SUMMARY Chronic itch is a prevalent and debilitating condition for which few effective therapies are available. We harnessed the natural variation across genetically distinct mouse strains to identify transcripts co-regulated with itch behavior. This survey led to the discovery of the serotonin receptor, HTR7, as a key mediator of serotonergic itch. Activation of HTR7 promoted opening of the ion channel TRPA1, which in turn triggered itch behaviors. In addition, acute itch triggered by serotonin or a selective serotonin reuptake inhibitor required both HTR7 and TRPA1. Aberrant serotonin signaling has long been linked to a variety of human chronic itch conditions, including atopic dermatitis. In a mouse model of atopic dermatitis, mice lacking HTR7 or TRPA1 displayed reduced scratching and skin lesion severity. These data highlight a role for HTR7 in acute and chronic itch, and suggest that HTR7 antagonists may be useful for treating a variety of pathological itch conditions.

Background:Chronic granulomatous disease (CGD) is an uncommon primary immunodeficiency that can be inherited in an X-linked (XL) or an autosomal recessive (AR) manner. We reviewed our large, single-center US experience with CGD.Methods:We reviewed 27 patients at Ann & Robert H. Lurie Children’s Hospital of Chicago from March 1985 to November 2013. Fisher exact test was used to compare differences in categorical variables, and Student t test was used to compare means for continuous variables. Serious infections were defined as those requiring intravenous antibiotics or hospitalization.Results:There were 23 males and 4 females; 19 were XL and 8 were AR. The average age at diagnosis was 3.0 years; 2.1 years for XL and 5.3 years for AR inheritance (P = 0.02). There were 128 serious infections. The most frequent infectious agents were Staphylococcus aureus (n = 13), Serratia (n = 11), Klebsiella (n = 7), Aspergillus (n = 6) and Burkholderia (n = 4). The most common serious infections were pneumonia (n = 38), abscess (n = 32) and lymphadenitis (n = 29). Thirteen patients had granulomatous complications. Five patients were below the 5th percentile for height and 4 were below the 5th percentile for weight. Average length of follow-up after diagnosis was 10.1 years. Twenty-four patients were compliant and maintained on interferon-γ, trimethoprim-sulfamethoxazole and an azole. The serious infection rate was 0.62 per patient-year. Twenty-three patients are alive (1 was lost to follow-up).Conclusions:We present a large, single-center US experience with CGD. Twenty-three of 27 patients are alive after 3276 patient-months of follow-up (1 has been lost to follow-up), and our serious infection rate was 0.62 per patient-year.

Absence seizures occur in several types of human epilepsy and result from widespread, synchronous feedback between the cortex and thalamus that produces brief episodes of loss of consciousness. Genetic rodent models have been invaluable for investigating the pathophysiological basis of these seizures. Here, we identify tetratricopeptide-containing Rab8b-interacting protein (TRIP8b) knockout mice as a new model of absence epilepsy, featuring spontaneous spike-wave discharges on electroencephalography (EEG) that are the electrographic hallmark of absence seizures. TRIP8b is an auxiliary subunit of the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which have previously been implicated in the pathogenesis of absence seizures. In contrast to mice lacking the pore-forming HCN channel subunit HCN2, TRIP8b knockout mice exhibited normal cardiac and motor function and a less severe seizure phenotype. Evaluating the circuit that underlies absence seizures, we found that TRIP8b knockout mice had significantly reduced HCN channel expression and function in thalamic-projecting cortical layer 5b neurons and thalamic relay neurons, but preserved function in inhibitory neurons of the reticular thalamic nucleus. Our results expand the known roles of TRIP8b and provide new insight into the region-specific functions of TRIP8b and HCN channels in constraining cortico-thalamo-cortical excitability.

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