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Biomedical subjects

A Poli

Publications and source records attributed to A Poli.

At least 37 records · Page 2Linked to original sources
PubMed2002

Contribution of F-actin to barrier properties of the blood-joint pathway.

OBJECTIVES: Because fibroblast filamentous actin (F-actin) influences cutaneous interstitial matrix swelling pressure (5), we investigated whether F-actin in fibroblast-derived synoviocytes influences the hydraulic permeability of the trans-synovial interstitial pathway. The study also tested whether F-actin in fenestrated synovial endothelium contributes to the blood-joint barrier in vivo. METHODS: The clearance of Evans blue-albumin (EVA) from plasma into the knee joint cavity was determined in joint infused with F-actin disrupting cytochalasin D (1-200 microM), latrunculin B (100 microM) or vehicle in anesthetized rabbits. The hydraulic permeability of the lining was determined as the slope relating net trans-synovial flow Q(s) to intra-articular pressure P(j). Synovium was examined histologically after i.v. Monastral blue to assess endothelial leakiness. RESULTS: EVA permeation in vivo was increased up to 25-fold by cytochalasin (p = 0.0002, ANOVA), with an EC(50) of 23 microM (95% confidence limits 13-43 microM). Washout quickly reversed the increase. Latrunculin had a similar effect. F-actin disruption switched Q(s) from drainage (control) to filtration into the cavity at low P(j) in vivo and raised the conductance Q(s)/dP(j) by 2.13 (p = 0.001, ANOVA). Circulatory arrest abolished these effects. Monastral blue revealed numerous endothelial leaks. CONCLUSIONS: F-actin is crucial to the barrier function of fenestrated endothelium in situ. No significant effect of synoviocyte F-actin on matrix permeability was detected.

Actins↗
PubMed2002

The impact of climate and traffic-related NO2 on the prevalence of asthma and allergic rhinitis in Italy.

BACKGROUND: Environmental factors are likely to be involved in explaining the wide geographical variation in asthma and atopic diseases that has been documented in many recent epidemiological studies. AIM: To evaluate to what extent climate and outdoor NO2 pollution can explain the geographical variation in the prevalence of asthma and allergic rhinitis, and to estimate the relative risk for exposure to different levels of these two factors. METHODS: The impact of climate and long-term exposure to nitrogen dioxide (NO2) pollution on asthma and allergic rhinitis was assessed in a cross-sectional study, carried out during 1998 to 2000 on young adults aged 20 to 44 years (n = 18 873), living in 13 areas from two different Italian climatic regions (subcontinental and Mediterranean). RESULTS: Mediterranean areas had a significantly higher prevalence of asthma-like symptoms (P < 0.001), higher annual mean temperature (16.2 degrees C vs. 12.9 degrees C), lower temperature range (16.0 C degrees vs. 22.1 degrees C) and lower NO2 levels (31.46 microg/m3 vs. 57.99 microg/m3) than subcontinental ones. Mediterranean climate was associated with an increased risk of wheeze (OR = 1.23; 95% CI 1.13 to 1.35), tightness in the chest (OR = 1.21; 95% CI 1.11 to 1.33), shortness of breath (OR = 1.21; 95% CI 1.08 to 1.36) and asthma attacks (OR = 1.19; 95% CI 1.07 to 1.31). After adjusting for climate, an increase of 18.3 microg/m3 in NO2 levels moderately increased the risk of asthma attacks (OR = 1.13; 95% CI 0.98 to 1.32), tightness in the chest (OR = 1.11; 95% CI 0.98 to 1.26) and wheeze (OR = 1.11; 95% CI 0.96 to 1.28). When the levels of outdoor NO2 exposure rose, the prevalence of allergic rhinitis increased significantly in the Mediterranean region (OR = 1.38; 95% CI 1.12 to 1.69), but not in the subcontinental one (OR = 1.03; 95% CI 0.83 to 1.28). CONCLUSION: Our results show that the prevalence of asthma increases when annual mean temperature increases and temperature range decreases. Furthermore, climate interacts with NO2 outdoor exposure, increasing the risk for allergic rhinitis in people exposed to high stable temperatures. A long-term role for the effect of traffic pollution on asthma is also suggested.

Adult↗
PubMed2002

MIB-1 labeling index in feline dysplastic and neoplastic mammary lesions and its relationship with postsurgical prognosis.

Samples from feline normal, dysplastic, and neoplastic mammary tissues were used to investigate the usefulness of MIB-1 labeling index (MIB-1 I) as a prognostic indicator. Forty-eight queens bearing invasive carcinomas were included in a 2-year follow-up study. Mammary lesions were classified according to the World Health Organization system, and invasive carcinomas were further graded on the basis of the degree of tubule formation, the degree of nuclear and cellular pleomorphism, and mitotic count. Additional sections were immunostained using MIB-1 antibody, and MIB-1 I was expressed as a percentage of positive nuclei. In normal mammary gland tissues, the mean MIB-1 I was <1%. A low proliferation rate was found in all mammary adenosis and in situ carcinomas, and the highest rates were observed in feline mammary hypertrophy and invasive carcinomas. Twenty-one (43.7%) of the queens bearing invasive carcinomas were still alive at the end of the trial, and 27 (56.2%) had died. The MIB-1 I was not significantly correlated with clinical outcome, age, histologic type, or grading of the tumors, but a borderline correlation was observed with invasion of lymphatic vessels. Univariate analysis showed that high MIB-1 I was also not associated with decreased overall survival, whereas the grading system of the tumors had high predictive value (P = 0.0040) for postsurgery survival. The lack of correlation between MIB-1 I and postsurgery survival suggests that this marker alone is not sufficient to determine a correct prognosis in feline mammary carcinomas, even if it is a useful proliferation marker.

Animals↗
PubMed2002

Correlation of vascular endothelial growth factor expression to overall survival in feline invasive mammary carcinomas.

Samples from feline invasive mammary carcinomas (FMCs) were used to determine the prognostic significance of the immunohistochemical expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD). Forty-eight queens bearing FMCs were included in a 2-year follow-up study. Mammary tumors were classified according to the World Health Organization system and graded on the basis of histologic criteria. Tumor sections were immunostained using anti-VEGF and anti-von Willebrand factor (vWf) antibodies. VEGF expression was quantified on the basis of the percentage of positive cells. MVD of vWf-positive microvessels was determined by both mean microvessel counts and highest microvessel counts. Normal mammary gland tissues showed an inconspicuous VEGF staining. In FMCs the proportion of VEGF-positive cells was significantly higher in papillary and solid carcinomas than in tubular and papillary cystic tumors. An increased number of cells expressing VEGF was also observed in poorly differentiated FMCS. Sixteen (33.3%) of the queens bearing invasive carcinomas were still alive at the end of the 2-year follow-up period, and 32 (66.7%) had died. The VEGF expression was significantly correlated with the clinical outcome, but no correlation was observed with the invasion of lymphatic vessels. A correlation between the higher percentage of VEGF-positive cells and the unfavorable prognosis was demonstrated by the estimation of curves for overall survival (P = 0.03). Univariate analysis showed that MVD did not correlate with the overall survival. The results of our study demonstrated that VEGF expression, although not associated with increased angiogenesis, is a prognostic indicator in feline mammary tumors. In contrast, there is no support for a role of neovascularization as an indicator of survivability.

Animals↗
PubMed2001

Densitometric analysis of Western blot assays for feline immunodeficiency virus antibodies.

Western blot (WB) strips for antibodies directed to feline immunodeficiency virus (FIV) were analysed using reflectance densitometry by a semiautomatic densitometer. This method was used to quantify the antibody responses to different FIV proteins in both vaccinated and naturally or experimentally-infected cats. In order to increase reproducibility, reagents and protocols were accurately standardised and internal controls were added. In a first format, an internal control band consisting of feline IgG was added to each blot to minimise the effect of band intensity variation. In a second format, antibody concentrations were calculated from the ratio of the densities produced by test sera and by positive and negative standard sera. The sera under scrutiny were also examined by standard enzyme-linked immunosorbent assay (ELISA) and the results obtained compared with those of the corresponding WB. A statistically significant positive correlation was found between the results obtained with the two methods, and this was especially evident when ELISA titres were compared to corrected WB values (P = 0.001). Densitometric analysis of WB assays allowed to quantify the antibodies against FIV proteins and might be useful to investigate possible humoral immune correlates of protection in FIV vaccination studies and antibody production in the early phase of infection. The quantitation of antibodies to Gag and Env FIV antigens might be used to obtain further informations on the course of FIV disease, as previously demonstrated in human immunodeficiency virus-1 (HIV-1) infections.

Animals↗
PubMed2001

Regional distribution of nitric oxide synthase and NADPH-diaphorase activities in the central nervous system of teleosts.

Neuronal nitric oxide synthase (nNOS) and NADPH-diaphorase activities were investigated in discrete areas of the central nervous system of goldfish and brown trout. Both species showed a similar distribution pattern of nNOS activity with regional differences in all examined areas. Telencephalon and hypothalamus showed the highest nNOS values, while in the goldfish cerebellum and its valvula nNOS was not detectable. In both species, NADPH-diaphorase activity showed a lower regional variability, compared to nNOS. The highest activity was measured in the olfactory bulbs where, conversely, low levels of nNOS activity were present. The non close correspondence between NOS and NADPH-diaphorase activities confirms the discrepancies indicated by morphological data. Western blot analysis revealed the presence of a nNOS isoform of about 150 kDa mol. wt. corresponding to that of mammals. The pattern of nNOS expression in the considered brain regions of the goldfish and trout was comparable to the levels of the nNOS activity.

Animals↗
PubMed2001

The calcium-dependent [3H]acetylcholine release from synaptosomes of brown trout (Salmo trutta) optic tectum is inhibited by adenosine A1 receptors: effects of enucleation on A1 receptor density and cholinergic markers.

Presynaptic inhibition is one of the major control mechanisms in the CNS. Previously we reported that A1 adenosine receptors are highly concentrated in the brain, including optic tectum, of trout and that they inhibited the release of glutamate. The optic tectum is heavily innervated by cholinergic nerve terminals. We have investigated whether A1 receptors inhibit the presynaptic release of acetylcholine and whether the inhibition is triggered by calcium. The release of [3H]ACh evoked by 30 mM KCl was Ca2+ dependent and it was dose-dependently inhibited by the A1 adenosine receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) ranging between 10 nM to 100 microM. The maximum of inhibition was reached at 10 microM. The A1 receptor antagonist 8-cyclopentyltheopylline (CPT, 10 microM), reversed almost completely the inhibition induced by CCPA 10 microM. In Fura-2/AM loaded synaptosomes, K(+) depolarization raised [Ca2+](i) by about 64%. CCPA (10 microM) reduced the K(+)-evoked Ca2+ influx increase by about 48% and this effect was completely antagonised by CPT 10 microM. Synaptosome pretreatment with different Ca2+ channel blockers differently affected K(+)-evoked Ca2+ influx. This was not significantly modified by nifedipine (1 microM, L-type blocker) nor by omega-agatoxin IVA (0.3 microM, P/Q-type blocker), whereas about 50% reduction was shown by 0.5 microMomega-conotoxin GVIA (N-type blocker). Neurochemical parameters associated with cholinergic transmission and the density of A(1) adenosine receptors were measured in the trout optic tectum 12 days after unilateral eye ablation. A significant drop of both acetylcholinesterase (AChE) activity (24%) and choline acetyltransferase (CAT) activity (32%) was observed in deafferentated optic tectum, whereas the high affinity choline uptake did not parallel the decrease in enzyme activity. Eye ablation caused a marked decrease (43%) of A1 receptor density without changing the affinity. The K(+)-evoked release of [3H]ACh from synaptosomes of deafferentated was not modify as well as the efficacy of 10 microMCCPA in decreasing [3H]ACh release was not apparently modified.

Acetylcholine↗
PubMed2001

Influence of actin cytoskeleton on intra-articular and interstitial fluid pressures in synovial joints.

Fibroblast microfilamentous actin (F-actin) influences interstitial fluid pressure via linkages to collagen in rat skin (Berg et al., 2001). The present aims were to determine whether the actin cytoskeleton of synovial endothelium, fibroblasts, and synoviocytes influences in vivo (i) fluid exchange between a joint cavity and synovial microcirculation and (ii) extracellular fluid pressures in joints. Rabbit knee joints were treated intra-articularly with the F-actin disrupting drugs cytochalasin D and latrunculin B while joint fluid pressure P(j) was recorded. In joints injected with small volumes of control solution, P(j) fell with time (-0.05 +/- 0.01 cm H2O x min(-1), mean +/- SEM, n = 9, equivalent drainage rate 3.9 microl x min(-1)). Cytochalasin or latrunculin reversed this in approximately 4 min in vivo; P(j) increased with time, e.g., +0.12 +/- 0.04 cm H2O x min(-1) at 200 microM cytochalasin (equivalent filtration rate into joint 6.6-12.5 microl x min(-1), n = 4), with a cytochalasin EC50 of 45 microM. Plasma gamma-globulin clearance into the joint cavity was also increased. Post mortem, cytochalasin did not reverse dP(j)/dt and had no more effect on P(j) than did control solution. Also, when synovial interstitial fluid pressures were measured by servonull micropipette post mortem (control -0.95 +/- 0.37 cmH2O, n = 18) cytochalasin had no significant effect on interstitial pressure over 60 min, even at 1 mM. It was concluded that synovial endothelial F-actin has an important role in the normal synovial microvascular resistance to fluid filtration and plasma gamma-globulin permeation and is thus a potential link between pro-inflammatory mediators and arthritic joint effusions. The results provided no support for the hypothesis that synoviocyte F-actin influences the swelling tendency of synovial matrix and hence extracellular fluid pressures, in contrast to the findings of Berg et al. (2001) in rat dermis.

Actins↗
PubMed2001

MPTP-induced apoptosis in the retina of goldfish.

Neuronal degeneration observed in the goldfish retina after MPTP administration, displays features of apoptosis, a physiological mechanism of cell death that occurs during development. The ultrastructural features of degenerating retinal neurons, that are seen in the inner nuclear layer two days after intravitreal MPTP administration, are consistent with classic changes observed in the programmed cell death. The DNA strand breaks that characterize apoptotic death are in situ detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling.

Journal Article↗
PubMed2001

Anticonvulsant preclinical profile of CHF 3381: dopaminergic and glutamatergic mechanisms.

Following intraperitoneal or oral administrations, CHF 3381 ([n-(2-indanyl)-glycinamide hydrochloride]) protected rats against maximal electroshock (MES) test seizures. As glutamatergic pathways play a pivotal role in epilepsy, to better characterize the molecular mechanisms of action of CHF 3381, the drug effects on the binding of the excitatory amino acid antagonist [3H]-MK-801 in the presence of n-methyl-D-aspartate (NMDA), spermidine, or the combination of both ligands, were studied. CHF 3381 inhibited the [3H]-MK-801 specific binding in a noncompetitive fashion in respect to NMDA and polyamines recognition sites. CHF 3381 failed to change the kinetic characteristic of glycine B receptors labeled with [3H]-glycine; in contrast, it significantly increased K(d) values when the receptors were labeled with the more specific compound [3H]-MDL 105,519. CHF 3381 antagonized dopamine (DA)-induced behavioral responses and inhibited, in a glycine-dependent manner, the NMDA-induced [3H]-DA release from rat striatal slices, but it failed to change either the kinetic characteristics of D1, D2, or D3 receptors in synaptic plasma membranes (SPM) or the [3H]-DA uptake from striatal synaptosomes. Moreover, in primary cell cultures of cortical neurons, this drug exhibited glycine-independent neuroprotective effects against glutamate-induced excitotoxicity. It is concluded that this compound could have a potential use in several disease states where a pathological high level of NMDA receptor activation is thought to occur.

Animals↗
PubMed2001

Safety of HMG-CoA reductase inhibitors: focus on atorvastatin.

Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease. Statins are in general well tolerated. Withdrawal rates related to adverse events are low (< or =3%). The most common adverse events are mild gastrointestinal symptoms. Elevated serum transaminase levels occur infrequently (< or = 1.5%). These are generally asymptomatic, reversible and rarely require drug withdrawal. Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk. Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g. erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme. The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions. Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins.

Atorvastatin↗
PubMed2001

Value of the dorsal cutaneous guinea pig model in selecting topical antiviral formulations for the treatment of recurrent herpes simplex type 1 disease.

Recurrent herpes simplex labialis represents a disease still difficult to treat, despite the availability of many established antiviral drugs used in clinical research since 30 years ago. Although differences between the human disease and that obtained in experimental animal suggest caution in predicting an effective clinical response from the experimental results, some of the animal models seem to be useful in optimising the topical formulation of single antiviral drugs. In the present work the dorsal cutaneous guinea pig model was used to compare 5 different topical antiviral formulations with clinical promise (active molecule: 5% w/w micronized aciclovir, CAS 59277-89-3), using both roll-on and lipstick application systems. The aim being to evaluate which vehicle (water, oil, low melting and high melting fatty base) and application system (roll-on, lipstick) enhances the skin penetration and the antiviral activity of the drug, after an experimental intradermal infection with Herpes simplex virus type 1 (HSV-1). As reference, a commercial formulation (5% aciclovir ointment) was used. The cumulative results of this study showed that the formulation A, containing 5% aciclovir in an aqueous base in a roll-on application system, has the better antiviral efficacy in reducing the severity of cutaneous lesions and the viral titer; among the lipsticks preparations, the formulation D, containing 5% aciclovir in a low melting fatty base, demonstrates a very strong antiviral activity, though slightly less than formulation A. This experimental work confirms the validity of the dorsal cutaneous guinea pig model as a rapid and efficient method to compare the antiviral efficacy of new formulations, with clinical promise, to optimise the topical formulation of the active antiviral drugs.

Acyclovir↗
PubMed2001

Interstitial pressure gradients around joints; location of chief resistance to fluid drainage from the rabbit knee.

The hypothesis has been advanced that synovium offers the main resistance to fluid escape from joints, even though it is under 20 microm thick. To test this, fluid was infused into the knee joint cavity of anaesthetised rabbits to set up a pressure gradient, then the profile of periarticular interstitial fluid pressure (P(if)) was measured by advancing a micropipette, connected to a servo-null pressure recorder, in steps through a periarticular tissue 'window' until the joint cavity was entered. With intra-articular pressure (P(j)) raised to 15 cmH(2)O (the pressure of an acute joint effusion) the pressure gradient dP(if) /dx (where x is distance) across the synovial lining was 0.47 +/- 0.04 cmH(2)O microm(-1) (n = 10 joints). This was 23.5-fold greater than the gradient in the subsynovium (0.02 +/- 0.01 cmH(2)O microm(-1); P < 0.0001, Student's t test), indicating that the hydraulic resistivity of the subsynovium is 4 % of that of the synovium. The pressure profile was not altered by circulatory arrest. To test the hypothesis further, the effect of a stab perforation of the synovial lining on fluid drainage rate ((.Q(s)) was studied. Perforation raised both.Q(s) and the conductance term d.Q(s)/dP(j) more than 10-fold (n = 6 joints; P < 0.0001, ANOVA). The results thus support the view that, despite its thinness, the synovial lining offers the main hydraulic resistance to fluid drainage from a synovial joint.

Animals↗
PubMed2001

[Histopathologic risk factors in patients with non-seminomatous germ tumors of the testis in clinical stage 1. Retrospective study of 75 patients].

OBJECTIVES: This retrospective study was performed to evaluate histopathologic prognostic risk factors in 75 patients on clinical stage 1 nonseminomatous germ cell cancer of the testis (NSGCTT). METHODS: From September 1976 to February 2000 we operated on 75 patients for NSGCTT on clinical stage 1 disease. Average age was 29.5 years (range 16-71). After orchiectomy, therapeutic options included retroperitoneal lymph node dissection (RLND) for 44 patients (58.6%), surveillance for 26 (34.6%) and neoadjuvant chemotherapy for 5 (6.6%). Testis primary tumor samples were assessed for studying prognostic risk factors that included vascular and/or lymphatic invasion (IV/IL+), percentage of embryonal carcinoma (%EC) and absence of yolk sac tumor (YS-). RESULTS: All patients were alive and disease-free. The average age follow-up was 84.5 months (range 1-254). Relapses occurred in 11 (14.6%) patients after an average follow-up of 9.09 months (range 3-24). Prognostic risk factors were detected as follows: IV/IL+ in 17 cases (22.7%), (50-80%) EC in 23 (30.6%), CE% > 80 in 23 (30.6%), YS- in 55 (72%). In 8 (10.6%) patients there was not any prognostic risk factor. Disease relapse related to prognostic risk factors was detected as follows: 18.1% for VI/LI, 90.9% for EC% > 50 (27.2% for 50-80% EC and 63.6% for CE% > 80) and 90.9% for YS-. Relapsing rates between patients with EC% > 80 and 50-80% EC resulted statistically significant (p = 0.02, odds ratio = 12.25). Relapsing rates between patients on surveillance and those who underwent RLND was next to be significant (p = 0.05, odds ratio 3.68). CONCLUSIONS: EC% > 80 is a prognostic risk factor for disease relapse in patients with clinical stage 1 NSGCT who are selected in a high risk group requiring RPLND or neoadjuvant chemotherapy as therapeutical option.

Adolescent↗
PubMed2000

N-Methyl-D-aspartate receptor stimulation activates tyrosinase and promotes melanin synthesis in the ink gland of the cuttlefish Sepia officinalis through the nitric Oxide/cGMP signal transduction pathway. A novel possible role for glutamate as physiologic activator of melanogenesis.

The tyrosinase-catalyzed conversion of l-tyrosine to melanin represents the most distinctive biochemical pathway in the ink gland of the cuttlefish Sepia officinalis; however, the molecular mechanisms underlying its activation have remained so far largely uncharted. In this paper we demonstrate for the first time that l-glutamate can stimulate tyrosinase activity and promote melanin synthesis in Sepia ink gland via the N-methyl-d-aspartate (NMDA) receptor/NO/cGMP signal transduction pathway. Incubation of intact ink glands with either l-glutamate or NMDA resulted in an up to 18-fold increase of tyrosinase activity and a more than 6-fold elevation of cGMP levels. Comparable stimulation of tyrosinase was induced by an NO donor and by 8-bromo-cGMP. An NMDA receptor antagonist, NO synthase (NOS) inhibitors, and a guanylate cyclase blocker suppressed NMDA-induced effects. Immunohistochemical evidence indicated that enhanced cGMP production was localized largely in the mature part of the ink gland. Increased de novo synthesis of melanin was demonstrated in NMDA- and NO-stimulated ink glands by a combined microanalytical approach based on spectrophotometric determination of pigment levels and high performance liquid chromatography quantitation of pyrrole-2,3, 5-tricarboxylic acid, a specific melanin marker, in melanosome-containing fractions. These results fill a longstanding gap in the understanding of the complex biochemical mechanisms underlying activation of melanogenesis in the mature ink gland cells of S. officinalis and disclose a novel physiologic role of the excitatory neurotransmitter glutamate mediated by the NMDA receptor/NO/cGMP signaling pathway.

Animals↗
PubMed2000

Phenotype-genotype correlation in Sicilian patients with Hb H.

We studied 15 Sicilian subjects with Hb H disease correlating clinical examinations with hematological and molecular data. Seven different alpha-tha1 mutations were identified: four deletion types (--MED --CAL, -alpha3.7, -alpha4.2) and three nondeletion types (alpha(Ncol)alpha, alpha(Hph)alpha, alphaCSalpha). All the patients had a zero-gene chromosome (--MED or --CAL), while the third alpha gene was deleted (-alpha3.7, -alpha4.2) or inactive (alpha(Ncol)alpha, alpha(Hph)alpha, alphaCSalpha). In patients with the nondeletion genotype the analysis of hematological values revealed lower levels of RBC and Hb A2 and significantly higher levels of Hb H. The clinical variability was remarkable, ranging from totally asymptomatic conditions, casually diagnosed, to severe thalassemia intermedia with marked hemolytic crises, liver and spleen enlargement and the necessity for frequent transfusions. The genotype did not justify the gravity of the phenotype in every case, and the differences in clinical manifestations, also notable, are not easily explainable in subjects who apparently have the same genotype.

Adolescent↗