Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.

Successful Use of Cidofovir in an Immunocompetent Child With Severe Adenoviral Sepsis.

Adenovirus infection is common in childhood and is generally associated with self-limited disease. Cidofovir, a viral DNA polymerase inhibitor, is used to treat adenovirus infection in select populations but is not often recommended for immunocompetent patients because of limited antiviral activity and nephrotoxicity. Here, we report a case of fulminant adenovirus infection associated with lymphopenia and multiple organ failure requiring extracorporeal membrane oxygenation support in a previously healthy child. After 1 week of supportive therapy, the patient had persistent organ failure and continued to have adenoviremia of >560 000 copies per mL. Weekly doses of cidofovir with concurrent probenecid for renal protection was initiated. Adenovirus blood load declined after the first cidofovir dose, becoming undetectable after 3 doses. The patient was successfully decannulated from extracorporeal membrane oxygenation, extubated, and eventually discharged at his functional baseline without need for ongoing respiratory support. Lymphopenia improved after viremia resolved, and a subsequent immunologic workup revealed no evidence of primary immunodeficiency. The viral isolate was genotyped as adenovirus type 7. This case reveals the successful use of cidofovir for management of severe adenovirus infection in a previously healthy child. To date, there are no universally accepted recommendations for the use of cidofovir in this population. Further study is warranted to determine the potential role of cidofovir in treating severe adenovirus infections in immunocompetent children.

Considerations in the Diagnosis of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease presents in most patients initially with infection, especially of the lymph nodes, lung, liver, bone, and skin. Patients with CGD are susceptible to a narrow spectrum of pathogens, and Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species are the most common organisms implicated in North America. Granuloma formation, most frequently in the gastrointestinal and genitourinary systems, is a common complication of CGD and can be seen even before diagnosis. An increased incidence of autoimmune disease has also been described in patients with CGD and X-linked female carriers. In patients who present with signs and symptoms consistent with CGD, a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function. The purpose of this review is to highlight considerations for and challenges in the diagnosis of CGD.

Performance of chromID® CARBA medium for carbapenemases-producing Enterobacteriaceae detection during rectal screening.

Chromogenic chromID® CARBA medium was compared with CDC method and MacConkey agar with imipenem for its performance in detecting carbapenemase-producing Enterobacteriaceae (CPE) during a faecal screening surveillance program. Double rectal swabs were collected from patients hospitalized in the ICU. One swab was inoculated onto the solid media chromID® CARBA and MacConkey agar with imipenem, while the other was tested according to CDC protocol. Suspected colonies from all procedures were identified to species level and tested for their susceptibility to carbapenems by phenotypic tests. All carbapenem non-susceptible isolates were tested by the modified Hodge test (MHT) and synergy tests. Positive results were confirmed by PCR testing for carbapenemase gene detection. Performance of all three procedures applied was statistically analyzed as compared to MHT and PCR results for the presence of carbapenemase-encoding genes. Out of 177 rectal samples tested, 86 samples were found to contain one or more CPE verified by molecular detection of carbapenemase encoding genes among isolated Enterobacteriaceae. Sensitivity of chromID® CARBA was 96.5 % in clinical samples. Specificity was 91.2 % at the reading level and 100.0 % after Gram staining. chromID® CARBA performed with high accuracy among the phenotypic methods applied, giving early results.

[Radiation-related caries: etiology and possible preventive strategies. What should the radiotherapist know?]. / Radiogene Karies: Ätiologie und Möglichkeiten der Prävention. Was sollte der Strahlentherapeut wissen?

BACKGROUND: After radiation treatment of head-and-neck cancer, the impairment of patient's quality of life still remains an issue. After completion of the treatment course, a substantial number of patients develop so-called radiation caries. In addition, almost 50% of all cases of infectious osteoradionecrosis (iORN) of the jaws are directly associated with radiation caries. This review addresses our current knowledge on the etiology and pathogenesis of radiation caries including possible preventive strategies. MATERIALS AND METHODS: A PubMed search using the terms "radiation caries" ("radiation related caries", "radiation related damage to dentition") and "radiogenic caries" ("postradiation caries", "dental complications and radiotherapy") was performed. The analysis of its content focused on the etiology, the pathogenesis, and the available knowledge on prophylaxis as well as treatment of radiation caries. RESULTS: For this review, 60 publications were selected. As main causal factors for radiogenic caries, either indirect impairment, resulting from alterations in the oral environment (e.g., radiation-induced xerostomia) or direct radiation-induced damage in teeth hard tissues are discussed. Radiation caries remains a lifelong threat and, therefore, requires permanent prevention programs. CONCLUSION: To enable optimal medical care of the patients during the time course of radiotherapy as well as afterwards, close interdisciplinary cooperation between radiotherapists, oral surgeons, otorhinolaryngologists, and dentists is absolutely essential.

Role of CXCR2 in cigarette smoke-induced lung inflammation.

It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. beta-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.

Inhibition of experimental acute pulmonary inflammation by pirfenidone.

Pirfenidone, a putative tumor necrosis factor-alpha (TNF-alpha) inhibitor, has recently gained recognition for its therapeutic use in the treatment of idiopathic pulmonary fibrosis. As pulmonary fibrosis may be the result of lung inflammatory processes, we examined the anti-inflammatory potential of pirfenidone in several models of acute pulmonary inflammation. In antigen-induced allergic paradigms, 24 h after antigen challenge, sensitized mice or guinea pigs develop a prominent pulmonary inflammation, reflected by a significant increase in the number of recoverable bronchoalveolar lavage (BAL) total cells and eosinophils. In both species, the pretreatment of animals with pirfenidone (10 and 30 mg/kg) resulted in a dose-dependent inhibition of the antigen-induced pulmonary inflammation, which was reflected by a significant decrease in the BAL eosinophils and total cells by the 30 mg/kg dose. In a non-allergic model of pulmonary inflammation, rats challenged with intratracheal LPS develop a significant increase in BAL neutrophils and total cells, along with significant increases in TNF-alpha and IL-6. Pretreatment with pirfenidone (3 and 30 mg/kg) showed a dose-dependent inhibition of the LPS-induced pulmonary inflammation, reflected by a significant decrease in the number of BAL total and neutrophilic cells at both the 3 and 30 mg/kg dose. However, pirfenidone had no effect on the peak BAL levels of TNF-alpha. In contrast, pirfenidone significantly inhibited BAL levels of IL-6. In summary, we have shown that pirfenidone can inhibit allergic and non-allergic inflammatory cell recruitment and that its pulmonary anti-inflammatory activity is independent of TNF-alpha inhibition.

Idiopathic intracranial hypertension with primary aldosteronism: report of 2 cases.

Although unconfirmed, the syndrome idiopathic intracranial hypertension (IIH), commonly seen in overweight 20- to 50-year-old women, has been proposed to have its origins in an endocrine-based disturbance of electrolytes. Herein we report on 2 women with IIH and primary aldosteronism (PAL). Aged 57 and 55 (patients 1 and 2), each had a longstanding history of mild-to-moderate arterial hypertension, recurrent hypokalemia, and headaches. They were found to have IIH at ages 51 and 45. PAL was diagnosed at ages 57 and 35, respectively, due to proven left adrenal adenoma in patient 1; and presumptive adrenal nodular hyperplasia in patient 2. This is the first report to appear in the English medical literature that describes an association between IIH and PAL. It raises the prospect that in some cases of IIH associated with arterial hypertension, an autonomous production of aldosterone should be considered.

Synergistic antiallergic activity of combined histamine H1- and cysteinyl leukotriene1-receptor blockade in human bronchus.

Mast cell histamine (HA) and cysteinyl leukotrienes (CysLT) account for most of the early phase bronchospasm in asthma. However, activation of the smooth muscle CysLT1-receptor plays a major role in asthmatic bronchospasms. CysLT-receptor antagonists or CysLT-synthesis inhibitors are efficacious in asthma but do not completely abolish asthmatic bronchospasms. A recent clinical study showed that combined antagonists loratadine (H1) and zafirlukast (CysLT1) were more effective against allergic bronchospasms than either drug alone. We examined the combined efficacy of H1- and CysLT1-receptor antagonists in allergic human bronchus. The H1- and CysLT1-receptor antagonists chlorpheniramine (CTM; 1 microM) and MK-571 (0.03 microM), were tested alone and in combination, against anti-human IgE antibody (Ab)-induced contractions of passively sensitized isolated human bronchus. Ab-induced allergic contractions were reduced 15% and 36% by CTM (1 microM) and MK-571 (0.03 microM), respectively. Combined CTM (1 microM) and MK-571 (0.03 microM) significantly inhibited the Ab response by 87%. Mechanistic investigations in isolated human bronchus and cultured human cord blood mast cells suggest that H1- and CysLT-receptor interactions likely occur at the airway smooth muscle level. CTM and MK-571 synergistically inhibited human allergic bronchospasm in the present in vitro model. The mechanism underlying this synergistic activity requires further investigation.

Postjunctional alpha(2C)-adrenoceptor contractility in human saphenous vein.

The postjunctional alpha(2)-adrenoceptor-mediated contractility was characterized in human saphenous vein derived from coronary artery bypass graft surgery. Human saphenous vein contracted to alpha(2)-adrenoceptor selective agonists BHT-920 (5,6,7,8-Tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride; pD(2)=6.7+/-0.1) and UK 14,304 (5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline; pD(2)=7.2+/-0.1). BHT-920-induced contractions were inhibited by the alpha(2)-adrenoceptor antagonist yohimbine (17-Hydroxy-yohimban-16-carboxylic acid methyl ester hydrochloride; pA(2)=8.7+/-0.5), but not by the alpha(1)-adrenoceptor antagonist prazosin (1-[4-Amino-6,7-dimethoxy-2-quinazolinyl]-4-[2-furanylcarbonyl]-piperazine hydrochloride; 300 nM). In contrast, prazosin (pK(b)=7.9+/-0.2) potently antagonized contractions elicited by the alpha(1)-adrenoceptor agonist phenylephrine ((R)-3-Hydroxy-alpha-[(methylamino)methyl] benzenemethanol hydrochloride; pD(2)=4.9+/-0.1), indicating that both alpha(2)- and alpha(1)-adrenoceptor evoke human saphenous vein contractions. Functional antagonist activity estimates (pA(2) or pK(b)) obtained for the alpha-adrenoceptor antagonists ARC 239 (2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride), WB 4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and HV 723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy) ethyl)amino)propyl)benzeneacetonitrile) against BHT-920-induced human saphenous vein contractions were 7.0+/-0.6, 8.3+/-0.6 and 7.7+/-0.3, respectively. The alpha(2)-adrenoceptor subtype affinities (pK(i)) obtained in recombinant human alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor competition binding assays were 8.6, 8.3 and 8.6 for yohimbine; 6.3, 8.4 and 7.0 for ARC 239; 8.4, 7.5 and 8.4 for WB 4101 and 7.5, 7.4 and 7.9 for HV 723, respectively. Taken together, the binding and functional antagonist activity estimates obtained in these investigations indicate that alpha(2C)-adrenoceptor is the predominant postjunctional alpha(2)-adrenoceptor subtype in human saphenous vein.

Receptor reserve analysis of the human alpha(2C)-adrenoceptor using.

Here we determine for norepinephrine, (5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline) (UK14,304), 5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (BHT-920), (2-[3-hydroxy-2,6-dimethyl-4-t-butylbenzyl]-2-imidazoline) (oxymetazoline), and ((R)-3-Hydroxy-alpha-[(methylamino)methyl]-benzenemethanol hydrochloride) (phenylephrine), affinities using a radiolabeled agonist and antagonist, and potency and efficacy values in membrane [(35)S]guanosine-5'-O-(3-thiotriphosphate) ([(35)S]GTP gamma S) binding and cAMP cellular inhibition assays, in Chinese hamster ovary cells (CHO-K1) expressing the human alpha(2c)-adrenoceptor. These cells express a high ratio of receptor to G-protein because each agonist, but not several antagonists, displaced [(3)H]UK14,304 with higher affinity than [(3)H]rauwolscine. The rank order of potency of high affinity K(i) and EC(50) in both functional assays was norepinephrine > or =UK14,304>BHT-920>oxymetazoline>phenylephrine. The receptor reserve of G-protein activation and cAMP responses was measured with the irreversible antagonist, benextramine; K(A) values of norepinephrine or UK14,304 were similar (289, 271 or 150, 163 nM, respectively). A 20-fold greater receptor occupancy was required for agonist-induced half-maximal [(35)S]GTP gamma S binding compared to cAMP inhibition, indicating significant signal amplification in cells. Therefore, the G-protein activation assay is better at distinguishing full and partial agonists.

A simple non-invasive method to measure the cough reflex in dogs.

INTRODUCTION: This study describes a method to measure the cough reflex in dogs that is simple to perform, requires no surgical intervention and can be used to profile efficacy and side-effect liabilities of antitussive drugs. METHODS: Experiments were performed in propofol-anesthetized dogs in which cardiopulmonary functions were non-invasively monitored before and after the induction of cough produced by spraying 0.75 ml of distilled water into the trachea. RESULTS: The magnitude of the cough response, measured by the frequency and amplitude was not different for individual dogs performed with repeated trials on different days. Treatment with the opioid antitussive drug, torbutrol (0.055-0.0055 mg/kg, s.c.) inhibited the cough frequency but not the amplitude induced by the water challenge. Furthermore, side effects of torbutrol were identified as mild respiratory depression and an anesthetic-sparing effect with propofol. DISCUSSION: This method offers many distinct advantages to evaluate efficacy of antitussive drugs including the fact that no surgery is required, it takes only 15-20 min to complete an experiment, and it can be used to simultaneously profile antitussive and side effect liabilities of drugs developed for the treatment of cough.

Cardiovascular profile of loratadine.

The extremely low reporting rate of cardiovascular adverse events for loratadine, the possible preferential use of loratadine in patients with pre-existing cardiovascular disorders, and the impressive lack of cardiovascular effects at extremely high concentrations in clinical and preclinical studies demonstrate the very safe cardiovascular profile of loratadine.

Sch 37224, an experimental antiallergy compound, inhibits the neuropeptide component of hyperventilation- and nicotine-induced bronchoconstriction in guinea pigs.

Sch 37224 is an experimental antiallergy compound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (CDyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/100 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/100 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 +/- 12%) and CDyn (-12 +/- 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (RL + 269 +/- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and CDyn -65 +/- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway C fibers.

Histamine H3 receptors inhibit sympathetic modulation of airway microvascular leakage in allergic guinea pigs.

Histamine H3 receptor modulation of antigen-induced airway microvascular leakage (AML) during sympathetic nerve stimulation was studied in guinea pigs. Intravenous administration of ovalbumin (100 micrograms) to sensitized guinea pigs produced AML that was reduced by electrical stimulation of sympathetic sites in the dorsal medulla. The sympatho-inhibition of this AML was attenuated by the histamine H3 receptor agonist, (R)-alpha-methylhistamine (30 and 100 micrograms/kg). The effect of (R)-alpha-methylhistamine was blocked by i.v. administration of the histamine H3 antagonists, thioperamide (1 and 3 mg/kg), burimamide (1-10 mg/kg) and impromidine (1 and 3 mg/kg). Thioperamide (3 mg/kg) and impromidine (3 mg/kg), but not burimamide (10 mg/kg) blocked the reduction in blood pressure due to (R)-alpha-methylhistamine. These results show that histamine H3 receptors inhibit sympathetic nerves that control the airway vasculature.

Hemorrhage following mandibular osteotomies: a report of 21 cases.

Hemorrhage associated with mandibular osteotomies, especially to the extent that it becomes life threatening, is a rare occurrence and its risk is less than that following maxillary orthognathic surgery. Twenty-one cases of significant bleeding following mandibular sagittal split ramus osteotomies, vertical and oblique ramus osteotomies, and genioplasties are presented. Life-threatening hemorrhage associated with mandibular osteotomies is primarily an intraoperative problem and the incidence of major postoperative and recurrent hemorrhage is not as great as following maxillary osteotomies. Suggestions for the avoidance and treatment of these bleeding complications are discussed.