Allergen immunotherapy in the prevention of asthma

PURPOSE OF REVIEW: Asthma is a disease causing significant morbidity and mortality. In the recent past, there has been an explosion of pharmacotherapeutic options attempting to control the disease. Unfortunately, none of the current options offers the promise of prevention or a permanent cure. However, there appear to be exciting, new data emerging to support the hypothesis that the prevention or early treatment of allergic rhinitis, such as with the use of allergen immunotherapy, may help mitigate the severity of bronchial symptoms and even prevent the development of asthma. In this paper, we review recent research published proposing immunotherapy as a means of preventing the development of, or at least ameliorating, allergic asthma. RECENT FINDINGS: There is evidence that the upper and lower airways may be considered a single unit, with the nasal and bronchial mucosa having features in common. Epidemiological, pathophysiological and clinical studies have shown that they can be affected by similar inflammatory triggers, with interconnected mechanisms amplifying the inflammatory cascade. Allergic rhinitis is interrelated to, and is a risk factor for, the development of asthma. An evidence-based review validates the successful use of allergen immunotherapy in treating allergic rhinitis and asthma. There is promising evidence advocating its use in the prevention of clinical asthma. SUMMARY: This article explores current research pertaining to the use of immunomodulation, such as by using allergen immunotherapy, to ameliorate and prevent the development of allergic asthma.     

Review of cetirizine hydrochloride for the treatment of allergic disorders

Cetirizine hydrochloride is an orally-active and selective histamine (H(1))-receptor antagonist. It is a second-generation antihistamine and a human metabolite of hydroxyzine. Therefore, its principal effects are mediated via selective inhibition of peripheral H(1) receptors. The antihistaminic activity of cetirizine has been documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth has been seen more commonly with cetirizine than with placebo. In vitro receptor binding studies have shown no measurable affinity for receptors other than H(1) receptors. Auto-radiographical studies with radiolabelled cetirizine in the rat have shown negligible penetration into the brain. Ex vivo experiments in the mouse have shown that systemically administered cetirizine does not significantly occupy cerebral H(1) receptors. Impairment of CNS function is comparable to other low-sedating antihistamines at the recommended dose of 10 mg/day for adults. It has anti-inflammatory properties that may play a role in asthma management. It does not interact with concomitantly administered medications, it has no cardiac adverse effects, and it does not appear to be associated with teratogenicity. Cetirizine is predominantly eliminated by the kidneys with a mean elimination half-life is 8.3 h. It is rapidly absorbed, and significant clinical inhibition of a wheal and flare response occurs in infants, children and adults within 20 min of a single oral dose and persists for 24 h. No tolerance to the wheal and flare response occurs even after 1 month of daily treatment. The clinical efficacy of cetirizine for allergic respiratory diseases has been established in numerous trials. There is evidence that cetirizine improves symptoms of urticaria. Concomitant use of cetirizine also decreases the duration and amount of topical anti-inflammatory preparations needed for the treatment of atopic dermatitis. Interestingly, several clinical studies suggest that cetirizine may be useful in the treatment and prevention of mild asthma.     

Plumbagin induces reactive oxygen species, which mediate apoptosis in human cervical cancer cells

There is an emerging evidence that plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) may have potential as a chemotherapeutic agent. However, the growth inhibitory mechanisms of plumbagin have remained unexplored. The aim of the study was to determine whether plumbagin-induced cell death in human cervical cancer cell line, ME-180, exhibited biochemical characteristics of apoptosis and to check whether N-acetyl-l-cysteine (NAC), which is a free radical scavenger, can reverse the cytotoxic effects of plumbagin. It can be concluded from the results that plumbagin inhibits the growth of ME-180 cells in a concentration and time-dependent manner. The cytotoxic effect of plumbagin induced cell death is through the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis as demonstrated by the present data. Treatment of cells with plumbagin caused loss of mitochondrial membrane potential (DeltaPsi(m)), and morphological changes characteristic of apoptosis, such as the translocation of phosphatidyl serine, nuclear condensation, and DNA fragmentation. Moreover, plumbagin-induced apoptosis involved release of mitochondrial cytochrome c and apoptosis inducing factor (AIF), thus activation of caspase-dependent and -independent pathways, as shown by the plumbagin-mediated activation of caspase-3 and -9. Our results also show that pretreatment of ME-180 cells with NAC blocks plumbagin-induced loss of DeltaPsi(m) and subsequent release of cytochrome c, AIF, and caspase-9 and -3 activation, thus inhibiting the apoptotic ability of plumbagin.     

Chronic morphine induces premature mitosis of proliferating cells in the adult mouse subgranular zone

The birth of cells with neurogenic potential in the adult brain is assessed commonly by detection of exogenous S phase markers, such as bromodeoxyuridine (BrdU). Analysis of other phases of the cell cycle, however, can provide insight into how external factors, such as opiates, influence the cycling of newly born cells. To this end, we examined the expression of two endogenous cell cycle markers in relation to BrdU: proliferating cell nuclear antigen (PCNA) and phosphorylated histone H3 (pHisH3). Two hours after one intraperitoneal BrdU injection, BrdU-, PCNA-, and pHisH3-immunoreactive (IR) cells exhibited similar distribution in the adult mouse subgranular zone (SGZ). Quantitative analysis within the SGZ revealed a relative abundance of cells labeled for PCNA > BrdU > pHisH3. Similar to our reports in rat SGZ, chronic morphine treatment decreased BrdU- and PCNA-IR cells in mouse SGZ by 28 and 38%, respectively. We also show that pHisH3-IR cells are influenced by chronic morphine to a greater extent (58% decrease) than are BrdU- or PCNA-IR cells. Cell cycle phase analysis of SGZ BrdU-IR cells using triple labeling for BrdU, PCNA, and pHisH3 revealed premature mitosis in chronic morphine-treated mice. These results suggest that morphine-treated mice have a shorter Gap2/mitosis (G(2)/M) phase when compared to sham-treated mice. These findings demonstrate the power of using a combination of exogenous and endogenous cell cycle markers and nuclear morphology to track proliferating cells through different phases of the cell cycle and to reveal the regulation of cell cycle phase by chronic morphine.     

Retrospective review of modafinil use for cerebral palsy

A retrospective review was undertaken at Texas Tech University Health Sciences Center regarding the use of modafinil for the treatment of spasticity associated with cerebral palsy. Neurology clinic records were reviewed from January 1, 2000, until October 1, 2001. Thirty pediatric patients with cerebral palsy were identified who were treated empirically with modafinil during this time period. Twenty-three (76%) patients reported diminished spasticity with treatment, which was confirmed by physical examination; these patients had improved joint mobility. Seventeen (56%) patients continued treatment with modafinil by the end of the formal review period (September 30, 2001). Twenty-three percent (seven) of the patients stopped taking modafinil during the study owing to one of the following: decreased sleep time (four), decreased appetite (one), hyperactivity, and irritability (two). Thus, this retrospective review shows a reduction in spasticity from cerebral palsy, with only minor and reversible side effects noted from modafinil. A blinded, crossover study using modafinil for spastic cerebral palsy is planned.     

Partial albinism, immunodeficiency, hypergammaglobulinemia and Dandy-Walker cyst--a Griscelli syndrome variant

A 6-year-old girl presented with recurrent infections, seizures, regression of milestones, silvery hair and organomegaly. A diagnosis of Griscelli syndrome with unusual features of a Dandy Walker cyst and hypergammaglobulinemia, not previously described in literature, was made. The child was treated with supportive measures.     

Rib defects in patterns of multiple malformations: a retrospective review and phenotypic analysis of 47 cases

Rib anomalies may occur in isolation, as well as in association with abnormalities of vertebral segmentation and multi-system malformations. Specific entities include the VACTERL and MURCS associations, spondylocostal dysostosis, and spondylothoracic dysostosis. The relative significance of rib anomalies in other lesser known syndromes and associations remains unclear. To document the diagnoses and related defects in patients with rib anomalies as part of broader pattern of anomalies, we retrospectively identified 47 cases from a hospital population, and evaluated specific costal findings and associated birth defects. In our study, fusion was the most common pattern of rib anomaly (72%), followed by bifid (28%) and hypoplastic ribs (26%). Unrecognized patterns of multiple congenital anomalies (MCA) and VACTERL association were the commonest specific diagnoses with a frequency of 30 and 28%, respectively. An associated vertebral defect was found in 72% of the patients. Of those with no vertebral anomaly, the combinations of "rib and cardiac defects alone" and "rib and renal defects alone" were seen in one-third of the patients (4/13). Both the occurrence and type of rib anomaly were helpful in defining certain syndromes and enhanced the likelihood of identifying related malformations.     

Validation of verbal autopsy to determine the cause of 137 neonatal deaths in Karachi,Pakistan

Verbal autopsy (VA) aims to estimate a community's mortality experience in the absence of contact with formal registration or health care systems. Application of VA to neonatal deaths is problematic as the agonal phase of a neonatal death tends to be indistinct. This is the first attempt to validate the technique exclusively on newborns who died. Seriously ill neonates (n = 137) were enrolled from the Civil Hospital, Karachi, Pakistan, between 31 October 1993 and 31 July 1994. All died as newborns, and caregivers were interviewed at home 3-230 days later. Surveillance physicians completed case questionnaires in the hospital, and investigator physicians assigned the main and associated causes of death using clinical criteria. Field questionnaires including a verbatim open-ended history, and syndrome modules were completed by a field worker, and investigator physicians again assigned the main and associated causes of death based on three diagnostic methods: verbatim alone, modules alone and verbatim and modules combined. We assessed the validity of VA by comparing field against hospital diagnoses by diagnostic (verbatim vs. modules vs. both) and analytic method (main vs. any diagnosis). VA identified at least one diagnosis accurately in 71% of the newborns. VA underdiagnosed low birthweight and prematurity in the field. Verbatim and modules diagnostic method comparing any field against main hospital diagnoses revealed high sensitivities for too early/too small syndrome (90%) and neonatal tetanus (84%). VA correctly identified some important causes of neonatal death in the field. Assigning multiple diagnoses using both open- and closed-ended questions increases the likelihood of correct ascertainment.