Development and results of the Spanish registry of patients with alpha-1-antitrypsin deficiency

The Spanish registry of alpha-1 antitrypsin deficiency was founded in 1993 and became a member of the International Registry (AIR) in 1999. We describe the updating process following its incorporation into AIR and compare the data collected in the first period (1993–1999) and the second period (1999–2005), during which time patients were included exclusively by internet.The registry included 301 patients during period 1, 69% males and 46% had a history of smoking. Their mean age was 46 years (SD = 13) and 284 (94%) had the ZZ phenotype, 49% received augmentation therapy. During period 2, 161 new cases were included, 63% of whom were males with a mean age of 44 years (SD = 16). A total of 126 (78%) had the ZZ phenotype. Only 12% received augmentation therapy. A total of 462 different patients were included in both periods. Significant differences were observed in the number of cases with the SZ phenotype and the severity of FEV₁ impairment between the two periods.Implementation of an internet-based collection of data did not result in a lower rate of reporting to the registry. However, data from a significant number of patient included in period 1 could not be actualized in the new data base.     

The usefulness of mouse breast tumor models for testing and optimization of breast cancer vaccines at old age

Cancer is an age-related disease and with the graying of the society, there is an increasing need to optimize cancer management and therapy for application in elderly patients. Cancer vaccines that can be applied in both prevention and therapy are potentially less toxic than chemotherapy or radiation and could, therefore, be especially suitable for older more frail cancer patients. In this study, we used syngeneic metastatic (4TO7) and non-metastatic (64pT) breast tumor models to obtain valuable information on the potential usefulness of MAGE-encoding cancer vaccines in metastatic and non-metastatic breast cancer at old age. First, we tested a mouse Mage-b DNA vaccine in young mice and found a significant preventive effect on the development of metastases. However, little effect was observed on primary breast tumors. Second, we studied tumor progression in relation to aging and found significant smaller tumors in old compared to young mice. This was associated with an increase in the percentage of CD8(+) T cells in the inguinal lymph nodes at the site of the tumor at old age. These findings suggest that breast cancer immunotherapeutic approaches could be a valid strategy even in elderly patients.     

Immune regulation by novel costimulatory molecules

CD4 helper T (Th)-cells and the cytokines that they produce play essential regulatory roles in immune and autoimmune responses. Th activation and differentiation is regulated by costimulatory receptors. CD28 and CTLA-4 are important in maintaining the threshold of T-cell activation. ICOS and PD-1 are novel costimulatory receptors expressed on activated T-cells. B7-H3 recognizes a putative costimulatory receptor on activated T-cells. Here we summarize the latest developments in the novel costimulatory molecules and their roles in regulating Th activation, differentiation, and function.     

Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice

Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. mu-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective kappa-opioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of mu-opioid receptors has no functional consequence on the response to the prototypical kappa-opioid receptor agonist, but decreases responses to the prototypical mu- and delta-opioid receptor agonists.     

Crosstalk Between Mucosal Inflammation and Bone Metabolism in Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a multifactorial and highly heterogeneous upper airway disease that affects approximately 12% of the general population. There is increasing evidence supporting the impact of osteitis on the pathophysiology of CRS. Osteitis is frequently observed in patients with CRS, and is associated with severe sinonasal inflammation and recalcitrant cases. The overlying inflammatory sinonasal mucosa plays a critical role in the initiation of osteitis; however, the underlying molecular mechanisms and functional significance remain unclear. Increasingly many studies have suggested that immune cells play a crucial role in the bone remodeling process in CRS. The purpose of this review is to summarize the current state of knowledge regarding the specific role of sinonasal inflammation in bone remodeling in CRS patients.     

Hyperpolarization‐activated channels shape temporal patterns of ectopic spontaneous discharge in C‐nociceptors after peripheral nerve injury

Background

Neuropathic pain is thought to be mediated by aberrant impulses from sensitized primary afferents, and the temporal summation of the discharges might also influence nociceptive processing. Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels (Ih current) generate rhythmic activity in neurons within the central nervous system and contribute to nociceptors excitability in neuropathic pain.

Methods

We searched for single fibres with ectopic spontaneous discharges from an in vitro preparation in mice containing a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches.

Results

Both damaged (axotomized) and undamaged fibres (putative intact) developed ectopic spontaneous activity with different temporal spike trains: Clock‐like, Irregular or Bursts. The Ih current blocker, ZD7288, significantly suppressed ectopic spontaneous discharges in nociceptive fibres (3/5 Aδ‐ and 24/31 C‐units and 1 nonclassified) by 64%. Additionally, ZD7288 changed the spike patterns of 5/7 Clock‐like and 3/4 Burst units to Irregular. Exogenous cAMP produced a significant ~65% increase in the ectopic firing in 5 Irregular fibres, which was restored by ZD7288. In six additional fibres (three Clock‐like and three Irregular), exogenous cAMP had no further effect, but co‐application with ZD7288 decreased their discharge by half. These units showed significant higher levels of discharges than the cAMP‐sensitive ones.

Conclusions

Our data suggest that HCN channels modulate ectopic spontaneous firing in C‐nociceptors and shape their temporal patterns of discharge which will, ultimately, modify the nociceptive message received and processed by second‐order neurons.

Significance

We show an involvement of HCN channels in the modulation of ectopic spontaneous discharges from C‐nociceptors. This finding exposes a mechanism of nociceptive transmission enhancement and highlights the clinical relevance of peripheral HCN blockade for spontaneous pain relief during neuropathy.