Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques.

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

Comparison of the Minimental State Examination Scale and the International HIV Dementia Scale in Assessing Cognitive Function in Nigerian HIV Patients on Antiretroviral Therapy.

Introduction. HIV-associated neurocognitive disorder (HAND) remains common despite the availability of antiretroviral therapy. Routine screening will improve early detections. Objective. To compare the performance of the minimental state examination (MMSE) and international HIV dementia scale (IHDS) in assessing neurocognitive function in HIV/AIDS patients on antiretroviral therapy. Methods. A case-control study of 208 HIV-positive and 121 HIV-negative individuals. Baseline demographic data were documented and cognitive function assessed using the two instruments. CD4 cell counts were recorded. Results. Cases comprised 137 females and 71 males. Controls were 86 females and 35 males. Mean MMSE score of cases was 27.7 ± 1.8 compared to 27.8 ± 1.3 in controls (P = 0.54). Mean IHDS score in cases was 8.36 ± 3.1 compared to 10.7 ± 0.9 in controls (P < 0.001). Using the MMSE scale, 6 cases but no controls had HAND (P = 0.09). Using the IHDS, 113 (54.3%) had HAND compared with 10 (8.3%) controls (P < 0.0001). Using IHDS, 56.5% cases with CD4 count > 200 had HAND compared with 92.5% with CD4 count < 200 (P < 0.001). Conclusion. These findings indicate that the IHDS detects higher rates of HAND and may identify HIV/AIDS patients who require further cognitive assessment using more robust assessment batteries.

Monochromatic excimer light (308 nm): an immunohistochemical study of cutaneous T cells and apoptosis-related molecules in psoriasis.

BACKGROUND: Various types of UVB radiation source (290-320 nm) are used in treating psoriasis and their therapeutic mechanism has been attributed to immunosuppressive properties. Recently, a new UVB source generated by a 308-nm excimer laser has been introduced for the treatment of psoriasis. OBJECTIVE: In this study we investigated the immunohistochemical evaluation of T cells and the expression of various apoptosis-related molecules in the psoriatic hyperproliferative skin before and after treatment with 308-nm monochromatic excimer light (MEL). METHODS: Ten patients (three women and seven men), ranging in age from 29 to 79 years, affected by plaque-type psoriasis vulgaris, were treated with MEL. Biopsies from psoriatic lesions of MEL-treated sites were taken before, 24 h and/or 48 h after the first irradiation and analysed by the immunophosphatase alkaline technique (APAAP). RESULTS: MEL treatment was found to cause a significant decrease in the rate of proliferation of keratinocytes and a relevant depletion of T cells in all psoriatic lesions, 48 h after the first irradiation: 308 nm light eliminated T cells from the psoriatic epidermis and also from the dermis, highlighting the ability of this UVB source to penetrate the skin compared with normal UVB and establish direct cytotoxic action on T cells infiltrating skin lesions. Rapid clearing of psoriatic lesions involves potential molecular targets of UVB in T cells including p53, which is upregulated after direct irradiation with 308-nm UVB. Moreover, Bcl-2 expression in healing psoriasis epidermis after MEL treatment is significantly decreased compared with untreated skin and the TUNEL (TdT-mediated dUTP-biotin nick end labelling) technique revealed the presence of relevant apoptotic keratinocytes in the irradiated epidermis. CONCLUSIONS: These results indicate that psoriatic skin after monochromatic excimer light therapy is associated with significant T-cell depletion and alterations of apoptosis-related molecules accompanied by a decreased proliferation index and clinical remission.

Electrophysiological instability in the acute phase: prognostic significance of early ventricular fibrillation in acute myocardial infarction.

BACKGROUND: In the prognostic stratification of patients affected by AMI is important to evaluate, besides the assessment of left ventricular function and residual ischemia, the presence of electrophysiological instability. METHODS: We have analysed 15 patients all affected by AMI complicated by early ventricular fibrillation. During the hospital phase we evaluated the E.F.% (ECHO) and the presence of late ventricular potentials (SAECG). After hospital discharge we followed up the patients for 6 months. RESULTS: None of the patients died during the hospital phase while the posthospital cardiac mortality was 20%. The three patients dead during the follow-up had an AMI localized in the anterolateral wall of the left ventricle, an E.F.% less than 40% and LVP positive in the hospital phase. Besides the clinical course was complicated by cardiac failure. CONCLUSIONS: We conclude that these three patients are a "high risk profile subgroup" and should be submitted to extensive evaluation with cardiac catheterization, coronary arteriography and programmed ventricular stimulation.

Characterization of [3H]substance P binding sites in human skin.

Radioligand binding experiments were performed with crude homogenates from normal human skin in order to investigate substance P receptor density. Binding of [3H]substance P ([3H]SP) reached equilibrium after 20 min and was saturable analysis of saturation curves gave a significantly better fit using two-site binding compared to the single-site model. Competition studies employing some selective agonists for NK1, NK2 and NK3 receptors have demonstrated that only the NK1 selective agonist, [Sar9, Met(O2)11]-SP, was a competitor for [3H]SP binding. In addition, the non-hydrolyzable guanosine 5'-0-(3-thiotriphosphate) altered the dissociation of SP from NK1 receptors by increasing the number of low-affinity sites. These data show that in the skin [3H]SP binds to a single population of substance P high-affinity sites, which represent NK1-type receptors.

Effects of K(ATP) channel blockade by glibenclamide on the warm-up phenomenon.

AIMS: The increased tolerance to myocardial ischaemia observed during the second of two sequential exercise tests, i.e. the warm-up phenomenon, has been proposed as a clinical model of ischaemic preconditioning. As ATP-sensitive K+ channels appear to be a mediator of ischaemic preconditioning in both experimental and clinical studies, the aim of this study was to investigate the role of K(ATP) channels in the warm-up phenomenon. METHODS AND RESULTS: Twenty-six patients with coronary artery disease were randomized to receive 10 mg oral glibenclamide, a selective ATP-sensitive K+ channel blocker, or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 ml x min(-1)) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusions, both patient groups underwent two consecutive treadmill exercise tests, with a recovery period of 15 min to re-establish baseline conditions. Before exercise tests, blood glucose levels were similar in placebo and glibenclamide groups (96 +/- 10 vs 105 +/- 22 mg x 100 ml(-1), P=ns). After placebo administration, rate-pressure product at 1.5 mm ST-segment depression significantly increased during the second exercise test compared to the first (220 +/- 41 vs 186 +/- 29 beats x min(-1) x mmHg x 10(2), P<0.01), but it did not change after glibenclamide (191 +/- 34 vs 187 +/- 42 beats x min(-1) x mmHg x 10(2), P=ns), with a significant drug-test interaction (P=0.0091, at two-way ANOVA). CONCLUSIONS: Glibenclamide, at a dose previously shown to abolish ischaemic preconditioning during coronary angioplasty, prevents the increase of ischaemic threshold observed during the second of two sequential exercise tests. These findings confirm that ischaemic preconditioning plays a key role in the warm-up phenomenon and that in this setting is, at least partially, mediated by activation of ATP-sensitive K+ channels.

Effects of A1 adenosine receptor blockade on the warm-up phenomenon.

The increased tolerance to myocardial ischemia observed during the second of two sequential exercise tests, i.e. the warm-up phenomenon, has been proposed as a clinical model of ischemic preconditioning. Adenosine appears to be a mediator of ischemic preconditioning in both experimental and clinical settings. The purpose of this study was to investigate the role of A1 adenosine receptors in the warm-up phenomenon. A double-blind, placebo-controlled, cross-over design was used. Twelve patients with coronary artery disease and positive exercise test were randomized to receive either bamiphylline, a selective A1 adenosine receptor antagonist, or placebo, immediately prior to two consecutive treadmill exercise tests carried out on day 1. Then, on day 2 all patients underwent two consecutive exercise tests immediately after administration of the remaining treatment. During the first exercise test, bamiphylline, compared to placebo, increased the time to and rate-pressure product at 1.5 mm ST-segment depression (from 317 +/- 118 to 423 +/- 127 s, p < 0.05 and from 199 +/- 38 to 230 +/- 36 b/min.mmHg.10(2), p < 0.05, respectively). After both placebo and bamiphylline infusions, time to 1.5 mm ST-segment depression during the second exercise test was greater than that during the first test (445 +/- 121 vs 317 +/- 118 s, p < 0.001 and 483 +/- 128 vs 423 +/- 127 s, p < 0.05, respectively), as was rate-pressure product at 1.5 mm ST-segment depression (228 +/- 40 vs 199 +/- 38 b/min.mmHg.10(2), p < 0.01 and 253 +/- 42 vs 230 +/- 36 b/min.mmHg.10(2), p < 0.05, respectively). In conclusion, bamiphylline, at a dose able to increase ischemic threshold and exercise tolerance compared to placebo, does not prevent the warm-up phenomenon. These findings suggest that, in the setting of the warm-up phenomenon, A1 adenosine receptor blockade is insufficient to prevent ischemic preconditioning.

Mechanisms of the warm-up phenomenon.

The warm-up phenomenon, described in patients with coronary artery disease, refers to the improved performance following a first exercise test. The aim of this study was to investigate the causes of the warm-up phenomenon. Fifteen patients with coronary artery disease and positive exercise test were enrolled. Patients were off treatment throughout the study. They underwent two consecutive treadmill exercise tests according to the Bruce protocol, with a recovery period of 10 min to re-establish baseline conditions. A third exercise test was then performed 2 h later. Before the onset of ischaemia, the rate-pressure product for a similar degree of workload was similar during the first and second exercise test, while it was lower during the third test (P < 0.05). Time to 1.5 mm ST-segment depression during the second and third exercise test was greater than during the first test (454 +/- 133 and 410 +/- 161 vs 354 +/- 127 s, P < 0.01, respectively). Similarly, the time to anginal pain onset was increased during the second and third exercise tests, compared to the first test (356 +/- 208 and 310 +/- 203 vs 257 +/- 204 s, P < 0.01, respectively). In contrast, rate-pressure product at 1.5 mm ST-segment depression during the second test was higher than that during the first test (232 +/- 47 vs 210 +/- 39 beats.min-1.mmHg.10(2), P < 0.01), while in the third test it was similar to that during the first (209 +/- 43 beats.min-1.mmHg.10(2), P = ns). The warm-up phenomenon observed a few minutes after exercise is characterized by an increase of both time to ischaemia and ischaemic threshold; this adaptation to ischaemia may be due to an improvement of myocardial perfusion or to preconditioning. Conversely, the warm-up phenomenon observed a few hours after repeated exercise is characterized by an increase of time to ischaemia but not of ischaemic threshold and is caused by a slower increase of cardiac workload. Thus, the mechanisms of the warm-up phenomenon may be different, time dependent and related to previous training.

Hemodynamic and clinical effects of captopril in patients with severe congestive heart failure.

In a group of 10 patients (9 male, 1 female, aged 16 to 56, mean 43 years) with severe congestive heart failure (CHF), due to ischemic heart disease (8 cases) or dilatative cardiomyopathy (2 cases), the acute hemodynamic response to captopril (CPT) (90 min after 50 mg po) was evaluated. CPT was then given starting with 15 mg q 8 hr, gradually increased within 2 or 3 days to 50 or 75 mg q 8 hr. A hemodynamic re-evaluation was performed after 20 days, and, in 5 patients, after 1 year of CPT treatment. The clinical follow-up done every 3 months in the outpatient clinic. CPT acutely produced a decrease in mean pulmonary wedge pressure: 23.8 +/- 8.9 to 18.6 +/- 8.6 mmHg, p less than 0.01, and an increase in cardiac index: 2.43 +/- 0.73 to 2.91 +/- 0.85 l/min/m2, p less than 0.01; systemic and pulmonary resistances decreased significantly, with no significant changes in heart rate and in mean brachial artery pressure. This favourable hemodynamic response persisted after 20 days of CPT treatment. In the group of 5 patients, who underwent a third hemodynamic evaluation, no statistically significant differences were demonstrated in respect to the previous control values. All patients on chronic CPT treatment experienced a gradual clinical improvement, reaching a steady state after 2 to 3 weeks; the surviving patients remained stable in the improved functional class for at least 6 months. The mortality rate was 30% in the first year, increasing to 50% in the second and to 60% in the third year of treatment. After a mean follow-up 35.7 months (range 33 to 39) the 4 surviving patients remained in the same functional class as after the first year for therapy. In our CHF patients CPT improved the quality of life, with the best clinical and hemodynamic results the first few months of treatment; life expectancy probably was not affected.

[Reliability of the ejection fraction determined with the nuclear stethoscope. Comparison with angiocardiography]. / Affidabilità della frazione di eiezione determinata con lo stetoscopio nucleare. Confronto con angiocardiografia.

The purpose of this investigation was to compare the Ejection Fraction values simultaneously obtained with the Nuclear Stethoscope and with Cineangiography, in 25 patients (17M-8W) subjected to diagnostic cardiac catheterization. In all patients the determination of Ejection Fraction with the Nuclear Stethoscope always preceded the Cineangiography. Ejection Fraction values obtained with Nuclear Stethoscope change from 32 to 75%; those calculated with Cineangiography, between 18 and 88%. The average Ejection Fraction values obtained with Nuclear Stethoscope (59 +/- 13%) doesn't differ significantly from Cineangiography (59 +/- 21%). There was a direct relationship between Ejection Fraction determined by the Nuclear Stethoscope and Cineangiography (r = 0.93; p less than 0.001). In the obtained results the Authors point out that the Ejection Fraction with Nuclear Stethoscope gives assurance in most patients, although in some particular conditions Nuclear Stethoscope provides Ejection Fraction values which differ from those obtained with Cineangiography. They conclude that Nuclear Stethoscope, for its safe, repeating and simple application, is a methodology of useful employment for Ejection Fraction determination in the single patient, which allows a correct definition of the prognosis and a conforming therapeutic strategy.

Nomogram for calculation of stenotic cardiac valve areas from cardiac output and mean transvalvular gradient.

In 15 patients (group 1) with isolated mitral stenosis and in 14 patients (group 2) with isolated aortic stenosis the stenotic valve areas were calculated according to: A) Gorlin's formula; B) Hakki's simplified formula, using mean mitral gradient by planimetry or peak-to-peak aortic gradient; C) the three-point simplified formula, using mean gradient calculated by the three-point method for both mitral and aortic valve. The three-point method is definitely easier to use than planimetry. The values (mean +/- SD) of mitral valve areas in group 1 patients were, respectively: 1.56 +/- 0.63 cm2; 1.56 +/- 0.55; 1.51 +/- 0.53. The values of aortic valve areas in group 2 patients were: 0.91 +/- 0.63; 0.77 +/- 0.41; 0.88 +/- 0.52. An excellent correlation was shown between the valve area calculated by Gorlin's formula and both Hakki's simplified formula and the three-point simplified formula. For aortic valve area the correlation is even better if the mean gradient by the three-point method is used instead of the peak-to-peak gradient. On the basis of the simplified formula, a nomogram was constructed which allows an immediate calculation of valve areas from cardiac output and transvalvular gradient.