The search for social safety and comfort in families raising children with complex chronic conditions

Social consequences of raising children who were medically fragile and developmentally delayed (MF/DD) were explored in an ethnographic study of 20 families with school-age children. The overarching theme was the families' search for safety and comfort in social situations. Major categories comprising this theme included the need to anticipate and plan for the child's care; overcoming environmental, child-related, and attitudinal barriers; and finding social activities that were comfortable for all members of the family. When this search was successful, families could relax, and all members could participate in a variety of social encounters and activities; but when safety and comfort could not be achieved, families were likely to limit social activities or split the family so that the child who was MF/DD could be cared for while other family members participated in social events.     

NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists

Spinal NMDA receptors (NMDA R) are important in neuropathic sensitisation and acute administration of antagonists can provide temporary attenuation of sensitisation. If establishment of the chronic pain state could be prevented by brief administration of such agents at or around the time of nerve injury (pre-emptive analgesia) it might be possible to avoid many of the unacceptable side effects associated with repeated administration of these or other antagonists. Several reports describe aspects of effective pre-emptive analgesia from NMDA R antagonists in animal models of neuropathic pain. The first aim of the present study was to make a direct comparison of changes in mechanical allodynia, cold allodynia and thermal hyperalgesia following nerve injury, demonstrating their increasing degree of susceptibility to pre-emptive NMDA R antagonist treatment. Secondly, we used immunoblotting and immunohistochemistry to investigate the effects of nerve injury on NMDA receptor subunit expression, revealing increased expression of NR2B, but not NR2A and reduced NR1 in the superficial dorsal horn. These changes were attenuated following NMDA receptor antagonist pre-treatment. Thirdly, we investigated the pharmacological properties of residual mechanical allodynia and cold allodynia that remained after pre-emptive treatment and revealed a greater sensitivity to NMDA R antagonists. These findings indicate that in addition to a marked suppression of thermal hyperalgesia and cold allodynia, pre-emptive treatment with NMDA R antagonist causes a lasting change in spinal NMDA R complexes such that remaining mechanical allodynia should be more effectively targeted by NMDA R antagonists.     

Noninvasive proportional assist ventilation and pressure support ventilation during arm elevation in patients with chronic respiratory failure. A preliminary, physiologic study

BACKGROUND: It has been shown that upper limbs activity increases the respiratory workload in patients with chronic respiratory failure (CRF). The object of the present study was to investigate whether, in these patients: (i) noninvasive positive pressure ventilation (NPPV) could sustain the inspiratory muscles to meet the greater ventilatory demand during upper limbs activity with the arm elevation test (AE); (ii) proportional assist ventilation (PAV) might be superior to pressure support ventilation (PSV) during AE, because of its potential more adaptable response to sudden changes in the ventilatory pattern. METHODS: The study was performed in the pulmonary function laboratory of the Pulmonary Division in Verona General Hospital, Verona, Italy. We studied 8 male patients with CRF due to chronic obstructive pulmonary disease (COPD). Each patient received 2 treatment in random order with a crossover design: spontaneous breathing (SB), SB with AE, either PSV or PAV without and with AE, SB without and with AE, either PSV or PAV without and with AE. We measured: lung function tests, lung mechanics, ventilatory pattern and diaphragmatic effort (pressure time product, PTP(di)). RESULTS: (i) AE increases minute ventilation (+14%) and PTP(di) (+64%); (ii) ventilatory support, both with PSV and PAV unloads the diaphragm both at rest (PTP(di) -77% and -54%, respectively) and during arm elevation (PTP(di) -54% and -44%, respectively). CONCLUSIONS: PAV and PSV unloads the diaphragm in patients with CRF due to COPD both during SB and AE; PAV can be more efficient than PSV in assisting the diaphragm during AE in producing a greater level of minute ventilation for a similar rise in PTP(di) compared to PSV. Noninvasive ventilatory support should be considered in rehabilitation programs for training of upper limbs activity.     

Bone mineral density of children and adolescents with congenital hypothyroidism

A cross sectional study was made on 60 patients (9.9 +/- 1.8 yr-old) with congenital hypothyroidism (CH) (group A): 40 girls (23 prepubertal) and 20 boys (18 prepubertal). Control group (group B) was constituted of 28 healthy children (10.4 +/- 2.1 yr-old): 18 girls (8 prepubertal) and 10 boys (9 prepubertal). AIMS: To evaluate bone mineral density (BMD) and content (BMC) and to correlate them with chronological and bone age (BA), sex, sexual maturation, l-T4 dose, TSH, TT4, FT4, and CH etiology. BA, total body BMD, and BMC (DXA) were obtained of both groups. TSH, TT4, and FT4 were measured in patients only. BMD was lower in group A (0.795 +/- 0.075 g/cm(2) vs. 0.832 +/- 0.092; p = 0.04) and higher in pubertal than in prepubertal girls (p = 0.004). There was no significant difference between BMD and BMC related to sex and CH etiology. Our data demonstrated that BMD was significantly lower in children with CH, different from what has been published in the literature.     

Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer

Tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs), have been implicated in tumor progression. We recently described a lineage of mouse monocytes characterized by expression of the Tie2 angiopoietin receptor and required for the vascularization and growth of several tumor models. Here, we report that TIE2 expression in human blood identifies a subset of monocytes distinct from classical inflammatory monocytes and comprised within the less abundant "resident" population. These TIE2-expressing monocytes (TEMs) accounted for 2% to 7% of blood mononuclear cells in healthy donors and were distinct from rare circulating endothelial cells and progenitors. In human cancer patients, TEMs were observed in the blood and, intriguingly, within the tumors, where they represented the main monocyte population distinct from TAMs. Conversely, TEMs were hardly detected in nonneoplastic tissues. In vitro, TEMs migrated toward angiopoietin-2, a TIE2 ligand released by activated endothelial cells and angiogenic vessels, suggesting a homing mechanism for TEMs to tumors. Purified human TEMs, but not TEM-depleted monocytes, markedly promoted angiogenesis in xenotransplanted human tumors, suggesting a potentially critical role of TEMs in human cancer progression. Human TEMs may provide a novel, biologically relevant marker of angiogenesis and represent a previously unrecognized target of cancer therapy.     

Impairment of skin capillary recruitment precedes chronic complications in patients with type 1 diabetes

Microvascular function in patients with type 1 diabetes without chronic complications was assessed using skin capillary recruitment during post-occlusive reactive hyperemia (PORH). Structural (maximal) capillary density was evaluated during venous occlusion. The study included 48 consecutive outpatients aged 26.3 +/- 10.8 years with type 1 diabetes (duration of 9.5 years) without chronic complications and 34 control subjects. Intravital capillary video-microscopy was used in the dynamic study of skin capillaries in the dorsum of the fingers and toes. Capillary recruitment during PORH (% increase in mean capillary density, MCD) was significantly higher in the controls than the patients in both the fingers (p < 0.001) and toes (p < 0.001). During venous occlusion, MCD increase was also higher in the controls than the patients in both the fingers (p < 0.05) and toes (p < 0.0001). In patients, no difference was found between MCD at baseline and after venous occlusion in the fingers but a decrease was observed in the toes (p < 0.001). It is concluded that skin capillary function is significantly impaired in both fingers and toes of patients with type 1 diabetes without chronic complications. Moreover, capillary density during venous occlusion did not increase in either extremity in the patients, suggesting that their capillaries at rest are already maximally recruited.     

A comparison between inhaled salmeterol and theophylline in the short-term treatment of stable chronic obstructive pulmonary disease

BACKGROUND: International guidelines indicate that the long-acting bronchodilators play a key role in the treatment of patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the short term efficacy and safety of 50 and 100 microg bid inhaled salmeterol, compared with placebo and orally dose titrated slow-release theophylline in patients with stable COPD. METHODS: Thirteen patients (67+/-7 years, three females) with moderate-to-severe COPD (FEV1<70% predicted and >30% predicted) and with poor reversibility (post-bronchodilator FEV1<12% and <200 ml from pre-bronchodilator values) completed this single centre randomised, double-blind, double-dummy, four-phase cross-over clinical trial. Patients were randomised to treatment after a 2-week oral corticosteroid trial and a theophylline titration phase. Each treatment lasted 2 week with a 2-week washout period. Values at the end of treatments were compared. RESULTS: Inhaled salmeterol at both tested doses was better than placebo in improving lung function (FEV1, FVC, and morning PEF) of stable patients with moderate COPD over a period of 2 weeks. Although slight (about 170 ml, 150 ml, and 120 ml/min on average, for FEV1, FVC, and PEF, respectively) the improvement was significant. The effects seem to improve only slightly with the higher dose. Salmeterol appeared to be more effective than theophylline treatment when compared to placebo, as theophylline improved significantly, but less, the FEV1 (about 80 ml, on average) without affecting any of the other lung function variables. Salmeterol 100 microg was significantly better than theophylline in improving morning PEF. Four patients reported five adverse events while receiving placebo and 2 and 3 patients reported 2 and 3 adverse events, respectively, during salmeterol 50 microg and salmeterol 100 microg phases. None was considered drug related. Five patients experienced 13 adverse events with theophylline treatment, four of which were considered drug related. CONCLUSION: Inhaled salmeterol improves lung function in stable patients with moderate-to-severe and poorly reversible COPD. The magnitude of improvement in FEV1 observed in this study is similar to that found in longer and larger studies on similar populations of patients. In those studies, that improvement was associated with a better quality of life and less symptoms. Theophylline determined a smaller improvement in FEV1 with more unpleasant side effects that both doses of inhaled salmeterol, though there was no significant difference. It is concluded that salmeterol is an effective and well tolerated therapy, potentially preferable to theophylline, at least in the short-term management of stable COPD.     

Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases

Nitrate-based vasodilators (NBVs) are commonly used to treat multiple sequelae of atherosclerosis. A commonly used NBV, glyceryl trinitrate (GTN) is bioactivated by mitochondrial, class 2 aldehyde dehydrogenase (ALDH2). ALDH2 and other ALDHs are NAD(P)⁺-dependent enzymes critical to the detoxification of cytotoxic lipid-aldehydes elevated in atherosclerotic lesions, such as trans-4-hydroxy-2-nonenal (HNE). The GTN bioactivation step, however, inactivates ALDH2 and may alter the metabolism of these aldehydes. In this study, we tested the hypothesis that multiple ALDH enzymes are inhibited by different NBVs. ALDH2, ALDH3A, and ALDH5A were present in aorta with ALDH2 and ALDH3A localized to the smooth muscle layers. GTN (1 μM) inhibited ALDH2 activity (55±6% of control) and ablated ALDH3 activity. In contrast, isosorbide-2,5-dinitrate (ISDN, 1 μM) inhibited ALDH3 activity (1.1±0.4% of control) but did not inhibit ALDH2 activity even up to 50 μM ISDN. In homogenates of rat aorta, GTN (1 μM) inhibited the NAD⁺-dependent (41±5% of control) and NADP⁺-dependent (25±6% of control) detoxification of HNE. The inhibition of ALDH3A, but not ALDH2, could be prevented by the addition of dithiothreitol. These studies demonstrate that GTN and ISDN possess selectivity for ALDH inactivation with different mechanisms of inactivation.     

Ghrelin,Hypothalamus-Pituitary-Adrenal (HPA) Axis and Cushing's Syndrome

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.