Trends in the prescribing of topical nasal agents Using an NHS England data base.

OBJECTIVES: Our aim is to present data depicting geographical prescribing trends and expenditure related to topical nasal agent prescriptions across clinical commissioning groups (CCG's) in England. We assess if prescribing trends can act as a surrogate marker for allergic rhinitis (AR) and rhinosinusitis disease burden (RS). DESIGN: NHS England primary care prescriptions dispensed for topical drugs used in nasal allergy (BNF chapter 12.2.1) were accessed using OpenPrescribing beta software. Graphical data over a 5-year period was generated to highlight nationwide trends in prescribing and expenditure. Out of 211 CCG districts, the highest and lowest 40 prescribing rate CCG's were subdivided according to rural/urban output and geographical location to highlight specific regional trends. Two sampled, paired and unpaired t tests of unequal variance were performed to determine the significance of observed trends. RESULTS: The 5-year trend in prescription rate (mean yearly expenditure £40 725 258) for drugs used in nasal allergy marginally increased. Peak prescription was during months of high environmental pollen. Regardless of pollen season (June 2016 vs November 2015), CCG's of urban districts had significantly lower rates of prescribing (P ≤ .001). Amongst the 40 lowest and 40 highest prescribing rate CCG's, prescription rates fell significantly between months of high and low environmental pollen (P ≤ .0001). Regardless of pollen season, rural eastern and eastern coastal districts of England had persistently high rates of prescription. CONCLUSIONS: This study shows marked geographical variation in prescribing for topical nasal agents in England. There is propensity for eastern districts to have higher rates of prescribing in England. Adopting prescribing trends as a surrogate marker for disease burden could allow allergy and endoscopic sinus surgery services to be concentrated to specific regions. This would provide more effective, economical treatment for both AR and RS.

Characterization of gait parameters in patients with Charcot-Marie-Tooth disease.

The gait of five patients with Charcot-Marie-Tooth(CMT) disease was analyzed using light-emitting diodes and a force plate. The flexion-extension motions of the hips, knees, and ankles, as well as their moments (vector sums of forces acting at the joints) in the flexion-extension and abduction-adduction planes, were quantified. The gait of the CMT patients showed abnormalities consistent with both distal weakness (ankle dorsi- and plantar-flexors) and weakness of the hip abductor muscles. The latter weakness appeared to produce asymmetric hip moments and truncal instability in the mediolateral plane during ambulation. However, the extent to which the gait was abnormal appeared not to be exclusively related to the severity of the sensorimotor conduction deficits in the peripheral nerves. In the four patients for whom nerve conduction velocity studies were available, decrease in the lower-extremity distal conduction velocities and evoked motor amplitude potentials did not correlate with the severity and extent of the gait abnormalities.

Nitric oxide synthase induction in lines of macrophages from different anatomical sites.

Induction of nitric oxide synthase (iNOS) and nitric oxide (NO) production have been demonstrated using three macrophage cell lines from different anatomical sites, which had been immortalized using a rapid and convenient procedure previously described. Lysis of tumor cells presumably was caused by NO accumulation in the supernatants of cultures of the three cell lines after induction with a mixture of recombinant murine interferon gamma (rMuIFNgamma) and lipopolysaccharide (LPS). Induction by these two biological response modifiers (BRM) caused lysis of tumor cells and was repressed by addition of 1 microM (final concentration) of methyl-L-arginine (MMA) to the mixture during induction of the enzyme. Research using readily generated macrophage cell lines may facilitate clarify basic aspects of iNOS induction in these cells.

Antitumor activity of interleukin 12 in preclinical models.

Interleukin 12 (IL-12) is a heterodimeric cytokine with a number of biological effects that are consistent with its potential role as an antitumor agent. The antimetastatic and antitumor activities of IL-12 have been demonstrated in a number of murine tumor models. Both the inhibition of established experimental pulmonary or hepatic metastases and a reduction in spontaneous metastases have been achieved by treatment with murine IL-12. Systemic treatment of mice bearing subcutaneous tumors with IL-12 results in tumor growth inhibition, prolongation of survival, and, in some models, tumor regression. The antitumor effect of IL-12 in these models is dose-dependent and can be initiated against well-established tumors. Mice cured of their tumor by IL-12 treatment are specifically immune to rechallenge with the same tumor. A series of experiments have demonstrated that both T-cells and interferon-gamma (IFN-gamma) induction are necessary for the optimal antitumor effects of IL-12. However, the antitumor efficacy of IL-12 has not been observed after exogenous administration of murine IFN-gamma, suggesting that additional factors may be important for the antitumor effects of IL-12. In several tumor models, IL-12 is more active or has a larger therapeutic window than either IL-2 or IFN-alpha, two cytokines with demonstrated antitumor activity against human malignancies. Combining IL-12 with other cytokines or chemotherapeutic drugs can improve antitumor effects.

Chronic toxicity of Great Lakes sediments to Daphnia magna: elutriate effects on survival, reproduction and population growth.

: Seventeen Great Lakes sediments ranging in degree of expected toxicity were evaluated using a 21 day sediment elutriate bioassay with Daphnia magna. Sediments differed in their effects on survival, age at first reproduction, the number of broods produced and the total number of young produced per adult. Sediments producing low survivorship (50-60%) also had negative effects on reproduction. However, both positive and negative effects on reproduction were found among sediments producing high survivorship. To integrate all test end-points, a stochastic matrix population model was constructed and parameterized with survival and reproduction data from each sediment. By including estimates of variability in vital rates, the model output provided quantitative estimates of uncertainty in projected population size. Sediment effects on survival and reproduction translated into large differences in projected population growth; mean estimates of projected population size at day 28 of the simulations ranged over two orders of magnitude among the 17 sediments. Reproductive timing (e.g. age at first reproduction), followed by fecundity and survivorship, had the largest effect on population growth. Results of this study also indicate that the presence of suspended sediment in elutriates may confound toxicity evaluations using cladocerans. The concentration of total suspended solids was negatively correlated with age at first reproduction and positively correlated with measures of fecundity and population growth. In order to realize the potential benefits of chronic testing we must develop ecologically relevant ways of interpreting sediment bioassay results and expressing the uncertainty associated with our estimates of ecological risk.

Characterization of gait parameters in adult-onset myotonic dystrophy: abnormal hip motion.

The gait of five patients with myotonic dystrophy was analyzed using light-emitting diodes and a force plate. When compared with the gait of control subjects, that of myotonics suggested weakness of the tibialis anterior and triceps surae muscles. Although the myotonics showed no evidence of lower-extremity myotonia (delayed muscle relaxation following contraction), or of weakness of the hip or knee musculature, all had striking abnormalities in their hip motion. In contrast to the smooth and consistent extension of the hip throughout stance phase observed during gait in control subjects, the hips of myotonics oscillated irregularly as they progressed through stance phase extension, with considerable variation between legs and during successive strides. Excessive use of hip musculature in an attempt to control the oscillatory hip motion may contribute to the chronic fatigue associated with myotonic dystrophy.

Characterization of protein interactions with positive and negative elements regulating the apoVLDLII gene.

Synthesis of avian apo very-low-density lipoprotein (apoVLDL)II is estrogen dependent and liver specific. Competence to express the apoVLDLII gene is not acquired until days 7-9 of embryogenesis and thus lags 5-6 days behind appearance of the liver primordial bud. It is not known whether the delayed ability to activate the gene is attributable to hepatic estrogen receptor profiles, or a requirement for other transcription factors not expressed at earlier stages of embryogenesis. The latter possibility is supported by developmental alterations in nuclease hypersensitivity flanking the gene that occur independently of estrogen administration. We have examined the influence of these hypersensitive regions on expression from the apoVLDLII promoter and have characterized novel protein-DNA interactions at two of them. One is located in a copy of the CR1 family of middle repetitive elements approximately 3.0 kb upstream from the start of the gene. We demonstrate by DNase I footprinting that the site contains an element which matches a predicted consensus silencer sequence. The other site contains no previously identified binding motifs. It is located between nucleotides -228 and -245 and is adjacent to an imperfect estrogen response element (ERE) that we demonstrate acts additively with a canonical ERE 30 nucleotides downstream. We have identified ubiquitous and liver-specific factors that display overlapping DNA contacts with the site. Mutation of G residues contacted by these proteins decreases hormone-inducible expression from the promoter 5- to 8-fold. Hepatic levels of the liver-enriched factor interacting with this site increase abruptly between days 7 and 9 of embryogenesis, suggesting that it may be an important determinant of the ability to express the apoVLDLII and possibly other liver-specific genes.

Enhanced antitumor efficacy in mice by combination treatment with interleukin-1 alpha and interferon-alpha.

The antitumor efficacy of recombinant murine interleukin-1 alpha (rMuIL-1 alpha) was evaluated either alone or in combination with recombinant human hybrid interferon alpha A/D (IFN-alpha A/D) against the murine B16 F10 malignant melanoma. Treatment of subcutaneous tumor-bearing mice intraperitoneally with rMuIL-1 alpha resulted in a dose-dependent inhibition of tumor growth with the greatest activity obtained with the maximum tolerated dose of rMuIL-1 alpha (10 micrograms per treatment). Augmented tumor inhibition comparable to that seen in mice treated with a high dose of rMuIL-1 alpha was observed in subcutaneous tumor-bearing mice injected with the combination of IFN-alpha A/D and a low dose of rMuIL-1 alpha. Similar inhibition of subcutaneous tumor growth was obtained in T-cell-deficient nude or natural killer cell-deficient beige mice. In contrast, treatment of mice bearing B16F10 experimental pulmonary metastases with rMuIL-1 alpha resulted in no decrease in the number of metastases, and rMuIL-1 alpha did not potentiate the antimetastatic activity of IFN-alpha A/D. A synergistic induction of IL-6 was induced in mice treated with the combination of rMuIL-1 alpha plus IFN-alpha A/D but the level of IL-6 induced was not correlated with inhibition of tumor growth because this elevation of IL-6 was not observed in tumor-bearing nude mice. No direct antiproliferative activity was demonstrable in vitro against B16 F10 cells with rMuIL-1 alpha, IL-6, or rMuIL-1 alpha plus IL-6, and addition of these cytokines did not enhance the antiproliferative activity of IFN-alpha A/D.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitumor and antimetastatic activity of interleukin 12 against murine tumors.

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.

Tumoricidal alveolar macrophage and tumor infiltrating macrophage cell lines.

Continuous alveolar macrophage (AM) and tumor-infiltrated (TIM) cell lines have been generated from C57B16J mice by in vitro infection with the J2 retrovirus carrying the v-raf and v-myc oncogens. Four cloned AM cell lines (AMJ2-C8, AMJ2-C10, AMJ2-C11, AMJ2-C20) and 3 cloned TIM cell lines (TIMJ2-C4, TIMJ2-C7 and TIMJ2-C15) were expanded for further characterization. Flow cytometry detected the product of the raf gene in the cytoplasm of all these cell lines. Studies on the tumoricidal properties of these AM and TIM cell lines demonstrated differences in their response to a panel of known macrophage activators. Four of these cell lines (AMJ2-C8, AMJ2-C10, TIMJ2-C7 and TIMJ2-C15) were activated following exposure to recombinant murine interferon gamma (rMuIFN-gamma) but not lipopolysaccharide (LPS) or muramyl dipeptide (MDP). AMJ2-C20 was only activated by incubation with rMuIFN-gamma plus LPS. AMJ2-C11 and TIMJ2-C4 are the cell lines that most closely resembled the response pattern of the parental AM and TIM, since they could be activated by either the combination of rMuIFN-gamma plus LPS or rMuIFN-gamma plus MDP. Constitutive expression of MHC-class-II antigens was low on AMJ2-C11 or TIMJ2-C4 but was increased following exposure to rMuIFN-gamma. Neither cell line secreted substantial amounts of IL-1 or TNF but both secreted large amounts of IL-6. Thus these cell lines could be powerful tools to study AM and TIM activation and cytotoxicity.

Tumoricidal activity and cytokine secretion by tumor-infiltrating macrophages.

Murine macrophages from different anatomical sites were compared for their ability to become tumoricidal and to secrete interleukin-1 (IL-1) and tumor necrosis factor (TNF) following stimulation in vitro by several biological response modifiers (BRM). Peritoneal macrophages (PM), alveolar macrophages (AM), and tumor-infiltrating-macrophages (TIM), isolated from B16F10 melanoma colonies in the lung, were incubated overnight with BRM [recombinant murine interferon gamma (rMulFN-gamma), lipopolysaccharide (LPS), muramyl dipeptide (MDP)], either alone or in combination. PM exhibited an increased cytotoxic response following incubation with LPS or rMuIFN-gamma but not with MDP. Both AM and TIM were induced to become tumoricidal following incubation with rMuIFN-gamma plus LPS or rMuIFN-gamma plus MDP but not after stimulation with any BRM alone; the level of cytotoxicity obtained with TIM incubated with rMuIFN-gamma plus LPS was slightly lower than that observed with PM or AM, while with rMuIFN-gamma plus MDP both AM and TIM had lower cytotoxicity than PM. Secretion of IL-I and TNF was observed in PM stimulated with LPS or MDP but not with rMuIFN-gamma. Likewise, secretion of IL-I by AM or TIM was also induced with LPS, although less than that obtained with PM. AM stimulated with LPS secreted larger amounts of TNF than PM while TIM secreted very low amounts of TNF. However, this result may be a consequence of the enzymatic isolation procedure used to obtain TIM since TNF secretion was also impaired in LPS-stimulated normal lung macrophages isolated by a similar enzymatic procedure, or enzyme-treated PM. Our results suggest that TIM obtained from lung metastases share certain functional characteristics with normal AM and respond to BRM in like manner with respect to induction of tumoricidal activity and cytokine secretion.

At risk with the Red Cross. Interview by Craig Little.

The founding of the International Red Cross drew its inspiration from a single, bloody battle in northern Italy. The multicomponent organization is more than 125 years old and still very active where there are war wounds to bind and natural disasters to relieve.

Modification of water-soluble coal-derived products by dibenzothiophene-degrading microorganisms.

To study mechanisms by which microorganisms oxidize thiophenic sulfur in coal, we tested bacterial cultures for the ability to degrade dibenzothiophene (DBT), DBT-5-oxide, and DBT-sulfone and to modify water-soluble coal products derived from Illinois no. 6 and Ugljevik coals. In yeast extract medium, the majority of selected isolates degraded DBT and accumulated DBT-5-oxide in culture fluids; all but one of the cultures degraded DBT-5-oxide, and none of them degraded DBT-sulfone. Elemental analysis data indicated that the microbial cultures were able to decrease the amount of sulfur in soluble coal products derived from Illinois no. 6 and Ugljevik coals. However, these data suggested that microbially mediated sulfur removal from soluble Ugljevik coal occurred by nonspecific mechanisms. That is, extensive degradation of the carbon structure was concurrent with the loss of sulfur. This conclusion was supported by X-ray photoelectron spectroscopic data which indicated that the reduced sulfur forms in the soluble Ugljevik coal product was not oxidized by microbial treatment.

Chromosome mapping of biological pathways by fluorescence-activated cell sorting and cell fusion: human interferon gamma receptor as a model system.

Human chromosome 6 encodes both the interferon gamma receptor as well as the class I major histocompatibility complex antigens, HLA-A, -B, and -C. However, the presence of chromosome 6 in somatic cell hybrids is insufficient to confer sensitivity to human interferon gamma (Hu-IFN-gamma) as assayed by class I HLA induction; it is necessary for both human chromosomes 6 and 21 to reside in the hybrid to generate a response to Hu-IFN-gamma. Treatment of such a hamster-human hybrid, Q72-18, with Hu-IFN-gamma induces the class I HLA antigens. Q72-18 cells selected by fluorescence-activated cell sorting for the loss of class I HLA induction also lost human chromosome 21. Fusions of such cells to a hybrid that contains only human chromosome 21 reconstitutes HLA antigen induction by Hu-IFN-gamma. Furthermore, fusions of hybrids containing a translocated human chromosome 6q and the HLA-B7 gene to a line containing only human chromosome 21 or a translocated 21q also reconstitutes HLA-B7 mRNA and antigen induction by Hu-IFN-gamma. Thus the segregation of cells on the basis of a biological effect by fluorescence-activated cell sorting and reconstitution by hybrid fusion provides a strategy by which some biological pathways can be mapped at a chromosomal level.

Hearing loss in myotonic dystrophy.

Seventeen of 25 patients with myotonic dystrophy had moderate to severe hearing loss, usually sensorineural, that was identified by routine audiometric screening and was treatable in some patients. Further testing failed to reveal a single pathophysiological process.

Central nervous system magnetic resonance imaging findings in myotonic dystrophy.

We evaluated findings in 14 patients with myotonic dystrophy (MD) using magnetic resonance imaging of the brain and compared them with those in age-matched controls with headache. There was an increased incidence of ventriculomegaly and a lumpy and/or thick pattern of periventricular hyperintensity in patients with MD as compared with the age-matched controls. These white matter abnormalities do not appear to be etiologically specific, but some possible explanations for these frequent findings in MD are discussed.