Immunotherapy Safety: What Have We Learned from Surveillance Surveys?

Subcutaneous allergen immunotherapy (SCIT) is beneficial for the treatment of allergic rhinitis, asthma, and in preventing stinging insect anaphylaxis, but is not without risks. Four retrospective surveillance surveys and one on-going national prospective study have attempted to characterize the incidence and risk factors for fatal and non-fatal SCIT reactions. These studies have contributed significantly to currently recommended SCIT safety guidelines. Recent surveillance studies indicate stable SR rates, and a possible decline in the incidence of fatal reactions since the implementation of evidence-based safety guidelines. This review will provide a detailed summary of the evidence from surveillance studies for risk factors associated with SCIT reactions, including: uncontrolled asthma, prior systemic reactions, dosing during peak pollen seasons, epinephrine being delayed or not given, dosing or administration errors, inadequate waiting times, reactions occurring more than 30 min after injections, injections given in medically unsupervised settings, concomitant beta-blocker and angiotensin-converting enzyme inhibitor (ACEi) use, and accelerated build-up regimens.     

A decision tree approach to screen drinking water contaminants for multiroute exposure potential in developing guideline values

The consideration of inhalation and dermal routes of exposures in developing guideline values for drinking water contaminants is important. However, there is no guidance for determining the eligibility of a drinking water contaminant for its multiroute exposure potential. The objective of the present study was to develop a 4-step framework to screen chemicals for their dermal and inhalation exposure potential in the process of developing guideline values. The proposed framework emphasizes the importance of considering basic physicochemical properties prior to detailed assessment of dermal and inhalation routes of exposure to drinking water contaminants in setting guideline values.     

Spontaneous bacterial peritonitis in alcoholic cirrhosis with ascites

Taking part in recreation or tourist pursuits far from medical resources can tax the ingenuity of even the best-prepared wilderness traveler. In part 1 of this three-part article, which appeared in the June issue, means of preventing illness and injury in the “wilds” were discussed. This part outlines the specific management of several illnesses and injuries that might occur on the trail. In part 3, to appear in August, items for inclusion in a medical kit for wilderness travel will be detailed.     

Effect of hypertonic saline on rat hypothalamic paraventricular nucleus parvocellular neurons in vitro

The effects of hypertonic saline on hypothalamic paraventricular nucleus (PVN) parvocellular neurons were examined using whole-cell patch-clamp technique. Under current-clamp, 50% (41/82) of parvocellular neurons were depolarized than the predicted values by hypertonic saline, and associated with increasing action potential frequency. Under voltage-clamp, unless hypertonic saline induced a shift of reverse potential to more positive values, neither mannitol nor hypertonic saline obviously increased the conductance in parvocellular neurons. Moreover, spontaneous excitatory postsynaptic currents (sEPSCs) were increased by isotonic increases in [Na⁺]_o in the parvocellular neurons. Bath application AMPA receptor antagonist CNQX or non-selective glutamate antagonist kynurenic acid almost completely blocked the sEPSCs. Extracellular application of gadolinium (Gd³⁺) blocked the hypertonic saline-induced response. These results suggested that subpopulation of PVN parvocellular neurons are selectively sensitive to NaCl. Hypertonic saline excited the PVN parvocellular neurons through Na⁺-detection and the excitatory glutamatergic synaptic input.     

Evaluation of beta defensin 2 production by chicken heterophils using direct MALDI mass spectrometry

Beta defensins (BD) are cysteine rich, cationic antimicrobial peptides (AMP) produced mainly by epithelial and myeloid cells such as neutrophils. In birds, the neutrophil equivalent heterophils produce avian beta defensins (AvBD) of which AvBD2 is the major isoform. Heterophils recognize pathogens or their derived products through a series of pattern recognition receptors called toll-like receptors (TLR) leading to their antimicrobial activities. This work is the first report of TLR modulation of AvBD2 expression in chickens. To measure the effect of TLR activation on AvBD2 production, the heterophils were cultured with different TLR agonists for 6 h. Modulation of AvBD2 levels by TLR activation was measured using direct MALDI mass spectrometry without stable isotopic labeling or chromatographic separation. Chemical modification of the conditioned media was performed using reduction/alkylation with dithiothreitol/iodoacetamide to distinguish TLR treated AvBD2 (reduced/alkylated) from controls (non-reduced). Changes in corrected ion intensity ratios were assumed to reflect AvBD2 modulation in heterophils upon activation with different TLR agonists. In general, TLR agonists increased AvBD2 production with LPS showing the greatest induction and CpG-ODN showing little or no effect. These data show that the direct MALDI-MS coupled with reduction/alkylation may provide a rapid relative quantitative approach to the measurement of agonist-induced differential expression of AvBD2.     

Long-term outcome of patients operated for large ventricular septal defects with increased pulmonary vascular resistance

BACKGROUND: There is a paucity of data regarding the long-term outcome of patients operated for ventricular septal defect with severe pulmonary arterial hypertension and elevated pulmonary vascular resistance. METHODS AND RESULTS: We evaluated the long-term follow-up results of a selected cohort of patients with nonrestrictive ventricular septal defect and elevated pulmonary vascular resistance (>6 Wood units). Thirty-eight patients, median age 7.5 years (range 6 months-27 years), with nonrestrictive ventricular septal defect with severe pulmonary hypertension were operated between 1985 and 1996 at our institute. Preoperative pulmonary vascular resistance, ratio of pulmonary blood flow to systemic blood flow, and ratio of pulmonary vascular resistance to systemic vascular resistance were 7.63+/-1.8 Wood units, 1.9+/-0.48, and 0.41+/-0.12, respectively. The majority (68.4%) had perimembranous ventricular septal defect. Thirty patients (79%) had a good outcome and were asymptomatic at a mean follow-up of 8.7 years, with significant reduction in pulmonary artery pressures. Eight patients (21%) had a poor outcome, which included 5 immediate postoperative deaths, 1 late death and 2 surviving patients with persistent severe pulmonary arterial hypertension. There was no significant difference regarding hemodynamic parameters at baseline between those who had a good outcome and those who did not. Eleven patients with a preoperative pulmonary blood flow to systemic blood flow ratio of <2:1. who had a good outcome following surgery, underwent repeat catheterization at follow-up. There was a significant reduction in their mean pulmonary vascular resistance (8.03+/-1.4 v. 4.16+/-1.6 Wood units, p=0.001) and pulmonary vascular resistance to systemic vascular resistance ratio (0.41+/-0.12 v. 0.19+/-0.06, p=0.05). CONCLUSIONS: The late results of surgery on this selected group of patients with nonrestrictive ventricular septal defect with high pulmonary vascular resistance are encouraging. Operative correction of the ventricular septal defect should be actively considered in all children presenting with nonrestrictive ventricular septal defect with a significant left-to-right shunt, despite moderately elevated pulmonary vascular resistance. Even among older patients with ventricular septal defect and moderately elevated pulmonary vascular resistance, there is a specific group that does well after operation.     

Identification of 32 novel mutations in the factor VIII gene in Indian patients with hemophilia A

Seventy-five unrelated hemophilia A patients from India were analyzed for factor VIII gene defects. Intron 22 inversion was identified in 22 patients and intron 1 inversion in 2 patients. In the remaining 51 patients without inversions screening the FVIII gene by denaturing high performance liquid chromatography (DHPLC) revealed 42 different mutations in 44 unrelated subjects. These included 14 missense, 7 nonsense, 9 splice site, 8 deletional, 3 insertional mutations and one indel mutation. Of these, 32 were novel gene alterations. The hotspots included intron 22 inversion, CpG and adenine runs.     

Hemophilia A: role of FVIIIC/vWF Ag in assisting linkage analysis for carrier detection.

Carrier detection for hemophilia A was carried out in 52 females from 30 families presenting to the Haematology Department AIIMS, using linkage analysis and factor VIIIC (FVIIIC)-von Willebrand factor (vWF) antigen assay. The allelic frequency for the marker Bcl 1 and Xba 1 was 0.58 and 0.54, respectively, for the positive alleles and 0.42 and 0.46, respectively, for the negative alleles. The heterozygosity frequency of Bcl I and Xba 1 was 0.65 and 0.55, respectively. Of the 52 females, 30 were mothers of hemophilic patients and 22 were sisters of hemophilic patients. Of the 30 mothers, positive family history was present in 14. In these patients, the defective X chromosome was tracked in 10, and in four the defective X chromosome could not be tracked because the mothers were homozygous for the marker used. Of the 16 mothers without a family history of disease, three were observed to be carriers based on linkage analysis and reduced factor VIII levels in mother/sister. Possible defective X chromosome was tracked in 11 mothers and five were noninformative because they did not show heterozygosity for the markers used. Using linkage analysis, nine of the 22 sisters were found to be definite carriers, 10 noncarriers, and three were noninformative. It is thus concluded that using Bcl 1 and Xba 1 linkage analysis, carrier status can be definitely ascertained in 50% females and this level of information can be increased to 61.5% by measuring FVIIIC/vWF antigen levels in them.