The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS

BACKGROUND AND PURPOSE: The histamine H(4) receptor is the most recently identified of the G protein-coupled histamine receptor family and binds several neuroactive drugs, including amitriptyline and clozapine. So far, H(4) receptors have been found only on haematopoietic cells, highlighting its importance in inflammatory conditions. Here we investigated the possibility that H(4) receptors may be expressed in both the human and mouse CNS. METHODS: Immunological and pharmacological studies were performed using a novel anti-H(4) receptor antibody in both human and mouse brains, and electrophysiological techniques in the mouse brain respectively. Pharmacological tools, selective for the H(4) receptor and patch clamp electrophysiology, were utilized to confirm functional properties of the H(4) receptor in layer IV of the mouse somatosensory cortex. RESULTS: Histamine H(4) receptors were prominently expressed in distinct deep laminae, particularly layer VI, in the human cortex, and mouse thalamus, hippocampal CA4 stratum lucidum and layer IV of the cerebral cortex. In layer IV of the mouse somatosensory cortex, the H(4) receptor agonist 4-methyl histamine (20 µmol·L(−1)) directly hyperpolarized neurons, an effect that was blocked by the selective H(4) receptor antagonist JNJ 10191584, and promoted outwardly rectifying currents in these cells. Monosynaptic thalamocortical CNQX-sensitive excitatory postsynaptic potentials were not altered by 4-methyl histamine (20 µmol·L(−1)) suggesting that H(4) receptors did not act as hetero-receptors on thalamocortical glutamatergic terminals. CONCLUSIONS AND IMPLICATIONS: This is the first demonstration that histamine H(4) receptors are functionally expressed on neurons, which has major implications for the therapeutic potential of these receptors in neurology and psychiatry

Cost-utility of the 21-gene recurrence score assay in node-negative and node-positive breast cancer

The 21-gene recurrence score (Oncotype DX: RS) appears to augment clinico-pathologic prognostication and is predictive of adjuvant chemotherapy benefit in node-negative (N-) and node-positive (N+), endocrine-sensitive breast cancer. RS is a costly assay that is associated with good 'value for money' in N- disease, while economic evaluations in N+ disease based on most recent data have not been conducted. We examined the cost-utility (CU) of a RS-guided adjuvant strategy, compared to current practice without RS in N- and N+, endocrine-sensitive, breast cancer from a Canadian health care system perspective. A generic state-transition model was developed to compute cumulative costs and quality-adjusted life years (QALYs) over a 25-year horizon. Patient outcomes with and without chemotherapy in RS-untested cohorts and in those with low, intermediate and high RS were examined based on the reported prognostic and predictive impact of RS in N- and N+ disease. Chemotherapy utilization (current vs. RS-guided), unit costs and utilities were derived from a Nova Scotia Canadian population-based cohort, local unit costs and the literature. Costs and outcomes were discounted at 3% annually, and costs were reported in 2011 Canadian dollars ($). Probabilistic and one-way sensitivity analyses were conducted for key model parameters. Compared to a non-RS-guided strategy, RS-guided adjuvant therapy was associated with$2,585 and $864 incremental costs, 0.27 and 0.06 QALY gains, and resultant CUs of$9,591 and $14,844 per QALY gained for N- and N+ disease, respectively. CU estimates were robust to key model parameters, and were most sensitive to chemo utilization proportions. RS-guided adjuvant therapy appears to be a cost-effective strategy in both N- and N+, endocrine-sensitive breast cancer with resultant CU ratios well below commonly quoted thresholds