Do we understand who benefits from resynchronisation therapy?

This editorial refers to "Interventricular and intraventriculardyssynchrony are common in heart failure patients, regardlessof QRS duration"¹ by S. Ghio et al. on page 571 Interest in ventricular dyssynchrony in heart failure patientshas been renewed recently by the introduction of cardiac resynchronisationtherapy (CRT). CRT is currently accepted as an adjunct to themedical treatment of symptomatic heart failure in patients withsevere left ventricular systolic dysfunction and ECG manifestationsof ventricular conduction delay.¹ It aims to reduce the electricalconduction delay by pre-excitation of late-activated regionswith left- or biventricular pacing to restore a more synchronouscontraction pattern. Although this strategy has been provento be effective at group     

Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury

Neuronal calcium (Ca²⁺)-binding proteins 1 and 2 (NECAB1/2) are members of the phylogenetically conserved EF-hand Ca²⁺-binding protein superfamily. To date, NECABs have been explored only to a limited extent and, so far, not at all at the spinal level. Here, we describe the distribution, phenotype, and nerve injury-induced regulation of NECAB1/NECAB2 in mouse dorsal root ganglia (DRGs) and spinal cord. In DRGs, NECAB1/2 are expressed in around 70% of mainly small- and medium-sized neurons. Many colocalize with calcitonin gene-related peptide and isolectin B4, and thus represent nociceptors. NECAB1/2 neurons are much more abundant in DRGs than the Ca²⁺-binding proteins (parvalbumin, calbindin, calretinin, and secretagogin) studied to date. In the spinal cord, the NECAB1/2 distribution is mainly complementary. NECAB1 labels interneurons and a plexus of processes in superficial layers of the dorsal horn, commissural neurons in the intermediate area, and motor neurons in the ventral horn. Using CLARITY, a novel, bilaterally connected neuronal system with dendrites that embrace the dorsal columns like palisades is observed. NECAB2 is present in cell bodies and presynaptic boutons across the spinal cord. In the dorsal horn, most NECAB1/2 neurons are glutamatergic. Both NECAB1/2 are transported into dorsal roots and peripheral nerves. Peripheral nerve injury reduces NECAB2, but not NECAB1, expression in DRG neurons. Our study identifies NECAB1/2 as abundant Ca²⁺-binding proteins in pain-related DRG neurons and a variety of spinal systems, providing molecular markers for known and unknown neuron populations of mechanosensory and pain circuits in the spinal cord.Calcium (Ca²⁺) plays a crucial role in many and diverse cellular processes, including neurotransmission (1). Glutamate and neuropeptides are neurotransmitters released from the central terminals of dorsal root ganglion (DRG) neurons in the spinal dorsal horn, where signals for different sensory modalities, including pain, are conveyed to higher centers (2–12). Neurotransmitter release is tightly regulated by Ca²⁺-dependent SNARE proteins whose activity is regulated by Ca²⁺-binding proteins (CaBPs) (1, 7, 13).Parvalbumin (PV), calbindin D-28K (CB), calretinin (CR), and secretagogin (Scgn) are extensively studied EF-hand CaBPs, and they have also emerged as valuable anatomical markers for morphologically and functionally distinct neuronal subpopulations (14–17). The expression of CaBPs in DRG neurons has been thoroughly studied (18). Moreover, neuronal Ca²⁺ sensor 1 and downstream regulatory element-antagonist modulator (DREAM) are also EF-hand Ca²⁺-binding proteins in DRGs and the spinal cord (19, 20). Despite these advances, a CaBP has so far not been characterized in the majority of small- and medium-sized DRG neurons, many of which represent nociceptors.The subfamily of neuronal Ca²⁺-binding proteins (NECABs) consists of three members (NECAB1–NECAB3), probably as a result of gene duplication (21). NECABs are also EF-hand proteins, with one pair of EF-hand motifs in the N terminus and a putative antibiotic biosynthesis monooxygenase domain in the C terminus, which are linked by a NECAB homogeneous region (22). NECAB1/2 are restricted to the nervous system, whereas NECAB3 is also expressed in the heart and skeletal muscle (21).NECAB1 was first identified as the target protein of synaptotagmin I C2A-domain by affinity chromatography, with its expression restricted to layer 4 cortical pyramidal neurons, inhibitory interneurons, and hippocampal CA2 pyramidal cells in mouse brain (21, 23). The gene of the second member was cloned from mouse and initially named Necab. It encodes a 389-aa (NECAB2) (24). NECAB2 was identified as a downstream target of Pax6 in mouse retina, which is involved in retinal development (24, 25), as well as being a binding partner for the adenosine A_2A receptor (22). Furthermore, an interaction between NECAB2 and metabotropic glutamate receptor 5 (mGluR5) was demonstrated in rat hippocampal pyramidal cells, possibly regulating mGluR5’s coupling to its signaling machinery (26). Finally, NECAB3, also known as XB51, was isolated as an interacting target for the neuron-specific X11-like protein and is possibly involved in the pathogenesis of Alzheimer’s disease (27, 28).Very recently, NECAB1/2 were shown to have complementary expression patterns in mouse hippocampus at the mRNA and protein levels, whereas NECAB3 is broadly distributed in the hippocampus (29). NECAB1-expressing cells were seen throughout the cell-sparse layers of Ammon’s horn and the hilus of the dentate gyrus. In contrast, NECAB2 is enriched in pyramidal cells of the CA2 region. A minority of NECAB1⁺ neurons were GABAergic yet did not coexpress PV, CB, or CR (29).Here, we investigated the expression of NECAB1/2 in mouse DRGs and spinal cord using quantitative PCR (qPCR), immunohistochemistry (also combined with CLARITY) (30), and Western blotting. We compared the distribution of NECABs with that of the four CaBPs restricted to neurons, PV, CB, CR, or Scgn. NECAB⁺ neurons in the spinal dorsal horn were phenotyped using transgenic mice harboring genetic markers for excitatory [vesicular glutamate transporter 2 (VGLUT2)] (31) or inhibitory [glutamate decarboxylase 67 (GAD67)] (32) cell identities. Finally, the effect of peripheral nerve injury was analyzed.     

One year follow-up of alcohol and illicit substance use in first-episode psychosis: Does gender matter?

Longitudinal studies on first-episode psychosis (FEP) patients have shown a decrease of substance use disorders (SUDs) over the first years of illness, but there has been less focus on the gender aspect. The present study examines stability of alcohol and illicit substance use, with specific focus on gender, in a one year follow-up investigation of 154 FEP patients (91 men, 63 women) in Oslo, Norway, using criteria for DSM-IV substance use disorder diagnosis, the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorders Identification Test (DUDIT). The results show that cannabis was the most frequently used illicit substance at both times. Significantly more men (34%) than women (13%) had a current illicit SUD at baseline. At follow-up, the rate of illicit SUDs was significantly reduced in men (18%) but not in women (11%). There were no significant gender differences in the rate of current alcohol use disorders (AUD) (men 14%; women 8%) at baseline, and no significant reduction in AUD in any of the genders at follow-up. At follow-up, total AUDIT and DUDIT scores were reduced in men only. In conclusion, the high and persistent rate of SUDs, particularly of cannabis, among men and women during the first year of treatment for psychosis should be addressed in the clinical management of the patients. Female FEP patients who are also substance users may be particularly vulnerable in this regard and warrant closer attention.