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Understanding the evolution of the B cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is fundamental to design the next generation of vaccines and therapeutics. We longitudinally analyze at the single-cell level almost 900 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants belong to the SH cohort. Repertoire analysis shows that the original Wuhan antigenic sin drives the convergent expansion of the same B cell germlines in vaccinated and SH cohorts. Only Omicron breakthrough infections expand previously unseen germ lines and generate broadly nAbs by restoring IGHV3-53/3-66 germ lines. Our analyses find that B cells initially expanded by the original antigenic sin continue to play a fundamental role in the evolution of the immune response toward an evolving virus., Competing Interests: Declaration of interests I.P., G.P., E.P., P.P., R.R., and E.A. are listed as inventors of full-length human mAbs described in Italian patent application nos. 102020000015754 filed on June 30, 2020, 102020000018955 filed on August 3, 2020, and 102020000029969 filed on December 4, 2020, and the international patent system no. PCT/IB2021/055755 filed on June 28, 2021. I.P., E.P., G.A., P.P., R.R., and E.A. are listed as inventors of full-length human mAbs described in the international patent system no. PCT/IB2022/061257 filed on November 22, 2022. All patents were submitted by Fondazione Toscana Life Sciences, Siena, Italy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study delves into the social identity of pro-vaccination and anti-vaccination supporters, emphasizing an understanding of the values that shape these distinct identities. Furthermore, the research highlights that user-generated content pertaining to vaccines offers valuable insights into the underlying personal values of both pro-vaccination and anti-vaccination groups., Method: We constructed a textual dataset based on 142,596 tweets. This data was analyzed in three steps. First, the linguistic characteristics of the textual data, together with the underlying personal values of the text creators, were identified using LIWC software. Second, the identified personal values were used as an input for the moderation analysis, which examined the relationship between personal values and social identity for pro- and anti-vaccination groups. Finally, an automated, in-depth text analysis was conducted in Mathematica to understand the narratives created by both groups., Results: The study findings indicate that both pro-vaccination and anti-vaccination supporters display characteristics of subcultures with distinct group identities. Consequently, based on the results, there is a need for more tailored public health communication strategies that address these two groups separately., Conclusions: Understanding how users create health-related content based on their personal values is crucial. Acknowledging and appreciating the diverse personal values and identities within different groups in the vaccination discourse can inform health communication efforts, aligning these efforts with the specific values of each group. This targeted communication is vital for effectively conveying relevant peer-reviewed health information amid the abundance of health-related user-generated content., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A growing body of evidence shows that fragment crystallizable (Fc)-dependent antibody effector functions play an important role in protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To unravel the mechanisms that drive these responses, we analyzed the phagocytosis and complement deposition mediated by a panel of 482 human monoclonal antibodies (nAbs) neutralizing the original Wuhan virus, expressed as recombinant IgG1. Our study confirmed that nAbs no longer neutralizing SARS-CoV-2 Omicron variants can retain their Fc functions. Surprisingly, we found that nAbs with the most potent Fc function recognize the N-terminal domain, followed by those targeting class 3 epitopes in the receptor binding domain. Interestingly, nAbs direct against the class 1/2 epitopes in the receptor binding motif, which are the most potent in neutralizing the virus, were the weakest in Fc functions. The divergent properties of the neutralizing and Fc function-mediating antibodies were confirmed by the use of different B cell germlines and by the observation that Fc functions of polyclonal sera differ from the profile observed with nAbs, suggesting that non-neutralizing antibodies also contribute to Fc functions. These data provide a high-resolution picture of the Fc-antibody response to SARS-CoV-2 and suggest that the Fc contribution should be considered for the design of improved vaccines, the selection of therapeutic antibodies, and the evaluation of correlates of protection., Competing Interests: Competing interests statement:R.R. owns Novartis and GSK stocks. I.P., E.P., E.A., and R.R. are listed as inventors of full-length human monoclonal antibodies described in Italian patent applications no. 102020000015754 filed on June 30th 2020, 102020000018955 filed on August 3rd 2020 and 102020000029969 filed on 4th of December 2020, and the international patent system number PCT/IB2021/055755 filed on the 28th of June 2021. All patents were submitted by Fondazione Toscana Life Sciences, Siena, Italy. Remaining authors have no competing interests to declare.

CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). IS defects were also observed ex vivo in CTLs from COVID-19 patients. These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells., (© 2022 Onnis et al.)

The continuous evolution of SARS-CoV-2 generated highly mutated variants able to escape natural and vaccine-induced primary immunity. The administration of a third mRNA vaccine dose induces a secondary response with increased protection. Here we investigate the longitudinal evolution of the neutralizing antibody response in four donors after three mRNA doses at single-cell level. We sorted 4100 spike protein specific memory B cells identifying 350 neutralizing antibodies. The third dose increases the antibody neutralization potency and breadth against all SARS-CoV-2 variants as observed with hybrid immunity. However, the B cell repertoire generating this response is different. The increases of neutralizing antibody responses is largely due to the expansion of B cell germlines poorly represented after two doses, and the reduction of germlines predominant after primary immunization. Our data show that different immunization regimens induce specific molecular signatures which should be considered while designing new vaccines and immunization strategies., (© 2023. The Author(s).)

In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC-GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocyte-specific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation. GR-cKO hearts showed increased expression of genes involved in glucose catabolism and reduced expression of genes promoting fatty acid oxidation and mitochondrial respiration. Accordingly, oxygen consumption in GR-cKO cardiomyocytes was less dependent on fatty acid oxidation, and glycolysis inhibition reverted GR-cKO effects on cardiomyocyte proliferation. GR ablation or transient pharmacological inhibition after myocardial infarction in juvenile and/or adult mice facilitated cardiomyocyte survival, cell cycle re-entry and division, leading to cardiac muscle regeneration along with reduced scar formation. Thus, GR restrains heart regeneration and may represent a therapeutic target., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

SARS-CoV-2 vaccines, administered to billions of people worldwide, mitigate the effects of the COVID-19 pandemic, however little is known about the molecular basis of antibody cross-protection to emerging variants, such as Omicron BA.1, its sublineage BA.2, and other coronaviruses. To answer this question, 276 neutralizing monoclonal antibodies (nAbs), previously isolated from seronegative and seropositive donors vaccinated with BNT162b2 mRNA vaccine, were tested for neutralization against the Omicron BA.1 and BA.2 variants, and SARS-CoV-1 virus. Only 14.2, 19.9 and 4.0% of tested antibodies neutralize BA.1, BA.2, and SARS-CoV-1 respectively. These nAbs recognize mainly the SARS-CoV-2 receptor binding domain (RBD) and target Class 3 and Class 4 epitope regions on the SARS-CoV-2 spike protein. Interestingly, around 50% of BA.2 nAbs did not neutralize BA.1 and among these, several targeted the NTD. Cross-protective antibodies derive from a variety of germlines, the most frequents of which were the IGHV1-58;IGHJ3-1, IGHV2-5;IGHJ4-1 and IGHV1-69;IGHV4-1. Only 15.6, 20.3 and 7.8% of predominant gene-derived nAbs elicited against the original Wuhan virus cross-neutralize Omicron BA.1, BA.2 and SARS-CoV-1 respectively. Our data provide evidence, at molecular level, of the presence of cross-neutralizing antibodies induced by vaccination and map conserved epitopes on the S protein that can inform vaccine design., (© 2022. The Author(s).)

ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. In vitro treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miano, Romaniello, Mazzeschi, Morselli, Da Pra, Sacchi, Bongiovanni, Sgarzi, Pantano, Lauriola and D’Uva.)

As the coronavirus disease 2019 (COVID-19) pandemic continues, there is a strong need for highly potent monoclonal antibodies (mAbs) that are resistant against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs). Here, we evaluate the potency of the previously described mAb J08 against these variants using cell-based assays and delve into the molecular details of the binding interaction using cryoelectron microscopy (cryo-EM) and X-ray crystallography. We show that mAb J08 has low nanomolar affinity against most VoCs and binds high on the receptor binding domain (RBD) ridge, away from many VoC mutations. These findings further validate the phase II/III human clinical trial underway using mAb J08 as a monoclonal therapy.

ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis.

The emergence of SARS-CoV-2 variants is jeopardizing the effectiveness of current vaccines and limiting the application of monoclonal antibody-based therapy for COVID-19 (refs. 1,2 ). Here we analysed the memory B cells of five naive and five convalescent people vaccinated with the BNT162b2 mRNA vaccine to investigate the nature of the B cell and antibody response at the single-cell level. Almost 6,000 cells were sorted, over 3,000 cells produced monoclonal antibodies against the spike protein and more than 400 cells neutralized the original SARS-CoV-2 virus first identified in Wuhan, China. The B.1.351 (Beta) and B.1.1.248 (Gamma) variants escaped almost 70% of these antibodies, while a much smaller portion was impacted by the B.1.1.7 (Alpha) and B.1.617.2 (Delta) variants. The overall loss of neutralization was always significantly higher in the antibodies from naive people. In part, this was due to the IGHV2-5;IGHJ4-1 germline, which was found only in people who were convalescent and generated potent and broadly neutralizing antibodies. Our data suggest that people who are seropositive following infection or primary vaccination will produce antibodies with increased potency and breadth and will be able to better control emerging SARS-CoV-2 variants., (© 2021. The Author(s).)

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bongiovanni, Sacchi, Da Pra, Pantano, Miano, Morelli and D'Uva.)

To investigate the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the immune population, we coincupi bated the authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for seven passages, but, after 45 d, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed, at day 80, by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom, South Africa, Brazil, and Japan of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed., Competing Interests: Competing interest statement: R.R. is an employee of the GSK group of companies. E.A., I.P., E.P., N.M., and R.R. are listed as inventors of full-length human monoclonal antibodies described in Italian patent applications 102020000015754 filed on June 30, 2020 and 102020000018955 filed on August 3, 2020., (Copyright © 2021 the Author(s). Published by PNAS.)

This study aims to understand the extent to which a time of emergency, (e.g. the COVID-19 pandemic), impacts consumer behaviour in terms of risk and expectations. The methodology involves the systematic content analysis of 15,000 tweets collected from three countries (UK, Italy and Spain) in April 2020. The results suggest that the top-of-mind expectation by consumers deals with escaping from home and enjoying freedom, either by having a good meal (UK), drinking alcoholic beverages (Spain), or travelling (Italy). They also suggest that the high levels of risk individuals were exposed to during the pandemic will not influence behavior in the long-term post-lockdown. Instead, they suggest consumers are willing to restore their consumption levels especially of activities that contribute to the sense of escapism. Finally, results provide evidence of the cultural differences emerging from consumers from different countries during the pandemic. Implications for international marketers and retailers are provided., (© 2021 Published by Elsevier Inc.)

Human monoclonal antibodies are safe, preventive, and therapeutic tools that can be rapidly developed to help restore the massive health and economic disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. By single-cell sorting 4,277 SARS-CoV-2 spike protein-specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The most potent neutralizing antibodies recognized the spike protein receptor-binding domain, followed in potency by antibodies that recognize the S1 domain, the spike protein trimer, and the S2 subunit. Only 1.4% of them neutralized the authentic virus with a potency of 1-10 ng/mL. The most potent monoclonal antibody, engineered to reduce the risk of antibody-dependent enhancement and prolong half-life, neutralized the authentic wild-type virus and emerging variants containing D614G, E484K, and N501Y substitutions. Prophylactic and therapeutic efficacy in the hamster model was observed at 0.25 and 4 mg/kg respectively in absence of Fc functions., Competing Interests: Declaration of interests R.R. is an employee of GSK group of companies. E.A., A.K., D.C., C.D.S, I.P., N.M., E.P., P.P., C.S., M.T., F.V., and R.R. are listed as inventors of full-length human monoclonal antibodies described in Italian patent applications no. 102020000015754 filed on June 30, 2020 and no. 102020000018955 filed on August 3, 2020., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In early 2020, the World Health Organization (WHO) developed the term "infodemic" to describe the velocity at which data can be exchanged among people, in a free virtual space where firms have limited control over the information diffusion. In particular, the diffusion of information on social media has analogies with the transmission (contagion) of social phenomena and infectious diseases. The aim of this research is to model the viral effects of a luxury marketing campaign when adopting negative stereotypes to increase the market share in a growing market. The campaign generated 506,127 likes of celebrity endorsers/influencers and 17,984 comments spread worldwide in a relatively short period, producing a "burst". Findings revealed the unexpected social burst occurred with negative consumers' evaluation, which has been amplified becoming dramatically damaging for the brand (brand hate)., (Crown Copyright © 2020 Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic (that started in early 2020) is causing several disruptions in the short- and mid-term, to which businesses have to adapt. Some retailers have reacted to the emergency immediately, displaying a plethora of different intervention types. The authors aim to synthesize the challenges that retailers are facing during the COVID-19 emergency. We do this from the perspective of both consumers and managers, with the goal of providing guidelines on and examples of how retailers can handle this unprecedented situation., (Crown Copyright © 2020 Published by Elsevier Inc. All rights reserved.)

Neisserial Heparin Binding Antigen (NHBA) is a surface-exposed lipoprotein of Neisseria meningitidis and a component of the Bexsero vaccine. NHBA is characterized by the presence of a highly conserved Arg-rich region involved in binding to heparin and heparan sulphate proteoglycans present on the surface of host epithelial cells, suggesting a possible role of NHBA during N. meningitidis colonization. NHBA has been shown to be cleaved by the meningococcal protease NalP and by human lactoferrin (hLF), a host protease presents in different body fluids (saliva, breast milk and serum). Cleavage occurs upstream or downstream the Arg-rich region. Since the human nasopharynx is the only known reservoir of infection, we further investigated the susceptibility of NHBA to human proteases present in the saliva to assess whether proteolytic cleavage could happen during the initial steps of colonization. Here we show that human saliva proteolytically cleaves NHBA, and identified human kallikrein 1 (hK1), a serine protease, as responsible for this cleavage. Kallikrein-related peptidases (KLKs) have a distinct domain structure and exist as a family of 15 genes which are differentially expressed in many tissues and in the central nervous system. They are present in plasma, lymph, urine, saliva, pancreatic juices, and other body fluids where they catalyze the proteolysis of several human proteins. Here we report the characterization of NHBA cleavage by the tissue kallikrein, expressed in saliva and the identification of the cleavage site on NHBA both, as recombinant protein or as native protein, when expressed on live bacteria. Overall, these findings provide new insights on NHBA as target of host proteases, highlights thepotential role of NHBA in the Neisseria meningitidis nasopharyngeal colonization, and of kallikrein as a defensive agent against meningococcal infection., Competing Interests: Sara Marchi, Massimiliano Biagini, Vincenzo Nardi-Dei, Silvia Rossi Paccani, Mariagrazia Pizza and Elena Cartocci were employees of Novartis Vaccines at the time of the study; in March 2015 the Novartis non-influenza Vaccines business was acquired by the GSK group of companies. Martina Di Fede was a PhD Student of the University of Siena at the time of the study and supervised by Novartis Vaccines and Diagnostics Srl (and then by GSK). Martina Di Fede is now an employee at Institute für Virologie und Medizinische Biochemie, Westfälische Wilhelms-Universität Münster, Von-Esmarch-Str. 56, 48149, Münster, Germany. Elisa Pantano was a student of the University of Perugia at the time of the study (Internship) supervised by Novartis Vaccines and Diagnostic Srl (and then by GSK). The declared conflicts of interest do not alter authors adherence to PLOS ONE policies on sharing data and materials, and there are no patents, products in development or marketed products to declare.

Objective: The purpose of this article is to assess whether unenhanced and gadobenate dimeglumine-enhanced MRI with dynamic and hepatobiliary phase may predict the diagnosis of dysplastic nodules in patients with liver cirrhosis., Materials and Methods: We retrospectively analyzed 75 cirrhotic patients (47 men and 28 women; mean [± SD] age, 55 ± 12 years) with 82 hepatocellular nodules, including histology-proven dysplastic nodules (n = 25; diameter, 1-3 cm) and hepatocellular carcinomas (n = 57; diameter, 2-3 cm) scanned by MRI before and after gadobenate dimeglumine injection during hepatic arterial phase (HAP), portal venous phase (PVP), equilibrium phase, and hepatobiliary phase. Nodule T1 and T2 intensities before contrast agent injection and nodule HAP, PVP, equilibrium phase, and hepatobiliary phase intensities were compared with the adjacent liver. Univariate and multivariate logistic regression analysis was conducted to assess how the nodule could predict dysplastic nodule diagnosis., Results: Some imaging findings were independent predictors of dysplastic nodule diagnosis-namely, nodule T2 isohypointensity (odds ratio [OR], 12.28; 95% CI, 3.88-38.82), T1 isohyperintensity (OR, 26.74; 95% CI, 7.53-94.90), HAP isohypointensity (OR, 97.16; 95% CI, 20.06-470.49), PVP-equilibrium phase isohyperintensity (OR, 20.53; 95% CI, 5.36-78.62), and hepatobiliary phase isohyperintensity (OR, 119.6; 95% CI, 21.59-662.40). Nodule T2 and HAP isohypointensity (OR 31.47; 95% CI, 7.88-125.58), nodule T2 isohypointensity and hepatobiliary phase isohyperintensity (OR, 28.77; 95% CI, 7.79-106.19), nodule T1 isohyperintensity and HAP isohypointensity (OR, 17.22; 95% CI, 4.85-61.14), and nodule T1 and hepatobiliary phase isohyperintensity (OR, 19.39; 95% CI, 5.38-69.90) were also predictors of dysplastic nodule diagnosis., Conclusion: The combination of nodule appearance on T2-weighted MRI and nodule enhancement after gadobenate dimeglumine injection may predict dysplastic nodule diagnosis in patients with liver cirrhosis.

A case of twin pregnancy with intrauterine death of one foetus during the 19th week of pregnancy has been described and the obstetric approach is reported. Pregnancy was actively continued with the following procedure: 1. Tocolysis, 2. Anti-infective prophylaxis; 3. Monitoring of coagulation on factor; 4. Weekly echotomography. In the 39th week the baby was delivered by caesarean section. The baby was discharged in good health on the 5th day after delivery.

Variations of plasma NEFA levels during oral glucose tolerance tests and after intravenous tolbutamide administration have been determined in normal subjects and in diabetic patients. The results are discussed on the bases of actual knowledges on glucose and lipid metabolisms.