C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition.

Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients' samples and by in silico analysis on an independent patient cohort from Taylor's platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients' risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.

A microRNA code for prostate cancer metastasis.

Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-ß and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients' cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.

Human HMGA2 protein overexpressed in mice induces precursor T-cell lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes. HMGA2 (high-mobility group AT-hook 2) gene expression is extremely low in normal adult tissues, but it is overexpressed in many tumors. To identify the biological function of HMGA2, we generated transgenic mice carrying the human HMGA2 gene under control of the VH promoter/Eµ enhancer. Approximately 90% of Eµ-HMGA2 transgenic mice became visibly sick between 4 and 8 months due to the onset and progression of a T-ALL-like disease. Characteristic features included severe alopecia (30% of mice); enlarged lymph nodes and spleen; and profound immunological abnormalities (altered cytokine levels, hypoimmunoglobulinemia) leading to reduced immune responsiveness. Immunophenotyping showed accumulation of CD5+CD4+, CD5+CD8+ or CD5+CD8+CD4+ T-cell populations in the spleens and bone marrow of sick animals. These findings show that HMGA2-driven leukemia in mice closely resembles spontaneous human T-ALL, indicating that HMGA2 transgenic mice should serve as an important model for investigating basic mechanisms and potential new therapies of relevance to human T-ALL.

Apparent diffusion coefficient obtained by magnetic resonance imaging as a prognostic marker in glioblastomas: correlation with MGMT promoter methylation status.

OBJECTIVE: To evaluate whether apparent diffusion coefficient (ADC) values can predict the status of MGMT of glioblastoma multiforme (GBM) and correlate with overall survival (OS) and progression-free survival (PFS). METHODS: This retrospective study included 47 patients with pathologically proven glioblastoma. All of them underwent MR DWI study before surgery (mean time 1 week) and the status of methylguanine-DNA-methyltransferase (MGMT) promoter methylation was searched for. Minimum apparent diffusion coefficient (ADC) values were evaluated. OS and PSF parameters were calculated, and Student's t-test, Kaplan-Meier curves, linear and Cox regression were performed. RESULTS: Twenty-five patients showed positive methylation of the MGMT promoter. Patients showing MGMT promoter methylation had higher minimum ADC values, and they survived longer than those without MGMT promoter methylation. The median ADCmin value of 0.80 represents the cutoff value able to distinguish between methylated and un-methylated patients. Patients showing minimum ADC values higher than 0.80 survived longer than patients with minimum ADC values lower than 0.80. A linear correlation between minimum ADC values vs. the OS and PFS was observed. CONCLUSIONS: Minimum ADC values in glioblastoma multiforme could be used as a preoperative parameter to estimate the status of MGMT promoter methylation and the survival of patients.

BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial-mesenchymal transition.

Prostate cancer is one of the leading causes of cancer-related death in men. Despite significant advances in prostate cancer diagnosis and management, the molecular events involved in the transformation of normal prostate cells into cancer cells have not been fully understood. It is generally accepted that prostate cancer derives from the basal compartment while expressing luminal markers. We investigated whether downregulation of the basal protein B-cell translocation gene 2 (BTG2) is implicated in prostate cancer transformation and progression. Here we show that BTG2 loss can shift normal prostate basal cells towards luminal markers expression, a phenotype also accompanied by the appearance of epithelial-mesenchymal transition (EMT) traits. We also show that the overexpression of microRNA (miR)-21 suppresses BTG2 levels and promotes the acquisition of luminal markers and EMT in prostate cells. Furthermore, by using an innovative lentiviral vector able to compete with endogenous mRNA through the overexpression of the 3'-untranslated region of BTG2, we demonstrate that in prostate tumor cells, the levels of luminal and EMT markers can be reduced by derepression of BTG2 from microRNA-mediated control. Finally, we show that the loss of BTG2 expression confers to non-tumorigenic prostate cells ability to grow in an orthotopic murine model, thus demonstrating the central role of BTG2 downregulaton in prostate cancer biology.

Clinical applications of dynamic susceptibility contrast perfusion-weighted MR imaging in brain tumours.

Magnetic resonance imaging (MRI) with a dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) sequence to study brain tumours provides information on the haemodynamic characteristics of the neoplastic tissue. Brain perfusion maps and calculation of perfusion parameters, such as relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV) and mean transit time (MTT) allow assessment of vascularity and angiogenesis within tumours of the central nervous system (CNS), thus providing additional information to conventional MRI sequences. Although DSC-PWI has long been used, its clinical use in the study of brain tumours in daily clinical practice is still to be defined. The aim of this review was to analyse the application of perfusion MRI in the study of brain tumours by summarising our personal experience and the main results reported in the literature.

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer.

The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.

Negative stress echo: further prognostic stratification with assessment of pressure-volume relation.

BACKGROUND: A maximal negative stress echo identifies a low risk for subsequent hard events subset. However, the potentially prognostically relevant information on global contractile reserve on the left ventricle is missed by standard regional wall motion assessment, and can be obtained by end-systolic pressure-volume relationship (PVR) evaluation. AIM: To assess the relative prognostic value of PVR in patients with negative stress echo. METHODS: We enrolled 99 consecutive patients (age=61+/-14 years; 81 males, LVEF 47+/-14%, WMSI=1.42+/-0.50) with negative exercise stress echo for standard wall motion criteria. To build the PVR, the force was determined at rest and peak stress as the ratio of the systolic pressure/end-systolic volume index. All patients were followed-up on medical therapy. RESULTS: Median follow-up was 21 months (interquartile range 12-26). Twenty-nine events have been observed: 6 deaths, 10 heart failure related hospitalization and 13 worsening NYHA class of >or=1 grade. Using Cox's proportional hazard model the best independent predictor of total events was SP/ESV index change (rest-stress) <1.5 mm Hg/ml/m(2) as determined by ROC analysis cut-off (RR=29, p=0.001, sensitivity=80%, specificity=93%). The overall survival and event-free survival was 34% in patients with change (rest-stress) SP/ESV index<1.5 mm Hg/ml/m(2) and 97% in whose with >1.5 mm Hg/ml/m(2). CONCLUSIONS: In patients with negative stress echo, a preserved global contractility response can be easily identified through stress-induced variation in SP/ESV index, with powerful further risk stratification.

Dissection of NT3 functions in vivo by gene replacement strategy.

The development of the peripheral nervous system is governed in part by a family of neurotrophic factors that signal through Trk tyrosine kinase receptors. Neurotrophin 3 (NT3) ablation in mice causes a more severe neuronal phenotype than deletion of its receptor TrkC, suggesting that NT3 acts also through other non-preferred Trk receptors. To study the role of low-affinity ligand receptor interactions in vivo, we have replaced the Nt3 gene with the gene for brain-derived neurotrophic factor (BDNF), a TrkB ligand. As in NT3 and TrkC null mice, the proprioception system of these mutants failed to assemble. However, sensory fiber projections in the embryonic spinal cord suggest chemotropic effects of BDNF in vivo. In the dorsal root ganglia, the developmental dynamic of neuron numbers demonstrates that NT3 is required for activation of TrkB during neurogenesis and that TrkA is required during target tissue innervation. In the inner ear, the ectopic BDNF rescued the severe neuronal deficits caused by NT3 absence, indicating that TrkB and TrkC activate equivalent pathways to promote survival of cochlear neurons. However, specific increased innervation densities suggest unique functions for BDNF and NT3 beyond promoting neuronal survival. This mouse model has allowed the dissection of specific spatiotemporal Trk receptor activation by NT3. Our analysis provides examples of how development can be orchestrated by complex high- and low-affinity interactions between ligand and receptor families.

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal.

Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms. Endogenous NT-3 expression, strikingly absent in noradrenergic neurons of postnatal and adult brain, is present in afferent sources of the dorsal medulla and is upregulated after chronic morphine exposure in noradrenergic projection areas of the ventral forebrain. NT-3 expressed by non-catecholaminergic neurons may modulate opiate withdrawal and noradrenergic signalling.

Spatial shaping of cochlear innervation by temporally regulated neurotrophin expression.

Previous work suggested qualitatively different effects of neurotrophin 3 (NT-3) in cochlear innervation patterning in different null mutants. We now show that all NT-3 null mutants have a similar phenotype and lose all neurons in the basal turn of the cochlea. To understand these longitudinal deficits in neurotrophin mutants, we have compared the development of the deficit in the NT-3 mutant to the spatial-temporal expression patterns of brain-derived neurotrophic factor (BDNF) and NT-3, using lacZ reporters in each gene and with expression of the specific neurotrophin receptors, trkB and trkC. In the NT-3 mutant, almost normal numbers of spiral ganglion neurons form, but fiber outgrowth to the basal turn is eliminated by embryonic day (E) 13.5. Most neurons are lost between E13.5 and E15.5. During the period preceding apoptosis, NT-3 is expressed in supporting cells, whereas BDNF is expressed mainly in hair cells, which become postmitotic in an apical to basal temporal gradient. During the period of neuronal loss, BDNF is absent from the basal cochlea, accounting for the complete loss of basal turn neurons in the NT-3 mutant. The spatial gradients of neuronal loss in these two mutants appear attributable to spatial-temporal gradients of neurotrophin expression. Our immunocytochemical data show equal expression of their receptors, TrkB and TrkC, in spiral sensory neurons and thus do not relate to the basal turn loss. Mice in which NT-3 was replaced by BDNF show a qualitative normal pattern of innervation at E13.5. This suggests that the pattern of expression of neurotrophins rather than their receptors is essential for the spatial loss of spiral sensory neurons in NT-3 null mutants.

Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice.

Mutations at the waltzer (v) locus result in deafness and vestibular dysfunction due to degeneration of the neuroepithelium within the inner ear. Here, we use a positional cloning approach to show that waltzer encodes a novel cadherin (Cdh23), which is most closely related to the Drosophila Fat protein. A single nucleotide deletion in the v(J) allele and a single nucleotide insertion in the v allele are predicted to truncate each protein near the N-terminus and produce a functional null allele. In situ hybridization analysis showed that Cdh23 is expressed in the sensory hair cells of the inner ear, where it has been suggested to be a molecule critical for crosslinking of the stereocilia. In addition, Cdh23 is expressed in the urticulo-saccular foramen,the ductus reuniens, and Reissner's membrane, suggesting that Cdh23 may also be involved in maintaining the ionic composition of the endolymph. Finally, mutations in human CDH23 have recently been described for two loci, DFNB12 and USH1D, which cause nonsyndromic deafness, identifying waltzer as a mouse model for human hearing loss.

Can benchmarking be applied to radiation protection? And is it useful?

PURPOSE: Any program of protection from the ionizing radiations used for health care must ultimately lead to the total prevention of graduated effects and to the limitation of probabilistic effects to acceptable levels. The latter are the more dangerous because they may occur even at very low doses and involve the whole population including unexposed subjects; these effects may appear in the generations to come. The specific protection of the health of operators, patients, and the general population, depends on a series of physical-technical and bureaucratic-administrative factors. These must be known and applied based on precise reference standards, recommended or stated by law, as well as on appropriately regulated and controlled procedures. We chose to apply the benchmarking method to radiation protection in order to standardize and increase the efficacy of prevention and to plan, according to Deming's cycle, the continuous improvement of radiation protection performance. METHOD: Benchmarking is a qualitative intercomparison method widely used in business economics to improve performance referring to best practice and the best in class. When applied in a department where all the partners belong (internal benchmarking), the method features a subdivision into different (sub)processes integrated according to the logic of problem-solving. These stages are: planning: 1) identifying benchmarking issues; 2) identifying the participants; 3) deciding the data collection method; 4) data collection; analysis: 5) measuring the gap; 6) planning future performance; integration: 7) reporting the results; 8) setting the functional goals; action: 9) developing and implementing plans; 10) checking results and resetting the target. The gross subdivision of resources into human and structural permits to check the gap between an actual and an ideal setting separately. Thus, the procedures will give information on the human factor which will be periodically checked in loco relative to all active and passive conducts, while standards will be used to assess the available spaces, facilities and equipment, as well as the relative regular activity. Specific physical-technical and bureaucratic-administrative indices will be needed in both cases. RESULTS AND DISCUSSION: Solving the operators' doubts and consequently decreasing the statistical errors and/or the cases of incorrect performance has resulted in improved rendered quality, which will be further increased after the planned replacement of substandard or unsafe equipment. Meanwhile, the early application of equipment quality controls has helped rationalize and markedly decrease maintenance costs, which results in possible technologic investment to improve emergency imaging. Greater attention to their protection has made patients feel an improvement in received quality and has increased empathy in general. Total quality, as compared with the best practice, has increased thanks to the positive stimulus from standardization, emulation and sharing, and not only to the controls performed. It is difficult to evaluate the management indices, especially the performance efficacy, that is the relationship between radiation protection and results, because the work is in progress and we still lack the actual data on the decrease in accidents at work or occupational diseases of the operators. Moreover, the epidemiological data on radiation-induced conditions will be difficult to collect and interpret, which will make the dynamics of lawsuits for unwarranted or excessive exposure a useful and more readily available piece of information. Finally, relative to economic results, we would like to stress that no additional costs have been necessary to implement safety and quality in a setting involving, directly or indirectly, thousands of people. (ABSTRACT TRUNCATED)

Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities.

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF(+/-) mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF(+/-) mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF(+/-) mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF(+/-) mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.

Criteria for planning radiologic equipment replacement.

INTRODUCTION: The correct procedure for acquiring new radiologic equipment includes technology assessment, the analysis of needs, equipment purchasing/renting, room setting, equipment installation, management, and planned replacement. Therefore we need a simple, independent and objective procedure to analyze the technical and economic need of replacing a piece of radiologic equipment. We report on a simple evaluation method permitting to judge radiologic equipment acceptability, as stated by the relevant Italian laws. MATERIAL AND METHODS: Our system is adapted from similar business applications; it analyzes five main parameters, namely: support services (equipment age and working age, maintenance charges and the availability of spare parts), equipment function (life-supporting, diagnostic or treatment units; in an emergency department), the cost/benefit ratio, clinical efficacy and overall safety. If needed, another parameter can be added: accessibility by patients, involving such issues as time and ease of access to the examination/equipment and its location. The different criteria of radiologic equipment acceptability can be used to calculate the acceptability index (AI), as follows: AI = 0.4 (a + b + c + d) + 0.2 (e + f + g) + (h) where: (a) = unit's age, (b) = maintenance charges, (c) = non-use times, (d) = availability of spare parts, (e) = equipment function, (f) = operational analysis, (g) = diagnostic efficacy, (h) = safety. Each parameter is given a score according to the existing situation. RESULTS: Four scenarios can result from the analysis: 1) the equipment needs not be replaced; 2) replacement is not urgent and another check is scheduled within 12 months; 3) replacement must be scheduled; 4) the equipment must be urgently replaced (within 12 months). In the latter case, the unit should be disconnected at once if safety measures are violated irremediable. CONCLUSIONS: Our method is easy to use and a valid tool also for radioprotection purposes: the main difficulty is collaborating with the administrative offices in charge of equipment purchasing and maintenance. The facility's head radiologist can use the analysis to provide economic (and thus objective and indisputable) data about the need to replace, supplement, update, or repair pieces of diagnostic imaging equipment. Also, maintenance form and terms could be renegotiated and radioprotection improved. The Italian Society of Medical Radiology (SIRM) might suggest this method to the Italian Ministry of Health as the basis of the parliamentary bill on radiologic equipment replacement.

[Management of human resources, materials, and organization processes in radioprotection]. / La gestione delle risorse umane e materiali e dei processi organizzativi nella radioprotezione.

INTRODUCTION: The radiologist must learn to face daily management responsibilities and therefore he/she needs the relevant knowledge. Aside from the mechanisms of management accounting, which differ only slightly from similar analysis methods used in other centers, the managing radiologist (the person in charge) is directly responsible for planning, organizing, coordinating and controlling radiation protection, a major discipline characterizing diagnostic imaging. We will provide some practical management hints, keeping in mind that radiation protection must not be considered a simple (or annoying) technical task, but rather an extraordinary positive element for the radiologist's cultural differentiation and professional identity. MATERIAL AND METHODS: The managing radiologist can use the theory and practice of management techniques successfully applied in business, customizing them to the ethics and economics of health care. Meeting the users' needs must obviously prevail on balancing the budget from both a logical and an accounting viewpoints, since non-profit organizations are involved. In radiological practice, distinguishing the management of human from structural resources (direct funding is not presently available) permits to use internal benchmarking for the former and controlled acquisition and planned replacement of technologies in the latter, obviously after evaluation of specific indicators and according to the relevant laws and technical guidelines. RESULTS AND DISCUSSION: Managing human resources means safeguarding the patient, the operator and the population, which can be achieved or improved using benchmarking in a diagnostic imaging department. The references for best practice will be set per tabulas based on the relevant laws and (inter)national guidelines. The physical-technical and bureaucratic-administrative factors involved will be considered as process indices to evaluate the gap from normal standards. Among the different elements involved in managing structural resources, the appropriate acquisition of a piece of radiological equipment is important from both a radiation protection and an economic viewpoints. In the acquisition process, the first and the last steps (technology assessment and planned replacement, respectively) are specifically important for the radiologist and play a major role in global management. In both cases the radiologist must be able to lay out autonomous and objective working projects, also using evaluation algorithms.

[Assessment of microvascularization around the plaques in Peyronie's disease with Doppler color ultrasonography, power Doppler and ultrasonography contrast media]. / Valutazione della microvascolarizzazione intorno alla placca nella malattia di La Peyronie con eco color Doppler, power Doppler e mezzo di contrasto ecografico.

INTRODUCTION: The origin of Peyronie's disease remains obscure although the first report of this condition dates back to 1743. The disease prevalence in 388.6 in 100,000 population and little physiopathologic information is available. Repeated microtrauma to the tunica albuginea appears to favor the onset of inflammatory phenomena which result in fibrosis and calcification. The disease activity produces a microvascularization around the fibrocalcific plaques. We studied the evolution of the inflammatory process in Peyronie's disease relative to clinical symptoms, in order to optimize treatment follow-up. MATERIAL AND METHODS: We examined 20 patients with Peyronie's disease aged 34 to 56 years using a GE Sonora Logic 500 MD US scanner with linear probes of 7.5 and 13 MHz. The microvascularization around the plaques was studied with color and power Doppler investigations before contrast agent administration and with combined color and power Doppler after contrast agent administration. We injected Levovist (300 mg/mL) and 10 micrograms prostglandin E1 (PGE1). Examinations were repeated after 2-4 months in the patients with evidence of microvascularization around the plaques. RESULTS: US demonstrated fibrocalcific plaques in all the patients. The microvascularization around the plaques was seen with color Doppler in 3 cases (15%), with power Doppler in 5 cases (25%) and with contrast-enhanced color and power Doppler in 7 cases (35%). At 2-4 months' follow-up, we observed slight plaque enlargement and worsened symptoms in 5 of 7 patients (71%) with evidence of some microvascularization around the plaque. CONCLUSIONS: The plaque presence allows to define the condition and the microvascularization provides information on its evolution. The disease activity can be distinguished into 3 stages which can be related to the painful symptoms. US exhibits a better cost/benefit ratio than contrast-enhanced MRI.

Frequency of a mutated CCR-5 allele (delta32) among Italian healthy donors and individuals at risk of parenteral HIV infection.

The aim of this study was to assess the frequency of a truncated allele of the CCR-5 gene (delta32) in Italy, and address its possible role in parenteral HIV transmission, as well as its influence in HIV-associated disease progression. In 371 unrelated seronegative healthy blood donors the delta32 allele frequency was 0.047; this figure was significantly different from those reported in northern America and northern Europe populations. However, delta32 allele frequency in healthy individuals did not differ significantly from that found in 54 seronegative drug users (0.065), 98 seronegative hemophiliacs (0.051), and 81 seropositive hemophiliacs (0.049). Although in seropositive hemophiliacs the wt/delta32 heterozygous genotype was associated with a trend to a slower decline in CD4+ cell counts, its presence did not seem to influence disease progression, as comparable delta32 allele frequency frequencies were found among progressing (0.042) and nonprogressing (0.111) patients. These data do not seem to support a protective role of the delta32 allele in preventing HIV infection through the parenteral route, or in influencing the natural history of the disease in this particular risk category, although the delta32 heterozygous state was associated with lower plasma viremia levels. On the other hand, the finding of non-syncytium-inducing HIV strains in the majority of delta32 heterozygous seropositive patients suggests that its presence could not be a major factor in driving a switch toward more cytopathic, T-tropic HIV strains through selective pressure in coreceptor usage.

Evidence for a role of truncated trkC receptor isoforms in mouse development.

The trkC locus encodes several receptors for neurotrophin-3, including the well studied full-length tyrosine kinase isoform, in addition to receptor isoforms lacking the kinase active domain. TrkC receptors are widely expressed throughout mouse development in many different organs. To investigate the function of truncated receptors in vivo and to identify cell types that are biologically responsive to this gene product, we have overexpressed a physiological truncated trkC isoform in the mouse. Mice overexpressing this receptor develop to term but die in the first postnatal days. High levels of transgene expression result in severe developmental defects in the peripheral nervous system and in the heart. The severity of neuronal losses observed in these animals suggests that truncated receptors may act by sequestering neurotrophin, thus, closely relating this mouse model to the neurotrophin-3-deficient one. Lower levels of exogenous truncated receptor in transgenic mice result in a more modest phenotype and, in some neuronal populations, do not cause neural deficits. Taken together, these data suggest that truncated trkC receptor isoforms may have modulatory functions in development.