In vitro fertilization: an unexpected finding in a cohort of patients with biliary atresia

In biliary atresia (BA), efforts to prevent premature liver transplantation (LT) are aimed at early diagnosis, timing of Kasai-portoenterostomy (KPE), and centralization of care. This report presents the clinical picture, treatment strategies, and outcomes of BA patients with no previous treatment. A retrospective cohort study (Jan/2001 to Jan/2021) was conducted to evaluate the outcome of patients with BA referred to a single team. Study groups were: 1) Kasai-only group (K-only) n=9), 2) LT-only group (n=7), and 3) Kasai+LT group (K+LT) (n=23). Survival with native liver and overall survival were 22.9 and 94.8%, respectively, at 120 months of follow-up. There was no difference in age at KPE in the K-only group (46.8±21.8 days) vs K+LT (52.1±22 days), P=0.4. Ten (25.6%) patients were babies conceived through in vitro fertilization (IVF). Four IVF patients (40%) presented associated congenital heart disease vs 5 patients (17%) in the remaining group (P=0.14). Two of the IVF patients were premature (<37 weeks). Median maternal age at birth was 35 years (33 to 41 years). Excellent patient survival is expected for patients with BA with the available treatment strategies. IVF+BA was an unexpected prevalent association in this cohort, and further studies are required to better understand these findings.

IFNγ-dependent silencing of TFF1 during Helicobacter pylori infection.

Chronic Helicobacter pylori infection is the leading cause of intestinal-type adenocarcinoma, as prolonged Helicobacter colonization triggers chronic active gastritis, which may evolve into adenocarcinoma of the intestinal type. In this environment, cytokines play a significant role in determining the evolution of the infection. In combination with other factors (genetic, environmental and nutritional), the pro-inflammatory response may trigger pro-oncogenic mechanisms that lead to the silencing of tumour-suppressor genes, such as trefoil factor 1 (TFF1). The latter is known to play a protective role by maintaining the gastric mucosa integrity and retaining H. pylori in the mucus layer, preventing the progression of infection and, consequently, the development of gastric cancer (GC). Since TFF1 expression is reduced during chronic Helicobacter infection with a loss of gastric mucosa protection, we investigated the molecular pathways involved in this reduction. Specifically, we evaluated the effect of some pro-inflammatory cytokines on TFF1 regulation in GC and primary gastric cells by RT-qPCR and luciferase reporter assay analyses and the repressor role of the transcription factor C/EBPß, overexpressed in gastric-intestinal cancer. Our results show that, among several cytokines, IFNγ stimulates C/EBPß expression, which acts as a negative regulator of TFF1 by binding its promoter at three different sites.

Intracranial compliance in type 2 diabetes mellitus and its relationship with the cardiovascular autonomic nervous control

The intracranial compliance in type 2 diabetes mellitus (T2DM) patients and the association with cardiovascular autonomic control have not been fully elucidated. The aim of this study was to assess intracranial compliance using the noninvasive intracranial pressure (niICP) and the monitoring of waveform peaks (P1, P2, and P3) and the relationship with cardiovascular autonomic control in T2DM patients. Thirty-two men aged 40-60 years without cardiovascular autonomic neuropathy (CAN) were studied: T2DMG (n=16) and control group CG (n=16). The niICP was evaluated by a noninvasive extracranial sensor placed on the scalp. Cardiovascular autonomic control was evaluated by indices of the baroreflex sensitivity (BRS), from temporal series of R-R intervals of electrocardiogram and systolic arterial pressure, during supine and orthostatic positions. The participants remained in the supine position for 15 min and then 15 min more in orthostatism. T2DMG presented a decrease of the P2/P1 ratio during the orthostatic position (P<0.001). There was a negative moderate correlation between the P2 peak with cardiovascular coupling (K2HP-SAPLF) in supine (r=-0.612, P=0.011) and orthostatic (r=-0.568, P=0.020) positions in T2DMG. We concluded that T2DM patients without CAN and cardiovascular complications presented intracranial compliance similar to healthy subjects. Despite preserved intracranial adjustments, T2DM patients had a response of greater magnitude in orthostatism. In addition, the decoupling between the heart period and blood pressure signal oscillations in low frequency appeared to be related to the worsening of intracranial compliance due to the increased P2 peak.

Impact of the COVID-19 outbreak on acute stroke pathways - insights from the Alsace region in France.

BACKGROUND AND PURPOSE: To date, no study has attempted to quantify the impact of the COVID-19 outbreak on the incidence and treatment of acute stroke. METHODS: This was a retrospective review of acute stroke pathway parameters in all three stroke units in the Alsace region during the first month of the outbreak (1-31 March 2020), using the similar period from 2019 as a comparator. A secondary detailed analysis of all stroke alerts and stroke unit admissions was performed in the centre with the largest case volume. RESULTS: Compared to the same period in 2019, in March 2020 there were 39.6% fewer stroke alerts and 33.3% fewer acute revascularization treatments [40.9% less intravenous thrombolysis (IVT) and 27.6% less mechanical thrombectomy (MT)]. No marked variation was observed in the number of stroke unit admissions (-0.6%). The proportion of patients with acute revascularization treatments (IVT or MT) out of the total number of stroke unit admissions was significantly lower in March 2020 (21.3%) compared to 2019 (31.8%), P = 0.034. There were no significant differences in time delays or severity of clinical symptoms for patients treated by IVT or MT, nor in the distribution of final diagnosis amongst stroke alerts and stroke unit admissions. CONCLUSION: These results suggest that the overall incidence of stroke remained the same, but fewer patients presented within the therapeutic time window. Increased public awareness and corrective measures are needed to mitigate the deleterious effects of the COVID-19 outbreak on acute stroke care.

Baroreflex sensitivity in frailty syndrome

Frailty is related to a decrease in the physiological reserves, which causes difficulties in maintaining homeostasis. An example of physiological mechanisms for cardiovascular homeostasis is the baroreflex. The aim of this study was to compare baroreflex among frail, prefrail, and nonfrail individuals, in supine and orthostatic positions. Community-dwelling older adults were evaluated and categorized into frail, prefrail, or nonfrail groups, according to frailty phenotype. The RR interval (RRi) and systolic blood pressure (SBP) series were recorded for 15 min in the supine and 15 min in the orthostatic positions. Mean and variance of RRi and SBP, and baroreflex evaluated by phase, gain (α), and coherence (K2) were determined. A two-way repeated measures ANOVA, with Tukey's post hoc, was applied for group, position, and their interaction effects. The significance level established was 5%. Prefrail and frail participants did not present a significant decrease in mean values of RRi after postural challenge (893.43 to 834.20 ms and 925.99 to 857.98 ms, respectively). Frail participants showed a reduction in RRi variance in supine to orthostatic (852.04 to 232.37 ms2). Prefrail and frail participants showed a decrease in K2 after postural change (0.69 to 0.52 and 0.54 to 0.34, respectively). Frail participants exhibited lower values of K2 (0.34) compared to nonfrail and prefrail participants (0.61 and 0.52, respectively). Baroreflex indicated the presence of decoupling between heart period and SBP in frail and prefrail. Thus, reduced K2 might be a marker of the frailty process.

Autonomic cardiovascular modulation with three different anesthetic strategies during neurosurgical procedures.

BACKGROUND: Autonomic cardiovascular modulation during surgery might be affected by different anesthetic strategies. Aim of the present study was to assess autonomic control during three different anesthetic strategies in the course of neurosurgical procedures by the linear and non-linear analysis of two cardiovascular signals. METHODS: Heart rate (EKG-RR intervals) and systolic arterial pressure (SAP) signals were analyzed in 93 patients during elective neurosurgical procedures at fixed points: anesthetic induction, dura mater opening, first and second hour of surgery, dura mater and skin closure. Patients were randomly assigned to three anesthetic strategies: sevoflurane+fentanyl (S-F), sevoflurane+remifentanil (S-R) and propofol+remifentanil (P-R). RESULTS: All the three anesthetic strategies were characterized by a reduction of RR and SAP variability. A more active autonomic sympathetic modulation, as ratio of low to high frequency spectral components of RR variability (LF/HF), was present in the P-R group vs. S-R group. This is confirmed by non-linear symbolic analysis of RR series and SAP variability analysis. In addition, an increased parasympathetic modulation was suggested by symbolic analysis of RR series during the second hour of surgery in S-F group. CONCLUSION: Despite an important reduction of cardiovascular signal variability, the analysis of RR and SAP signals were capable to detect information about autonomic control during anesthesia. Symbolic analysis (non-linear) seems to be able to highlight the differences of both the sympathetic (slow) and vagal (fast) modulation among anesthetics, while spectral analysis (linear) underlines the same differences but only in terms of balance between the two neural control systems.

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

1H and 10B NMR and MRI investigation of boron- and gadolinium-boron compounds in boron neutron capture therapy.

(10)B molecular compounds suitable for Boron Neutron Capture Therapy (BNCT) are tagged with a Gd(III) paramagnetic ion. The newly synthesized molecule, Gd-BPA, is investigated as contrast agent in Magnetic Resonance Imaging (MRI) with the final aim of mapping the boron distribution in tissues. Preliminary Nuclear Magnetic Resonance (NMR) measurements, which include (1)H and (10)B relaxometry in animal tissues, proton relaxivity of the paramagnetic Gd-BPA molecule in water and its absorption in tumoral living cells, are reported.

Spectral and symbolic analysis of the effect of gender and postural change on cardiac autonomic modulation in healthy elderly subjects

The objective of this study was to use linear and non-linear methods to investigate cardiac autonomic modulation in healthy elderly men and women in response to a postural change from the supine to the standing position. Fourteen men (66.1 ± 3.5 years) and 10 women (65.3 ± 3.3 years) were evaluated. Beat-to-beat heart rate was recorded in the supine and standing positions. Heart rate variability was studied by spectral analysis, including both low (LFnu-cardiac sympathetic modulation (CSM) indicator) and high (HFnu-cardiac vagal modulation (CVM) indicator) frequencies in normalized units as well as the low frequency/high frequency (LF/HF) ratio. Symbolic analysis was performed using the following indexes: 0V percent (CSM indicator), 1V percent (CSM and CVM indicators), 2LV percent (predominantly CVM indicator) and 2ULV percent (CVM indicator). Shannon entropy was also calculated. Men presented higher LFnu and LF/HF ratio and lower HFnu and 1V percent symbolic index (57.56, 4.14, 40.53, 45.96, respectively) than women (24.60, 0.45, 72.47, 52.69, respectively) in the supine position. Shannon entropy was higher among men (3.53) than among women (3.33) in the standing position, and also increased according to postural change in men (3.25; 3.53). During postural change, the LFnu (24.60; 49.85) and LF/HF ratio (0.45; 1.72) increased, with a concomitant decrease in HFnu (72.47; 47.56) and 2LV percent (14.10; 6.95) in women. Women presented increased CSM in response to postural change and had higher CVM and lower CSM than men in the supine position. In conclusion, women in the age range studied presented a more appropriate response to a postural change than men, suggesting that cardiac autonomic modulation may be better preserved in women than in men.

Perioperative management of four anaemic female Jehovah's Witnesses undergoing urgent complex cardiac surgery.

Previous studies have demonstrated that preoperative haemoglobin concentration and female gender are related to an increased need for perioperative allogeneic transfusions in cardiac surgery. Hence, urgent cardiac surgery presents a dilemma for female patients who are Jehovah's Witnesses, because of their refusal of allogeneic transfusion. This report describes the management of four high-risk anaemic female patients undergoing urgent complex cardiac surgery. In these Jehovah's Witness patients, strict application of a comprehensive blood-sparing protocol permitted safe avoidance of allogeneic transfusions. The protocol involved intraoperative acute normovolaemic haemodilution, intraoperative administration of tranexamic acid, intra- and postoperative use of a cell-saver system, postoperative administration of erythropoietin, iron and folic acid, and a careful surgical technique to avoid perioperative bleeding.

U-shaped osteotomy in management of paranasal deficiency.

When paranasal deficiencies are not accompanied by occlusal alterations, mobilization of the maxilla via Le Fort I osteotomy may not be justified. In this preliminary, report for the first time is presented a U-shaped osteotomy (USO) that mobilizes anteriorly and/or superiorly the maxillary bone surrounding the pirifom aperture. Advantages and indications of this new procedure are discussed.

Beam dumps design and local radiation protection at TERA synchrotron.

The realisation of the National Center of Hadrontherapy was funded by the Italian Government in 2002. The Centre will be built in the area of Pavia (Italy). The synchrotron designed in the framework of this programme will accelerate protons and carbon ions up to 250 MeV and 400 MeV u(-1), respectively. Some of the main aspects which were taken into account in the design of the acceleration system are the patient's safety and the beam control. From this point of view an important role is played by the beam dumps in the synchrotron ring and upstream of the extraction system. In particular, an horizontal and a vertical beam dump will be installed in the synchrotron ring: the former will be used for lowering the beam intensity and the latter for beam abortion. The dump at the extraction will absorb the particles during the mounting and the falling ramps of the synchrotron magnetic cycle, thus extracting only the flat top of the ion spill. Beam dumps can produce intense fields of secondary radiation (neutrons, charged light-hadrons and photons) and high rates of induced activity, since they can absorb the beam completely. Usually they have to be shielded to protect the electronics during machine operation and to attenuate the radiation dose below the limits imposed by the law when the personnel access to the synchrotron hall. The part of the shielding design of the beam dumps concerning with the acceleration of protons was made using Monte Carlo simulations with the FLUKA code. Both induced activity and secondary radiation were taken into account. The shields against secondary radiation produced by carbon ions were designed, referring only to secondary neutrons, taking double-differential distributions from the literature as sources for the FLUKA simulations. The induced activity from carbon ions interactions was estimated analytically, using the data generated by the EPAX 2 code. The dose-equivalent rates from the induced radionuclides were calculated at 1 m from the shielded dumps, taking into account the contribution of activated components of the synchrotron ring.

Orthostatic intolerance: different abnormalities in the neural sympathetic response to a gravitational stimulus.

In this paper we shall focus on the different abnormalities in the neural sympathetic response to a gravitational stimulus, characterising syndromes with symptoms of orthostatic intolerance. In Vaso vagal Syncope, an increase or a reduction of cardiac and vascular sympathetic modulation have been described in occasional and habitual fainters, respectively. Pure Autonomic Failure (PAF) is characterized by a global cardiovascular denervation. Accordingly, the spectral markers of cardiac and vascular sympathetic modulation are absent or reduced. However, a concomitant vagal diminished activity is present. In Chronic Orthostatic Intolerance (COI), the most common form of dysautonomia in young female, an abnormal regional distribution of sympathetic discharge has been hypothesized during standing. Indeed, an overall increased sympathetic activity is present in recumbent position; during tilt a blunted vascular sympathetic discharge, with a concomitant exaggerated cardiac sympathetic modulation, is evident. Baroreflex Failure is a syndrome that may result from neck surgery or irradiation due to different forms of regional cancer. It is characterized by a volatility of blood pressure and heart rate, without habitual orthostatic hypotension. In the present paper, we describe a case of Baroreflex Failure with marked orthostatic hypotension in spite of a huge muscle sympathetic nerve activity (MSNA) and high levels of plasma cathecolamines. The most relevant finding was the absence of any coordinate rythmicity in blood pressure, heart rate and MSNA, both at rest and during tilt, particularly in the frequency band likely to be related with sympathetic modulation, i.e. at 0.1 Hz. We hypothesize that the absence of 0.1 Hz spontaneous fluctuations might play a role in sustaining orthostatic hypotension.

Virulent Newcastle disease in Australia: molecular epidemiological analysis of viruses isolated prior to and during the outbreaks of 1998-2000.

Gene sequence analysis of fusion (F) gene cleavage motifs and haemagglutinin-neuraminidase (HN) carboxyl-terminal extension sequences was used to analyse Newcastle disease viruses (NDV) associated with virulent outbreaks of the disease which occurred in New South Wales, Australia in 1998-2000. PCR fragments were amplified directly from diseased tissue or allantoic fluids and sequence analyses used for phylogenetic comparisons between these viruses and Australian reference NDV. F and HN gene sequence comparison showed a strong relationship to sequences derived from endemic Australian NDV rather than those of overseas viruses or wild bird isolates. Prior to notification of the 1998 outbreak, an NDV was isolated from chickens suffering respiratory disease that appeared to be the progenitor virus from which the virulent virus originated. In turn, these viruses are closely related to two previously isolated 'ancestor' viruses that have the same unique HN extension sequence.

Host response and Histoplasma capsulatum/macrophage molecular interactions.

Histoplasma capsulatum is the etiological agent of histoplasmosis, a chronic respiratory infection that is generally asymptomatic in healthy individuals, but severe or fatal in patients who are immunosuppressed or otherwise debilitated. H. capsulatum is found as a mould in soil and becomes a pathogenic yeast in the mammalian host. The first line of defense that H. capsulatum faces during host invasion is the attack of polymorphonuclear neutrophils and resident macrophages. In animal models, once phagocytosed, H. capsulatum is not killed by fusion of the phago-lysosomes, instead it multiplies within non-activated macrophages and destroys them. Upon induction of cell-mediated immunity, cytokines activate macrophages and destroy the yeast cells. Some aspects of the fungus-macrophage interaction have been elucidated, and it is clear that some of the mechanisms by which H. capsulatum escapes the lethal effects of this very hostile environment, involve the regulation of specific genes. Recently, using the differential display reverse transcriptase polymerase chain reaction technique, a number of H. capsulatum genes that are induced after the yeasts are ingested by macrophages have been identified. However, the mechanisms that underlie the capacity of H. capsulatum to adapt to the new environmental conditions present in macrophages remain to be clarified.

[A case of primary non-Hodgkin lymphoma of the breast]. / Un caso di linfoma non-Hodgkin primitivo della mammella.

Primary non-Hodgkin's lymphomas (NHL) of the breast represent less than 3% of extranodal NHL; in comparison to extranodal NHL at other sites, they are characterized by rapid progression and worse prognosis. We report a case of primary NHL of the breast treated, after surgery, with a sequential combination of chemotherapy and radiotherapy. Literature data suggest that the most important factors in therapeutic decisions making are the initial stage of the disease and the histological subtype.

[Metaplastic tumors of the breast: a case of primary squamous cell carcinoma]. / Tumori metaplasici della mammella: un caso di carcinoma squamoso primitivo.

We report a case of primary squamous cell carcinoma of the breast in a 58 years old woman. The diagnosis of this rare tumor is possible after excluding a skin primary lesion or an epidermoid cancer of a distant site. In reviewing the reported cases we didn't find any significant prognostic difference between this form and the breast adenocarcinoma with squamous metaplasia.

Pathotyping isolates of Newcastle disease virus using antipeptide antibodies to pathotype-specific regions of their fusion and hemagglutinin-neuraminidase proteins.

Antipeptide antibodies have been evaluated for their abilities to predict the characteristics of the cleavage motifs of the fusion protein precursors (F0) of 25 isolates of Newcastle disease virus (NDV) with a range of virulences, grouped into 12 sets according to their monoclonal antibody reactivities. A Western blot format was used to show that antisera to synthetic peptides representing sequences at the C-termini of the F2-polypeptides of defined pathotypes of NDV usually distinguish between pathotypes on the basis of their Fo cleavage sequences. However, exceptions were found with three groups of virulent isolates. Protein sequencing and mass spectral analysis of the F2-polypeptide of isolate Texas GB from one of these groups, identified an anomalous cleavage/activation process which removed the amino acids required for recognition by the antisera. This probably also explained the lack of reactivity of the Roakin isolate and low reactivity of the Komarov isolate from this group. The other exceptions involved isolates in groups with cleavage region variations from the usual motif of virulent isolates or isolates with undefined cleavage motifs. Antipeptide antisera were also raised to sections of the 45 residue C-terminal extension the hemagglutinin-neuraminidase precursor (HN0) encoded by the genes of some avirulent isolates. Western blot analysis showed that positive reactions with antibodies to peptides based on sequences between residues 577 and 613 of the HN0 was evidence for the presence of an avirulent isolate but did not exclude the presence of other pathotypes. Antisera designed to target residues 569-577 detected HN0 extensions of 6 residues on isolates known to encode such extensions. These antisera also enabled differentiation of isolates with HN0 extensions of 6 residues from those with no extension, however, it was not possible to determine the virulence of isolates based on reaction with these antisera.