Clinical and biological effects of treatment with amifostine in myelodysplastic syndromes

We treated six patients with primary myelodysplastic syndrome (MDS) with amifostine (200 mg/m(2) i.v./three times a week for three consecutive weeks). Neutrophil counts were more frequently increased than platelet and reticulocyte counts, but no reduction of the transfusion requirement was observed. Significant reduction of the marrow blasts was observed in one case of refractory anaemia with excess of blasts. In vitro stimulation of haematopoiesis was observed in five cases. The apoptotic rate of marrow cells was significantly diminished even after the first course. Our findings show fairly good clinical and biological response to amifostine in MDS.     

Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro

OBJECTIVE: The goal of this study was to determine if the properties of the transient outward potassium (I(to)), TTX-resistant sodium (I(Na)) and L-type calcium (I(Ca)) currents are altered during changes in cardiac cell shape. METHODS: Ventricular myocytes were isolated from 3- to 4-day-old neonatal rats and cultured on either non-aligned or aligned collagen thin gels. In contrast to the flat, stellar-shaped myocytes obtained when the cells are plated on non-aligned collagen gels, myocytes plated on aligned gels display an elongated, rod-like shape. Ion channel expression was measured using the whole-cell arrangement of the patch clamp technique and Western blot analysis. RESULTS: Peak values for I(to), I(Na) and I(Ca) were 9+/-1, 71+/-13 and 7+/-1 pA/pF, respectively, in the flat cells, and increased to 21+/-2, 190+/-26 and 13+/-1 pA/pF, respectively, in the aligned cells. Application of forskolin (2 microM) and 3-isobutyl-1-methylxanthine (100 microM) resulted in a 101+/-18% increase in I(Ca) in the flat cells, but increased the current by only 43+/-9% in the aligned cells. Internal dialysis of the myocytes with cAMP strongly increased the peak I(Ca) in the flat cells, but caused no significant change in the aligned cells. While both basal and forskolin-stimulated levels of cAMP were the same in the two cell morphologies, the expression of the calcium channel alpha(1C) subunit was increased in the aligned cells. CONCLUSIONS: The expression and regulatory properties of voltage-gated calcium channels are modified during changes in neonatal rat myocyte shape.     

Methods of using interleukin 2 to enhance HIV-specific immune responses

Interleukin 2 (IL-2) in combination with highly active antiretroviral therapy (HAART) can significantly increase CD4+ T cell counts but does not improve HIV-specific T cell-mediated immune responses that are associated with the control of viral replication. To characterize the immunomodulatory activity of IL-2 in HIV-infected individuals we studied the virus-specific immune response (VIR) by intracellular cytokine expression (interferon gamma, IFN-gamma) after mimicking HIV rebound in peripheral blood mononuclear cells (PBMCs). We found that the whole virus used as HIV antigen was able to activate HIV-specific T cells in the presence of a low concentration (50 IU/ml) of IL-2. Interestingly, increasing concentrations of IL-2 (400 or 1000 IU/ml) in combination with the same amount of HIV doubled the number of HIV-specific T cells. These cells were functionally intact because all of the IFN-gamma-producing CD8+ T cells contained perforin, a marker for cytotoxic T lymphocytes (CTLs). Induction of HIV-specific immune responses by IL-2 was not detected in the absence of HIV antigen both in vitro and in patients treated with HAART, indicating that IL-2 can amplify HIV-specific T cells in the presence of HIV antigen. Therefore, a combination of IL-2 with either structured treatment interruption, which results in a controlled viral load rebound, or with therapeutic vaccination is expected to improve HIV-specific T cell-mediated immune responses.     

Neuroadrenergic denervation of the lung in type I diabetes mellitus complicated by autonomic neuropathy

STUDY OBJECTIVE: To verify whether autonomic neuropathy (AN) complicating type I, insulin-dependent diabetes mellitus affected neuroadrenergic bronchopulmonary innervation. PATIENTS: Twenty nonsmoking diabetic patients without respiratory diseases were studied: 11 patients with AN (group AN) and 9 patients without AN (control; group C) diagnosed by standardized criteria. DESIGN: Patients underwent respiratory function tests and ventilatory scintigraphies with (123)I-metaiodobenzylguanidine (MIBG) and with (99m)Tc-diethylenetriaminepenta-acetic acid (DTPA) to assess both bronchopulmonary neuroadrenergic innervation and also permeability of the alveolar-capillary barrier to water-soluble tracers. Rates of pulmonary clearance of the two tracers were computed, and correlates were identified by nonparametric statistics. SETTING: University hospital. RESULTS: The AN and C groups had normal respiratory function test results and comparable duration of diabetes and quality of metabolic control. (99m)Tc-DTPA clearance did not distinguish the groups. (123)I-MIBG clearance was faster in the AN group than in the C group (mean +/- SD half-time of the radiotracer time-activity curve [T(1/2)], 116.1 +/- 22.8 min in the AN group vs 139.5 +/- 18.3 min in the C group, p = 0.022), which is consistent with neuroadrenergic denervation in the AN group. (123)I-MIBG clearance was independent from (99m)Tc-DTPA clearance. Faster (123)I-MIBG clearance was significantly associated with worse performance in three of the four autonomic tests. CONCLUSIONS: Neuroadrenergic bronchopulmonary denervation may occur in diabetic patients with AN despite normal clinical and respiratory function findings. Further research is needed to identify clinical and prognostic implications of these findings.     

An ATG repeat in the 3'-untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance

Resistin is overexpressed in human adipose tissue of obese individuals and is likely to modulate insulin sensitivity. Resistin is, therefore, a candidate gene for insulin resistance. We searched for polymorphisms in the resistin gene by single strand conformation polymorphism and direct sequencing. An ATG triplet repeat in the 3'-untranslated region was identified and considered for association with insulin resistance. Three alleles were identified (allele 1: 8 repeats, allele frequency, 0.3%; allele 2: 7 repeats; allele frequency, 94.5%; allele 3: 6 repeats; allele frequency, 5.2%). Two hundred and three unrelated white Caucasian nondiabetic subjects from Sicily and 456 from the Gargano area (center east coast of Italy) were analyzed. Among Sicilians, subjects carrying allele 3 had a lower fasting insulin and insulin resistance index (homeostasis model assessment of insulin resistance; P < 0.001 for both) and glucose (P = 0.025) and insulin (P = 0.002) levels during the oral glucose tolerance test. In subjects from Gargano, those carrying allele 3 had lower fasting plasma glucose levels and serum triglycerides (P = 0.01 for both). When the 2 populations were analyzed together, subjects carrying allele 3 had lower fasting insulin levels (P < 0.005), homeostasis model assessment of insulin resistance (P < 0.005), and serum triglycerides (P = 0.01). In conclusion, our data suggest that subjects carrying allele 3 of the resistin gene are characterized by relatively high insulin sensitivity.     

Mitral valve reserve in double-orifice technique: an exercise echocardiographic study

BACKGROUND AND AIM OF THE STUDY: The edge-to-edge technique is used to restore valvular competence in mitral insufficiency. The efficacy of the method is under debate due to the potential for creating functional mitral stenosis. An exercise echocardiographic study was carried out to investigate valve function and hemodynamics in patients who had undergone double-orifice mitral valve repair. METHODS: Thirty patients (mean age 49.1 +/- 12.7 years) with previous double-orifice mitral valve repair underwent exercise echocardiography (10 W/min). An annular prosthesis was present in 28 patients (93%). The mean and maximum mitral valve gradient, planimetric valve area, stroke volume, systolic pulmonary artery pressure, heart rate and systolic blood pressure were measured at baseline and at peak stress. RESULTS: At peak stress, heart rate (77.7 +/- 12.2 versus 118.6 +/- 26.0 beats/min, p < 0.00001), systolic blood pressure (124.1 +/- 10.9 versus 146.6 +/- 22.8 mmHg, p < 0.00001) and stroke volume (78.0 +/- 10.2 versus 97.0 +/- 15.1 ml, p < 0.00001) were significantly increased, showing a physiological behavior of the mitral valve. The mean mitral valve gradient (2.8 +/- 1.3 versus 4.6 +/- 1.9 mmHg, p < 0.00001), maximum mitral valve gradient (6.4 +/- 2.8 versus 10.5 +/- 4.6 mmHg, p < 0.00002) and systolic pulmonary artery pressure (22.8 +/- 6.1 versus 28.2 +/- 9.9 mmHg, p < 0.001) were increased, but not to pathologic levels. Planimetric valve area increased significantly (3.2 +/- 0.6 versus 4.3 +/- 0.7 cm2, p < 0.00001). A significant negative linear correlation was found between the relative change in mitral valve area and planimetric valve area at rest (r = -0.51, p < 0.05). CONCLUSION: The double-orifice repair, even with concomitant ring annuloplasty, does not cause mitral valve obstruction, either at baseline or during physical exercise, and does not affect valve hemodynamic and valve reserve.     

Erythrocyte deformability and white blood cell count are associated with aspirin resistance in high-risk vascular patients

Recently the phenomenon of aspirin resistance has been object of several studies, but no data are available on the possible role of the haemorheologic parameters in affecting platelet function and resistance to antiplatelet agents. Aim of our study was to evaluate platelet function and haemorheology in patients with acute coronary syndromes (ACS), receiving double antiplatelet therapy with aspirin and clopidogrel. The study population included 301 (231M/70F; age: 66 +/- 13 yrs) consecutive adult patients admitted to the Coronary Care Unit of the Azienda Ospedaliero-Universitaria Careggi, with diagnosis of acute myocardial infarction or unstable angina. We assessed: whole blood viscosity (WBV) at shear rates of 0.512 s(-1) and 94.5 s(-1), plasma viscosity (PLV) at 94.5 s(-1) shear rate, erythrocyte deformability index (DI) and PFA-100 closure times with ADP (PFA/ADP) and epinephrine (PFA/EPI). We considered any PFA-100-EPI result < 203 sec (95th percentile of control distribution) to be indicative of aspirin resistance. 104/301 patients (34.5%) had PFA/EPI CTs in the reference range (group 1) whereas the remaining had values higher than 203 sec (group 2). WBV at 94.5 sec (-1) s.r. was similar in group 1 and 2 (WBV: 4.43 +/- 0.25 vs 4.45 +/- 0.61 mPa.sec, respectively). PLV and WBV at 0.512 sec (-1) s.r. were slightly higher, but not significantly, in group 1 than in group 2 (PLV: 1.47+/-0.13 vs 1.44 +/- 0.15 mPa.sec; p = 0.08 and WBV: 23.37 +/- 4.6 vs 22.54 +/- 3.90 mPa.sec; p = 0.07). DI was significantly lower in group 1 with respect to group 2 (4.05 +/- 2.93 vs 5.71 +/- 3.30, p < 0.0001). White blood count (WBC) was significantly higher in group 1 than in group 2 (11464 +/- 3504 vs 7867 +/- 2162, p < 0.0001). In conclusion, these results demonstrate that in patients with acute coronary syndromes the antiaggregant effect of aspirin is modulated not only by the direct action on platelets, but also by erythrocyte deformability and white blood cell count.     

Six novel mutations in the proopiomelanocortin and melanocortin receptor 4 genes in severely obese adults living in southern Italy

BACKGROUND: The genetic characterization of obese individuals could clarify the molecular mechanisms underlying body weight regulation and lead to targeted therapy. Here we report variants of the proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) genes detected in severely obese adults living in southern Italy. METHODS: A total of 196 unrelated nondiabetic severely obese individuals [111 females and 85 males; mean (SD) age, 32.2 (11.5) years; mean body mass index, 48.8 (8.1) kg/m(2)] and 100 normal-weight healthy volunteers (34 males and 66 females) entered the study. POMC and MC4R were genotyped by sequencing analysis. Leptin, insulin, glucose, and the lipid profile were measured in fasting serum samples. We used the protein truncation test to verify the stop-codon mutation. Anthropometric measurements, sitting blood pressure, and heart rate were also recorded. RESULTS: Of the obese participants, 1.5% had mutations in POMC exon 3 (new mutations, P231L and E244X; known, R236G) and 2.5% had MC4R mutations (new mutations, W174C, Q43X, S19fsX51, and I317V; known, A175T). These mutations were not present in the controls. Gene polymorphisms were identified in similar percentages of severely obese and nonobese individuals, i.e., respectively, 52.5% and 51% (POMC) and 1% and 2% (MC4R). CONCLUSIONS: We detected 2 new POMC mutations and 4 new MC4R mutations in a large number of severely obese adults living in southern Italy. These mutations, not present in normal-weight individuals, are further evidence that defects in the melanocortin pathway are related to severe obesity.     

Transition from intravenous to subcutaneous insulin: effectiveness and safety of a standardized protocol and predictors of outcome in patients with acute coronary syndrome

OBJECTIVE

The study objectives were 1) to assess the effectiveness and safety of a standardized protocol for the transition to subcutaneous insulin and oral feeding in diabetic or hyperglycemic patients with acute coronary syndrome (ACS) who were receiving intravenous insulin and glucose at the time of the transfer from the intensive cardiac care unit to a general ward and 2) to identify predictors of transition outcome.

RESEARCH DESIGN AND METHODS

This was a prospective observational study. The protocol specifies that patients receive a 100% of their daily subcutaneous insulin requirement from the first day of oral feeding, calculated from the intravenous insulin rate during the final 12 h divided into two: 50% basal and 50% prandial.

RESULTS

In 142 patients (93 male, 49 female, age range 47–88 years, 135 with known diabetes) the first day after transition, 44.8% of blood glucose (BG) measurements were within the strict range of 100–140 mg/dL before meals and 100–180 mg/dL after meals, and 70.8% were within the broader ranges of 80–160 mg/dL and 80–200 mg/dL, respectively. Pre- or postprandial hypoglycemia (BG <70 mg/dL) occurred in 11 patients (7.7%) on the first day and in 38 patients (26.8%) on the first 3 days after transition. Old age, high doses of intravenous insulin, and wide BG variations in the 24 h before insulin infusion was stopped were predictive of poor BG control after transition.

CONCLUSIONS

This study shows the effectiveness and safety of a standardized protocol for the transition from intravenous to subcutaneous insulin in patients with ACS when regular oral feeding was resumed.In critically ill patients with diabetes or hyperglycemia who are admitted to intensive care units, intravenous infusion of insulin is the recommended treatment (1–6). During the postacute phase, many guidelines and recommendations suggest switching to subcutaneous insulin when patients begin eating regular meals and are moved to a lower-intensity care setting (1–6).There are few observational and intervention studies on the procedure for the transition from intravenous to subcutaneous insulin, and almost all concerned patients who had undergone operation and took little if any food (7–11). The transition is delicate because of the patients’ clinical condition and the organizational context in which they are transferred from an intensive care unit to a general ward. The few studies that have examined the course of blood glucose (BG) after interruption of intravenous insulin have documented inadequate control in the absence of a standardized transition protocol (9,12). In addition, the literature reporting the predictors of optimal transition is scarce and refers mainly to patients postsurgery (7,9,10).The objectives of this prospective observational study were to

1. assess the effectiveness and safety of a standardized protocol for conversion from intravenous to subcutaneous insulin therapy in patients with acute coronary syndrome (ACS) during the transfer from the intensive cardiac care unit (ICCU) to the general ward; and
2. identify predictive factors of transition outcome.

     

Risk for decreased cardiac output: validation of a proposal for nursing diagnosis

Aim: To verify the content validity of the nursing diagnosis risk for decreased cardiac output (RDCO). Background: DCO is a phenomenon that is not restricted to individuals or environments that specifically focus on cardiovascular care. It is not only prevalent in cardiovascular care units, but also in post‐anaesthesia units and non‐cardiac care units among individuals with non‐cardiogenic disorders. A significant decrease in cardiac output is a life‐threatening situation, demonstrating the need for developing a risk nursing diagnosis for early intervention. The development of this diagnosis requires the construction of a diagnosis label, a definition of the diagnostic concept and the risk factors associated with the diagnosis. Methods: The research was carried out in two methodological stages based on the Fehring diagnosis content validation model. The quantitative analysis consisted of the calculation of the weighted mean of the values attributed by experts to each risk factor, the level of agreement/disagreement between the experts regarding the operational definitions of risk factors and the index of diagnostic content validity (DCV). Results: The label ‘risk for decreased cardiac output' was considered representative of a nursing diagnosis defined as ‘at risk of developing a health status characterized by an insufficient quantity of blood pumped by the heart to meet physical metabolic demands'. Critical risk factors (DCV ≥ 0·7) were myocardial dysfunction (0·887), blood loss (0·875), increase in intrapericardial pressure (0·825), condition that leads to changes in cardiac rhythm and/or electrical conduction (0·812), deficient fluid volume (0·725), plasma loss (0·712), ineffective tissue perfusion (0·712) and electrolyte imbalance (0·7). Conclusions: The research identified eight risk factors with valid content for assessment of RDCO. Implications for nursing practice: The identification of risk factors for DCO assists nurses to intervene early and minimize the consequences of a deficient cardiac function.