Role of neuroinflammation in hypertension-induced brain amyloid pathology

Hypertension and sporadic Alzheimer's disease (AD) have been associated but clear pathophysiological links have not yet been demonstrated. Hypertension and AD share inflammation as a pathophysiological trait. Thus, we explored if modulating neuroinflammation could influence hypertension-induced β-amyloid (Aβ) deposition.Possible interactions among hypertension, inflammation and Aβ-deposition were studied in hypertensive mice with transverse aortic coarctation (TAC). Given that brain Aβ deposits are detectable as early as 4 weeks after TAC, brain pathology was analyzed in 3-week TAC mice, before Aβ deposition, and at a later time (8-week TAC mice).Microglial activation and interleukin (IL)-1β upregulation were already found in 3-week TAC mice. At a later time, along with evident Aβ deposition, microglia was still activated. Finally, immune system stimulation (LPS) or inhibition (ibuprofen), strategies described to positively or negatively modulate neuroinflammation, differently affected Aβ deposition.We demonstrate that hypertension per se triggers neuroinflammation before Aβ deposition. The finding that only immune system activation, but not its inhibition, strongly reduced amyloid burden suggests that stimulating inflammation in the appropriate time window may represent a promising strategy to limit vascular-triggered AD-pathology.     

Umbilical cord blood CD34(+)cell-derived progeny produces human leukocyte antigen-G molecules with immuno-modulatory functions

Human umbilical cord blood units (UCBs) are an alternative source in allogeneic-stem-cell transplantation. Human leukocyte antigen (HLA)-G is a tolerogenic molecule with a possible implication in UCB immunoregulatory effect. HLA-G expression was observed in UCB myeloid and plasmacytoid dendritic cells; in contrast, CD34(+) cells did not produce this molecule. CD34(+) cells are primitive hematopoietic progenitor cells that are present in UCB and are necessary for long-term engraftment via production of immunoregulatory molecules and a hematopoietic progeny that supports cellular recovery. The role of these cells in UCB transplantation needs further evaluation of HLA-G expression in CD34(+) cells and their hematopoietic progeny. We confirmed the absence of HLA-G expression in CD34(+) cells, whereas CD34(+)-derived progeny secreted HLA-G molecules and expressed HLA-G mRNA in in vitro cultures. Furthermore, soluble HLA (sHLA)-G molecules purified from the culture supernatants of CD34(+)-derived progeny were able to suppress lymphoproliferative response in an HLA-G dose-dependent manner. Overall these results identify CD34(+)-derived hematopoietic progeny as producers of HLA-G molecules and support a role of this antigen as an immuno-modulatory factor in UCB.     

Interstitial deletion of chromosome 2p15-16.1: report of two patients and critical review of current genotype-phenotype correlation

We report two individuals with developmental delay and dysmorphic features, in whom array-based comparative genomic hybridization (array CGH) led to the identification of a 2p15p16.1 de novo deletion. In the first patient (Patient 1) a familial deletion of 6q12, inherited from her father, was also detected. In the second patient (Patient 2) in addition to the 2p15p16.1 microdeletion a de novo deletion in Xq28 was detected. Both individuals shared dysmorphic features and developmental delay with the six reported patients with a 2p15p16.1 microdeletion described in medical literature. Conclusion: in the first patient a 642 kb 2p16.1 deletion (from 60.604 to 61.246 Mb), and a 930 kb 6q12 familial deletion, was detected and in the second a 2.5 Mb 2p15p16.1 deletion (from 60.258 to 62.763 Mb), with a Xq28 deletion, was discovered. The common dysmorphic features and neurodevelopmental delay found in these patients are in agreement with the clinical phenotype of a microdeletion syndrome involving 2p15p16.1. Our data confirm the hypothesis suggesting that 2p15p16.1 deletion is a contiguous gene syndrome.     

Dosing Nomograms for Attaining Optimum Concentrations of Meropenem by Continuous Infusion in Critically Ill Patients with Severe Gram-Negative Infections: a Pharmacokinetics/Pharmacodynamics-Based Approach

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL_Cr) estimates for use in daily clinical practice to target the steady-state concentrations (C_sss) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL_m) and CL_Cr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C_ss. The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C_sss. A significant relationship between CL_m and CL_Cr was observed in group 1 (r = 0.72, P < 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CL_Cr (ml/min) + 2.85] × target C_ss × (24/1,000), led to a significant correlation between the observed and the predicted C_sss (r = 0.92, P < 0.001). Dosing nomograms based on CL_Cr were created to target the meropenem C_ss at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase producers and/or of pathophysiological conditions which may enhance meropenem clearance.     

Successful long-term treatment of cerebral nocardiosis with unexpectedly low doses of linezolid in an immunocompromised patient receiving complex polytherapy

Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bacterial cerebral abscesses. We report on a case in an immunocompromised patient which was successfully treated with unexpectedly low doses of linezolid. Therapeutic drug monitoring was very helpful in highlighting issues of poor compliance and of drug-drug interactions.     

Restless legs syndrome in end-stage renal disease

BACKGROUND AND PURPOSE: Patients undergoing dialysis therapy due to end-stage renal disease (ESRD) present a high prevalence of sleep disorders, including restless legs syndrome (RLS). However, the known data generally have been obtained from relatively small patient samples, coming from single or very few dialysis units. Moreover, some data were collected prior to the recent improvements in dialysis techniques, pharmacological therapies and to the establishment of internationally recognised diagnostic criteria for RLS. PATIENTS AND METHODS: In order to study the incidence of the different sleep disorders, and of RLS in particular, in a large population of dialysis patients, a questionnaire was administered to all the patients in dialysis units of the 'Triveneto' area (Italy) who agreed to participate. The first part of the questionnaire included questions about demographic data, general medical history, history of renal disease, dialytic treatment and pharmacological therapy. The second part, which was self-administered, explored the patient's complaints about sleep, the presence of the minimal International Restless Legs Syndrome Study Group (IRLSSG) criteria for the diagnosis of RLS, the Epworth Sleepiness Scale and questions particularly related to somnolence. Patients whose responses indicated a diagnosis of RLS according to the IRLSSG criteria were requested to answer the 10 questions of the IRLSSG Severity Scale. The same group of patients was compared to those who did not fulfil any of the four minimal criteria for RLS. Statistical analysis was performed by using ANOVA and non-parametric tests. Whenever possible, data were compared with the database of the Veneto Dialysis Register. The first 601 consecutive questionnaires that we were able to analyse are presented in this paper. RESULTS: Applying the IRLSSG criteria for the diagnosis, the percentage of RLS patients in our sample was 21.5%, with a score of 20.5+/-8.7 on the IRLSSG Severity Scale. Comparing patients who are definitely affected by RLS (n=127) with unaffected patients (n=280), we found that the two groups did not differ as to age, sex, weight, body mass index (BMI), and intake of nicotine, alcohol and caffeine. Similarly, the two groups did not differ as to the etiology of ESRD, type of dialysis or percentage of previous transplantations; however, the period of dialysis dependence was significantly lower in the group negative for RLS. The use of drugs did not differ in the two groups, except for lower intake of phosphorus binders and antihypertensive drugs among RLS patients. No patient was receiving specific treatment for RLS. RLS patients reported more fragmented, less restful nightly sleep and more daytime somnolence, more often presented symptoms of other sleep disorders and were more affected by anxiety or depression. CONCLUSIONS: The high prevalence of RLS and other sleep disorders among uremics requires careful investigation of nocturnal sleep; although often underdiagnosed, correct identification of these disorders can lead to better therapy and improvement of clinical conditions and quality of life. Sleep fragmentation and sleep deprivation caused by RLS may contribute to the cardiovascular complications and infections, often with bad prognosis in dialysis patients.     

Monitoring neonatal fungal infection with metabolomics

Abstract

The objective of our study was to evaluate the capability of the metabolomics approach to identify the variations of urine metabolites over time related to the neonatal fungal septic condition. The study population included a clinical case of a preterm neonate with invasive fungal infection and 13 healthy preterm controls. This study showed a unique urine metabolic profile of the patient affected by fungal sepsis compared to urine of controls and it was also possible to evaluate the efficacy of therapy in improving patient health.     

Laparoscopically guided minilaparotomy: a minimally invasive approach for the treatment of gynaecologic diseases in morbidly obese patients

Objective

Obese patients are at greater risk of gynaecologic surgery. Laparotomy is generally performed, even though this approach is regarded as highly invasive, whereas laparoscopy, though minimally invasive, is relatively contraindicated because of the high conversion rates to laparotomy. In light of this, we propose laparoscopically guided transverse minilaparotomy (LGTM) as a minimally invasive alternative technique. The rationale of diagnostic laparoscopy is to evaluate the feasibility of a minimally invasive approach. We have evaluated the feasibility and compared the outcomes with a historical group treated with laparotomy (LPTM), in morbidly obese patients (MOP) subjected to gynaecologic surgery.

Study design

From November 2004, MOPs with body mass index (BMI) ≥40 kg/m² and admitted for gynaecologic surgery (early stage endometrial cancer and benign disease) were enrolled in this observational study and submitted to LGTM. Patients with a uterine size greater than the umbilical transverse line and with indication for vaginal surgery were excluded operative data and outcome were prospectively recorded.

Results

LGTM was feasible in 34 cases (87%) out of 39. In two women, the procedure was aborted due to intraperitoneal and ovarian malignant disease spread diagnosed at laparoscopy. In three cases, conversion was necessary due to severe adhesions in one case; laparoscopically unrecognized disease spread in the parametria in the second, and in the remaining case a right common iliac vein injury during lymphadenectomy. When compared to LPTM, haemoglobin drop and postoperative stay were significantly reduced with LGTM. Complications were higher in the control group: due to a significantly higher incidence of wound dehiscence (OR 0.27, 95% CI 0.05-1.32, p < 0.05).

Conclusions

LGTM is feasible in the vast majority of MOPs and achieves significantly better results when compared to the standard approach.