Evidence on the benefits of probiotics for preterm infants.

Introduction: This article reviews the evidence for the use of different strains of probiotics in the prevention of prevalent pathologies in premature neonates. A systematic review was conducted of the use of probiotics in neonates with less than 37 weeks of gestational age, based on a search for systematic reviews and observational and experimental studies performed during the period from January 2014 to February 2021. For this purpose, the PubMed, MEDLINE and Cochrane Library databases were consulted. The aim of this article was to review the existing data on the relationship between the administration of probiotics (with different strains and doses) and the risk of necrotising enterocolitis, mortality, late sepsis and other disease parameters in premature infants. The literature search obtained 240 articles, of which we selected 16, representing a total sample of over 200,000 premature infants. Analysis of the data obtained reveals statistical evidence that the combined administration of probiotics (especially of Lactobacillus and Bifidobacterium strains) reduces the incidence of grade II or higher necrotising enterocolitis, all-cause mortality, late sepsis, length of hospital stay and time until complete enteral nutrition is achieved. However, no benefits were apparent with respect to alleviating bronchopulmonary dysplasia, retinopathy of prematurity or intraventricular haemorrhage. Further research is needed to determine the most appropriate strains, doses and treatment duration for preterm infants to achieve the health benefits identified.

Introducción: En este artículo se revisa la evidencia del uso de las diferentes cepas de probióticos en la prevención de diversas patologías prevalentes en recién nacidos prematuros. Se ha realizado una revisión sistemática sobre el uso de probióticos en recién nacidos de menos de 37 semanas de edad gestacional, realizando una búsqueda de revisiones sistemáticas, estudios observacionales y experimentales desde enero de 2014 hasta febrero de 2021. Para ello se han utlizado motores de búsqueda como PubMed, MEDLINE y la biblioteca Cochrane. El objetivo de este artículo fue revisar los datos existentes sobre la relación entre la administración de probióticos (con diferentes cepas y dosis) y el riesgo de enterocolitis necrotizante, mortalidad, sepsis tardía, y otros parámetros de enfermedad en prematuros. En la búsqueda se obtuvieron 240 artículos, de los que seleccionamos 16, obteniendo más de 200.000 recién nacidos prematuros como muestra. En esta revisión se muestra con evidencia estadística, que la administración combinada de probióticos (espcialmente cepas de Lactobacillus y Bifidobacterium) reducen la incidencia de NEC en grado II o mayor, mortalidad por todas las causas, sepsis tardía, días de estancia hospitalaria y tiempo en lograr nutrición enteral completa. No se han podido evidenciar beneficios en cuanto a la displasia broncopulmonar, retinopatía de la prematuridad y hemorragia intraventricular. Se precisan nuevos estudios para conocer las cepas, dosis y tiempo de tratamiento más adecuados en neonatos prematuros para lograr beneficios en salud.

Breast-feeding as protective factor against bronchopulmonary dysplasia in preterm infants.

Breast-feeding is associated with fewer comorbidities in very-low-birth-weight (VLBW) preterm infants. Bronchopulmonary dysplasia (BPD) of VLBW infants is a multifactorial pathology in which nutritional aspects may be of special importance. The aim of this study is to determine, in a cohort of VLBW infants, whether breast milk nutrition is associated with a reduced prevalence and severity of BPD. A retrospective study was conducted to record the intake of mother's own milk (MOM), pasteurised donor human milk or preterm formula milk in the first 2 weeks of postnatal life of 566 VLBW newborns at our hospital during the period January 2008-December 2021. After applying the relevant exclusion criteria, data for 489 VLBW infants were analysed; 195 developed some degree of BPD. Moderate or severe BPD is associated with less weight gain. Moreover, the preferential ingestion of breast milk in the first and second postnatal weeks had effects associated with lower OR for BPD, which were statistically demonstrable for mild (OR 0·16; 95 % CI 0·03, 0·71) and severe (OR 0·08; 95 % CI 0·009, 0·91) BPD. Breast-feeding during the first weeks of postnatal life is associated with a reduced prevalence of BPD, which is frequently associated with less weight gain as a result of greater respiratory effort with greater energy expenditure.

Response to local corticosteroid injections in carpal tunnel syndrome with normal conduction studies.

INTRODUCTION: Nerve conduction studies (NCS) have been considered as the gold standard in carpal tunnel syndrome (CTS) diagnosis, despite correlation between clinical symptomatology and NCS severity has shown to be poor. In fact, clinical symptoms precede NCS changes in months or years. Few papers have been published about the clinical response to treatment of clinically typical CTS, but with normal NCS (NNCS). OBJECTIVE: To compare the clinical response to local corticosteroid injections (LCI) in clinically typical CTS, with NNCS and abnormal NCS (ANCS). METHOD: We included patients older than 18, with typical CTS symptoms (ongoing daily nocturnal pain/paresthesias in hand, at least during 3 months). Follow-up was done at 3, 6 and 12 months. Primary outcome was the visual analog scale for pain (p-VAS), comparing NNCS CTS wrists with ANCS CTS wrists. Statistic signification was established by the Student's t test, Mann-Whitney's "U", χ2 test and Yates' correction. RESULTS: We included 44 wrists in the NNCS group, and 83 in the ANCS group. There was no statistical significance between data in both groups, except in the 12-month follow-up, where the NNCS group achieved better results than the ANCS group in the 20% response (p=0.006). There was a trend toward a better 50% response in the 12-month follow-up. CONCLUSIONS: Our data suggest that LCI are similarly effective in both CTS with NNCS and ANCS. Nonetheless, there is a mild better effect in NNCS than in ANCS at 12-month follow-up.

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome-associated glioma.

Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.

Long-term Outcome of Local Steroid Injections Versus Surgery in Carpal Tunnel Syndrome: Observational Extension of a Randomized Clinical Trial.

Background: In a previous paper, we have demonstrated that: (1) local injection of corticosteroids for carpal tunnel syndrome (CTS) is as effective as decompressive surgery, at 1-year follow-up; and (2) surgery has an additional benefit in the 2-year follow-up. In this study, we assess the long-term outcomes of both therapies in an observational extension of the patients originally enrolled in our randomized clinical trial. Methods: Patients were included in an open, randomized clinical trial, comparing injections versus surgery in CTS. After the end of the clinical trial, patients received the treatment prescribed by their general practitioner or specialist. Therapeutic failure was defined as the need of any new therapeutic intervention on the involved wrist. Comparison between groups was made using Cox multiple regression analysis. Estimation of the accumulated incidence of new therapeutic failure was made considering the withdrawal as a competitive risk (Gooley's test). Results: Of 163 randomized wrists at the beginning of the study, only 148 were available at the final follow-up. The mean follow-up was 6.3 and the median was 5.9 years. In the long-term follow-up, the accumulated incidence of therapeutic failure in the surgery group was 11.6% versus 41.8% in the injection group. The Cox multiple regression analysis showed a risk of failure associated with injection group of 4.5 (95% confidence interval [CI], 2.1-9.8; P < .0001). Conclusions: In long-term follow-up, surgery seems more effective than local corticosteroid injections in primary CTS. Nonetheless, about 58% of the patients in the injection group will not need further therapeutic interventions during the follow-up.

Methylphenidate ameliorates the homeostatic balance between levels of kynurenines in ADHD children.

The kynurenine pathway of tryptophan metabolism has been involved in ADHD We quantified basal levels and daily fluctuations of tryptophan and several kynurenine metabolites, as well as their changes after treatment with methylphenidate (MPH). A total of 179 children were recruited, grouped into ADHD (n = 130) and healthy controls (CG,n = 49). Blood samples were drawn at 20:00 and 09:00 h and only in the ADHD group after 4.63±2.3 months of treatment. Nocturnal urine was collected between both draws. Factorial analysis (Stata12.0) was performed with Groups, Time, Hour of Day and Depressive Symptoms (DS) as factors. MPH significantly increased plasma Kynurenic acid (2.4 ± 1.03/2.78±1.3 ng/mL; baseline/post-treatment, morning; z = 1.96,p<0.05) and Xanthurenic acid (2.39±0.95/2.88±1.19 ng/mL; baseline/post, morning; z = 2.7,p<0.007) levels, both with higher values in the evening. In DS+ patients, MPH caused a pronounced decrease in evening Anthranilic acid [3.08±5.02/ 1.82±1.46 ng/mL, z = 2.68,p = 0.0074] until matching values to other subgroups. In urine, MPH decreased the excretion of both Nicotinamide and Quinolinic acids, but only in the DS- subgroup. The kynurenine pathway may participate in the highly clinical favorable response to MPH. The observed changes could be considered as protective (i.e. increased plasma kynurenic acid vs. decreased quinolinic acid excretion) based on the knowledge of its physiological homeostatic functions.

Response to Local Corticosteroid Injections in Carpal Tunnel Syndrome With Normal Conduction Studies.

INTRODUCTION: Nerve conduction studies (NCS) have been considered as the gold standard in carpal tunnel syndrome (CTS) diagnosis, despite correlation between clinical symptomatology and NCS severity has shown to be poor. In fact, clinical symptoms precede NCS changes in months or years. Few papers have been published about the clinical response to treatment of clinically typical CTS, but with normal NCS (NNCS). OBJECTIVE: To compare the clinical response to local corticosteroid injections (LCI) in clinically typical CTS, with NNCS and abnormal NCS (ANCS). METHOD: We included patients older than 18, with typical CTS symptoms (ongoing daily nocturnal pain/paresthesias in hand, at least during 3 months). Follow-up was done at 3, 6 and 12 months. Primary outcome was the visual analog scale for pain (p-VAS), comparing NNCS CTS wrists with ANCS CTS wrists. Statistic signification was established by the Student's t test, Mann-Whitney's "U", χ2 test and Yates' correction. RESULTS: We included 44 wrists in the NNCS group, and 83 in the ANCS group. There was no statistical significance between data in both groups, except in the 12-month follow-up, where the NNCS group achieved better results than the ANCS group in the 20% response (p=0.006). There was a trend toward a better 50% response in the 12-month follow-up. CONCLUSIONS: Our data suggest that LCI are similarly effective in both CTS with NNCS and ANCS. Nonetheless, there is a mild better effect in NNCS than in ANCS at 12-month follow-up.

Morbidity Outcomes of Very Low Birth Weight Neonates Receiving Parenteral Nutrition with Fish Oil Enriched Lipid Emulsion or Lipid Emulsion with Soybean Oil: An Observational Study.

Intralipid (Fresenius Kabi) was the most commonly used lipid emulsion in parenteral nutrition (PN), with a 100% soybean oil composition, a low vitamin E content, and a ω-6: ω-3 ratio of 7:1. A recent alternative formulation is SMOFlipid (Fresenius Kabi), with a ω-6: ω-3 ratio of 5:2 and higher vitamin E content. A retrospective observational study was conducted to determine neonatal morbidity in very low birth weight (VLBW) premature infants during two periods: P1, when PN was based exclusively on Intralipid, and P2, when only SMOFlipid was supplied. In total, 170 VLBW neonates were analyzed, of whom 103 received PN for more than 6 days, 56 during P1, and 47 during P2. In both periods, the antenatal and neonatal characteristics of the cohort were comparable. In this analysis, the prevalence of associated comorbidities was determined. During P2, there were fewer cases of moderate to severe bronchopulmonary dysplasia (BPD) and of cholestasis, but more cases of late sepsis, mainly Staphylococcus epidermidis. No changes in the prevalence of other neonatal comorbidities were observed. We believe that the SMOFlipid used in PN could discreetly improve the prevalence of cholestasis or BPD.

Indole Tryptophan Metabolism and Cytokine S100B in Children with Attention-Deficit/Hyperactivity Disorder: Daily Fluctuations, Responses to Methylphenidate, and Interrelationship with Depressive Symptomatology.

Background: Indole tryptophan metabolites (ITMs), mainly produced at the gastrointestinal level, participate in bidirectional gut-brain communication and have been implicated in neuropsychiatric pathologies, including attention-deficit/hyperactivity disorder (ADHD). Method: A total of 179 children, 5-14 years of age, including a healthy control group (CG, n = 49), and 107 patients with ADHD participated in the study. The ADHD group was further subdivided into predominantly attention deficit (PAD) and predominantly hyperactive impulsive (PHI) subgroups. Blood samples were drawn at 20:00 and 09:00 hours, and urine was collected between blood draws, at baseline and after 4.63 ± 2.3 months of methylphenidate treatment in the ADHD group. Levels and daily fluctuations of ITM were measured by tandem mass spectrometer, and S100B (as a glial inflammatory marker) by enzyme-linked immunosorbent assay. Factorial analysis of variance (Stata 12.0) was performed with groups/subgroups, time (baseline/after treatment), hour of day (morning/evening), and presence of depressive symptoms (DS; no/yes) as factors. Results: Tryptamine and indoleacetic acid (IAA) showed no differences between the CG and ADHD groups. Tryptamine exhibited higher evening values (p < 0.0001) in both groups. No changes were associated with methylphenidate or DS. At baseline, in comparison with the rest of study sample, PHI with DS+ group showed among them much greater morning than evening IAA (p < 0.0001), with treatment causing a 50% decrease (p = 0.002). Concerning indolepropionic acid (IPA) MPH was associated with a morning IPA decrease and restored the daily profile observed in the CG. S100B protein showed greater morning than evening concentrations (p = 0.001) in both groups. Conclusion: Variations in ITM may reflect changes associated with the presence of DS, including improvement, among ADHD patients.

Pure Membranous Lupus Nephritis: Description of a Cohort of 150 Patients and Review of the Literature.

OBJECTIVES: The course and long-term outcome of pure membranous lupus nephritis (MLN) are little understood. The aims of this study are to evaluate the clinical features, course, outcome and prognostic indicators in pure MLN and to determine the impact of ethnicity and the type of health insurance on the course and prognosis of pure MLN. METHODS: We conducted a retrospective review of medical records of 150 patients with pure MLN from Spain and the USA. RESULTS: Mean age was 34.2±12.5 and 80% were women. Sixty-eight percent of patients had nephrotic syndrome at diagnosis. The average serum creatinine was 0.98±0.78mg/dl. Six percent of patients died and 5.3% developed end-stage renal disease (ESRD). ESRD was predicted by male sex, hypertension, dyslipidemia, high basal 24h-proteinuria, high basal serum creatinine and a low basal creatinine clearance. Age, cardiac insufficiency, peripheral artheriopathy, hemodialysis and not having received mycophenolate mofetil or antimalarials for MLN predicted death. CONCLUSIONS: Pure MLN frequently presents with nephrotic syndrome, high proteinuria and normal serum creatinine. Its prognosis is favourable in maintaining renal function although proteinuria usually persists over time. Baseline cardiovascular disease and not having a health insurance are related with poor prognosis.

An observational mixed-methods approach to investigate the fear of cancer recurrence cognitive and emotional model by Lee-Jones et al with women with breast cancer during radiotherapy treatment.

There is minimal qualitative research on fear of cancer recurrence (FCR) in patients who are still undergoing treatment. This study explored how breast cancer patients' illness beliefs changed during radiotherapy treatment, so as to provide their longitudinal perspective across sessions. These beliefs were mapped to Lee-Jones et al FCR model to assess its applicability to patients during this key treatment phase. A framework qualitative analysis was employed for verbatim interactions between patients (n = 8) and their radiographer (n = 2) over a minimum of three weekly review sessions (26 review consultations in total). Results proved suggested evolution and repetition of themes within and across sessions. Most themes were consistent with the early stages of the Lee-Jones et al model (antecedents and FCR) such as internal and external cues, cognitions and emotions. The crucial observation was that somatic stimuli were interpreted as side effects of radiotherapy treatment rather than cancer symptoms. Patients were still undergoing their last phase of major treatment, whereas the Lee-Jones et al model has been constructed to explain patients' past treatment experience. New themes emerged, including current exercise, concurrent illnesses/problems, cancer treatment as a constant reminder (of diagnosis) and associated sleeping difficulties. Decatastrophising of symptoms and experiences relating to cancer and its treatment was also a prominent theme indicating a possible coping mechanism to reduce worries about treatment side effects and associated experiences. Finally, some evidence was found from failure of emotional/fear processing in patients due to early surface reassurance by health professionals - a possible explanation of how FCR might arise. Early detection of FCR and promoting support while patients are still undergoing treatment might prevent patients from developing FCR after treatment.

Acute tubulointerstitial nephritis and polyclonal hypergammaglobulinaemia: Which is the culprit?

Proton pump inhibitors (PPIs) are among the most frequent implicated drugs in acute tubulointerstitial nephritis (ATIN), nevertheless it is important to report cases with atypical profiles. A 80-year-old female, exposed during 34 months to omeprazole, presented with polyclonal hypergammaglobulinaemia and renal failure. After stopping omeprazole there was a partial improvement in serum creatinine and IgG. Renal biopsy revealed ATIN; immunohistochemistry for IgG4 was negative. Treatment with steroids and mycophenolate sodium improved renal function and normalized immunoglobulins. The lack of data of other entities and the patient's evolution strongly point omeprazole as the culprit. After 27 months of follow-up, she remains clinical and analytically stable. ATIN caused by PPIs may appear after a long period of exposure and may be accompanied by analytical anomalies that simulate a systemic disease.

Reducing Uncertainties in Carbonate Clumped Isotope Analysis Through Consistent Carbonate-Based Standardization.

About a decade after its introduction, the field of carbonate clumped isotope thermometry is rapidly expanding because of the large number of possible applications and its potential to solve long-standing questions in Earth Sciences. Major factors limiting the application of this method are the very high analytical precision required for meaningful interpretations, the relatively complex sample preparation procedures, and the mass spectrometric corrections needed. In this paper we first briefly review the evolution of the analytical and standardization procedures and discuss the major remaining sources of uncertainty. We propose that the use of carbonate standards to project the results to the carbon dioxide equilibrium scale can improve interlaboratory data comparability and help to solve long-standing discrepancies between laboratories and temperature calibrations. The use of carbonates reduces uncertainties related to gas preparation and cleaning procedures and ensures equal treatment of samples and standards. We present a set of carbonate standards of diverse composition, discuss how they can be used to correct for mass spectrometric biases, and demonstrate that their use significantly improves the comparability among four laboratories. We propose that the use of these standards or of a similar set of carbonate standards will improve the comparability of data across laboratories.

An admission medication reconciliation programme carried out by pharmacists: impact on surgeons' prescriptions.

OBJECTIVES: To describe a medication reconciliation (MR) procedure prepared by the pharmacist for patients admitted for elective surgery and to assess the surgeon's degree of acceptance. METHODS: A 1-year retrospective observational study was conducted. The patient population consisted of patients aged ≥18 years admitted during 2016 for elective surgery and whose planned length of hospital stay was >24 hours. A pharmacist performed MR following a specific protocol. A review of the reconciliations prescribed later by the surgeons was conducted. Statistical analyses were performed for qualitative and quantitative variables. RESULTS: The pharmacist prepared a total of 1986 reconciliation reports. The 179 patients reviewed in this study had a mean age of 65.7±11.8 years, 49.2% were women and 98.9% of patients were reconciled by the surgeon in the operating theatre using an electronic prescribing system (85.5% were fully reconciled). CONCLUSION: The hospital's MR protocol resulted in almost 100% of patients being reconciled within the subgroup of elective surgery patients by the prescribing surgeons.

BDNF concentrations and daily fluctuations differ among ADHD children and respond differently to methylphenidate with no relationship with depressive symptomatology.

RATIONALE: Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD). OBJECTIVE: We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment. METHOD: A total of 148 children, 4-5 years old, were classified into groups as follows: ADHD group (n = 107, DSM-IV-TR criteria) and a control group (CG, n = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0). RESULTS: Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive-impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms. CONCLUSIONS: Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.

Indentation hardness: A simple test that correlates with the dissipated-energy predictor for fatigue-life in bovine pericardium membranes for bioprosthetic heart valves.

The aim of this study was to evaluate the variation of hardness with fatigue in calf pericardium, a biomaterial commonly used in bioprosthetic heart valves, and its relationship with the energy dissipated during the first fatigue cycle that has been shown to be a predictor of fatigue-life (García Páez et al., 2006, 2007; Rojo et al., 2010). Fatigue tests were performed in vitro on 24 pericardium specimens cut in a root-to-apex direction. The specimens were subjected to a maximum stress of 1MPa in blocks of 10, 25, 50, 100, 250, 500, 1000 and 1500 cycles. By means of a modified Shore A hardness test procedure, the hardness of the specimen was measured before and after fatigue tests. Results showed a significant correlation of such hardness with fatigue performance and with the energy dissipated in the first cycle of fatigue, a predictor of pericardium durability. The study showed indentation hardness as a simple and reliable indicator of mechanical performance, one which could be easily implemented in improving tissue selection.

BRCA2 gene mutations and coagulation-associated biomarkers.

Thromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 non-mutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.

Cytomegalovirus Immunoglobulin for Prophylaxis and Treatment of Cytomegalovirus Infection in the (Val)Ganciclovir Era: A Single-Center Experience.

BACKGROUND: Evidence concerning the effectiveness of anti-cytomegalovirus immunoglobulin (CMVIg) following lung transplantation in the era of new antiviral agents is limited and controversial. MATERIAL AND METHODS: At-risk patients (donor seropositive/recipient seronegative [D+/R-] and R+) received valganciclovir for 3 months (R+) or 6 months (D+/R). CMVIg (2 mg/kg) was given to D+/R- patients on days 1, 4, 8, 15, and 30 post-transplant, then monthly for a further year. Patients with valganciclovir-induced leukopenia were switched to CMVIg (2 mg/kg) prophylaxis. Tissue-invasive disease was treated with intravenous ganciclovir with CMVIg (2 mg/kg) every other day for 1 week and then weekly until discharge. RESULTS: Of 159 patients analyzed, 26 (17%) were D+/R-. Cytomegalovirus (CMV) viremia was more frequent in D+/R- recipients than in R+ patients (61% vs. 35%; P<0.05), but developed at a similar time (mean 10±6 vs. 11±7 months) and resolved in all cases following treatment. One patient developed clinical and laboratory signs of CMV syndrome (fever >38°C), leukopenia, and detection of CMV in blood. Ten patients developed tissue-invasive disease after completion of prophylaxis (5 pneumonitis and 5 gastrointestinal disease); all were successfully treated with combined intravenous ganciclovir and CMVIg. None of the 18 donor seropositive/recipient seronegative patients who were switched from valganciclovir to CMVIg for persistent leukopenia developed CMV viremia during treatment. No cases of CMV infection or disease were attributable to ganciclovir-resistant strains. During follow-up, 44 patients died (4/26 R+/D- [15%], 40/133 R+ [30%), none directly due to CMV infection. CONCLUSIONS: Combined prophylaxis with valganciclovir and CMVIg delayed CMV viremia and tissue-invasive disease in D+/R- lung transplant recipients, and prevented CMV-related mortality and development of ganciclovir resistance. CMVIg monotherapy prophylaxis was effective in R+ patients with ganciclovir-related toxicity.