reactions as being ‘allergic’ reactions although this is rarely the case. Syncope, cardiovascular and central nervous system reactions are much more common. There is also a risk of methaemoglobinaemia to prilocaine and articaine. A small series of cases referred to one of the authors were also reported. Conclusions: Recommendations are made as to the prevention, acute care and subsequent investigation of adverse reactions. The most important conclusion is not to just label the response as allergic and to use an alternative agent. Detailed investigation and reporting should be made for all cases of suspected severe adverse reaction to local anaesthetic agents.     

Barriers to implementation of the HIV guidelines in the IMCI algorithm among IMCI trained health workers in Zambia

Background  

Zambia adopted integrated management of Childhood illnesses (IMCI) in 1995 and a number of adaptations have been made to the generic WHO/UNICEF IMCI guidelines to better conform to Zambia's health service needs. One significant adaptation is the incorporation of HIV guidelines into the IMCI algorithm. Since 2004, health workers that have undergone IMCI case management training have also received training in HIV assessment. During initial follow-up visits in 11 districts 90 health workers were assessed in 2007 to determine their adherence to the IMCI algorithm. The assessment showed that 97% of the health workers assessed did not review or mention the HIV guidelines even though they had received HIV training as part of IMCI. This study aimed to explore reasons for non-adherence to HIV guidelines in the IMCI algorithm and make recommendations on how this can be improved.     

ACS-NSQIP has the potential to create an HPB-NSQIP option

Background:

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) was started in 2004. Presently, 58% of the 198 hospitals participating in ACS-NSQIP are academic or teaching hospitals. In 2008, ACS-NSQIP initiated a number of changes and made risk-adjusted data available for use by participating hospitals. This analysis explores the ACS-NSQIP database for utility in developing hepato-pancreato-biliary (HPB) surgery-specific outcomes (HPB-NSQIP).

Methods:

The ACS-NSQIP Participant Use File was queried for patient demographics and outcomes for 49 HPB operations from 1 January 2005 through 31 December 2007. The procedures included six hepatic, 16 pancreatic and 23 complex biliary operations. Four laparoscopic or open cholecystectomy operations were also studied. Risk-adjusted probabilities for morbidity and mortality were compared with observed rates for each operation.

Results:

During this 36-month period, data were accumulated on 9723 patients who underwent major HPB surgery, as well as on 44 189 who received cholecystectomies. The major HPB operations included 2847 hepatic (29%), 5074 pancreatic (52%) and 1802 complex biliary (19%) procedures. Patients undergoing hepatic resections were more likely to have metastatic disease (42%) and recent chemotherapy (7%), whereas those undergoing complex biliary procedures were more likely to have significant weight loss (20%), diabetes (13%) and ascites (5%). Morbidity was high for hepatic, pancreatic and complex biliary operations (20.1%, 32.4% and 21.2%, respectively), whereas mortality was low (2.3%, 2.7% and 2.7%, respectively). Compared with laparoscopic cholecystectomy, the open operation was associated with higher rates of morbidity (19.2% vs. 6.0%) and mortality (2.5% vs. 0.3%). The ratios between observed and expected morbidity and mortality rates were <1.0 for hepatic, pancreatic and biliary operations.

Conclusions:

These data suggest that HPB operations performed at ACS-NSQIP hospitals have acceptable outcomes. However, the creation of an HPB-NSQIP has the potential to improve quality, provide risk-adjusted registries with HPB-specific data and facilitate multi-institutional clinical trials.     

The cyanobacteria derived toxin Beta-N-methylamino-L-alanine and amyotrophic lateral sclerosis

There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis). The non-protein amino acid beta-N-methylamino-L-alanine (BMAA) was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer's disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin.     

Protected Graft Copolymer Excipient Leads to a Higher Acute Maximum Tolerated Dose and Extends Residence Time of Vasoactive Intestinal Peptide Significantly Better than Sterically Stabilized Micelles

Purpose

To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP).

Methods

VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined.

Results

Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1–5 μg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP.

Conclusions

While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP.