Inflammatory responses in blood samples of human immunodeficiency virus-infected patients with pulmonary infections

We analyzed the characteristics of the inflammatory response occurring in blood during pulmonary infections in human immunodeficiency virus (HIV)-infected patients. A prospective study of consecutive hospital admissions of HIV-infected patients with new-onset radiologic pulmonary infiltrates was carried out in a tertiary university hospital from April 1998 to May 2001. Plasma cyclic AMP receptor protein (CRP), interleukin 1beta (IL-1beta), IL-6, IL-8, IL-10, and tumor necrosis factor alpha (TNF-alpha) levels were determined at the time of admission and 4, 5, and 6 days later. Patients were included in a protocol addressed to study etiology and outcome of disease. A total of 249 episodes of infection were included, with the main diagnoses being bacterial pneumonia (BP) (118 episodes), Pneumocystis carinii pneumonia (PCP) (41 episodes), and mycobacteriosis (36 episodes). For these three patient groups, at the time of admission the median CRP and cytokine levels were as follows: CRP, 10.2, 3.8 and 5 mg/dl, respectively (P = 0.0001); IL-8, 19, 3, and 2.9 pg/ml (P = 0.045); and TNF-alpha, 46.4, 44, and 75 pg/ml, respectively (P = 0.029). There were no significant differences in levels of IL-1beta, IL-6, or IL-10 among the patient groups. A total of 23 patients died. At the time of admission, HIV-infected patients with BP had higher plasma CRP and IL-8 levels than did PCP and mycobacteriosis patients. TNF-alpha levels were higher in patients with mycobacteriosis. An elevated IL-8 level (>61 pg/ml) at the time of admission was an independent factor associated with higher mortality (odds ratio, 12; 95% confidence interval, 1.2 to 235.5).     

A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring short attacks of fever and serositis. Secondary AA amyloidosis is the worst complication of the disease and often determines the prognosis. The MEFV gene, on chromosome 16p13.3, is responsible for the disease and around 30 mutations have been reported to date. Colchicine is the standard FMF treatment today, and prevents both attacks and amyloid deposition in 95% of patients. Here we describe a three-generation Spanish kindred with five family members affected by a severe periodic inflammatory disorder associated with renal AA amyloidosis and colchicine unresponsiveness. Clinical diagnosis of definite FMF disease was made based on the Tel-Hashomer criteria set. Genetic analyses revealed that all subjects were heterozygous for the new H478Y MEFV variant, segregating with the disease. In addition, mutations in the TNFRSF1A and CIAS1/PYPAF1/NALP3 genes, related to the dominantly inherited autoinflammatory periodic syndromes, were ruled out. However, the dominant inheritance of the disease, the long fever episodes with a predominant joint involvement, and the resistance to colchicine in these patients raise the question of whether the periodic syndrome seen in this kindred is a true FMF disease with unusual manifestations or rather another MEFV-associated periodic syndrome. We conclude that the new H478Y MEFV mutation is the dominant pathological variant causing the inflammatory periodic syndrome in this kindred and that full-length analyses of the MEFV gene are needed to obtain an adequate diagnosis of patients with clinical suspicion of a hereditary periodic fever syndrome, especially those from non-ancestral populations.     

Frequency of hereditary non-polyposis colorectal cancer and other colorectal cancer familial forms in Spain: a multicentre, prospective, nationwide study

BACKGROUND: Colorectal cancer is the third leading cause of cancer mortality in Western countries. Hereditary nonpolyposis colorectal cancer is the most common type of hereditary colorectal cancer, but its incidence remains controversial, ranging from 1 to 5%. OBJECTIVE: This present prospective, multicentre, nationwide study was aimed at compiling prominent epidemiological and clinical data with respect to hereditary non-polyposis colorectal cancer and other familial colorectal cancer forms in Spain, where information is lacking. METHODS: All patients with a de-novo diagnosis of colorectal cancer and who attended between November 2000 and October 2001 in 25 hospitals all over Spain were registered. Demographic, clinical and tumour-related characteristics of probands, and detailed family history, were obtained. RESULTS: A total of 1872 colorectal cancer patients were included. Clinical diagnosis of hereditary non-polyposis colorectal cancer was established in 46 (2.5%) patients according to the Amsterdam II criteria. Comparison between patients fulfilling either the Amsterdam I or the Amsterdam II criteria revealed no differences with respect to demographic, clinical and tumour-related characteristics. A total of 504 (27.0%) patients had a family history of hereditary non-polyposis colorectal cancer-related neoplasm not fulfilling the Amsterdam criteria (familial colorectal cancer), while 360 (19.2%) patients fulfilled at least one of the Bethesda's criteria. CONCLUSION: These clinicoepidemiological data provide a more accurate characterization of hereditary non-polyposis colorectal cancer and other familial colorectal cancer forms in Spain, with potential implications in preventive strategies.     

Prevention of catheter-related bloodstream infection in critically ill patients using a disinfectable, needle-free connector: a randomized controlled trial

OBJECTIVE: The aim of this study was to assess the efficacy of a disinfectable, needle-free connector in the prophylaxis of catheter-related bloodstream infection. METHODS: A randomized controlled trial was performed in a polyvalent intensive care unit. Patients who needed multilumen central venous catheters were randomly assigned to a study or a control group. All catheters were inserted and manipulated according to the Centers for Disease Control and Prevention (CDC) recommendations. Study group patients were equipped with catheters with disinfectable, needle-free connectors whereas control group patients were equipped with catheters with 3-way stopcocks. Two peripheral blood cultures and a semiquantitative culture of the catheter tip were performed on removal of the catheter. RESULTS: The study included 243 patients, with a total of 278 central venous catheters. The catheters' mean insertion duration was 9.9 days. Both groups were comparable regarding patient and catheter characteristics. Incidence rate of catheter-related bloodstream infection was 0.7 per 1000 days of catheter use in the study group, compared with 5.0 per 1000 days of catheter use in the control group (P=.03). CONCLUSIONS: To add a disinfectable, needle-free connector to the CDC recommendations reduces the incidence of catheter-related bloodstream infection in critically ill patients with central venous catheters.     

Characteristics of lentiviral vectors harboring the proximal promoter of the vav proto-oncogene: a weak and efficient promoter for gene therapy.

Recent published data have shown the efficacy of gene therapy treatments of certain monogenic diseases. Risks of insertional oncogenesis, however, indicate the necessity of developing new vectors with weaker or cell-restricted promoters to minimize the trans-activation activity of integrated proviruses. We have inserted the proximal promoter of the vav proto-oncogene into self-inactivating lentiviral vectors (vav-LVs) and investigated the expression pattern and therapeutic efficacy of these vectors. Compared with other LVs frequently used in gene therapy, vav-LVs mediated a weak, though homogeneous and stable, expression in in vitro-cultured cells. Transplantation experiments using transduced mouse bone marrow and human CD34(+) cells confirmed the stable activity of the promoter in vivo. To investigate whether the weak activity of this promoter was compatible with a therapeutic effect, a LV expressing the Fanconi anemia A (FANCA) gene was constructed (vav-FANCA LV). Although this vector induced a low expression of FANCA, compared to the expression induced by a LV harboring the spleen focus-forming virus (SFFV) promoter, the two vectors corrected the phenotype of cells from a patient with FA-A with the same efficacy. We propose that self-inactivating vectors harboring weak promoters, such as the vav promoter, will improve the safety of gene therapy and will be of particular interest for the treatment of diseases where a high expression of the transgene is not required.     

Differences in the frequency of osteoporosis according to the skeletal site evaluated. Analysis in 987 Spanish postmenopausal women referred to a bone densitometry unit

ObjectiveTo analyze the differences in the frequency of osteoporosis according to the skeletal site evaluated in a group of Spanish postmenopausal women.MethodsWe reviewed the data of 987 postmenopausal women (mean age, 53.8±5.5 years). BMD status was evaluated by DXA. We used the WHO thresholds to classify the patients. T-score was obtained from the single evaluation of each lumbar vertebra (L2, L3 and L4), the mean value of lumbar spine (L2-L4), femoral neck and total hip.ResultsIn 144 (14.7%) women, discrepancies were observed when we considered the single vertebral analysis versus the L2-L4 analysis; 62 (6%) women who presented osteoporosis in at least one vertebra would have been due to the osteopenia category when L2-L4 value was selected. In 271 (27.8%) women, discrepancies were observed when we considered the total hip analysis versus the femoral neck analysis. The frequency of osteoporosis ranged from 3% when only the analysis of the total hip was considered to 16% when the results of L2-L4 and proximal femur (total hip or femoral neck) measurements were selected.ConclusionsFrequency of osteoporosis varies notably according to the skeletal zone considered.     

Emerging insights into the role of albumin with plasma exchange in Alzheimer’s disease management

Alzheimer’s disease (AD) is a neurodegenerative process that inexorably leads to progressive deterioration of cognition function and, ultimately, death. Central pathophysiologic features of AD include the accumulation of extracellular plaques comprised of amyloid-β peptide (Aβ) and the presence of intraneuronal neurofibrillary tangles. However, a large body of evidence suggests that oxidative stress and inflammation are major contributors to the pathogenesis and progression of AD. To date, available pharmacologic treatments are only symptomatic. Clinical trials focused on amyloid and non-amyloid-targeted treatments with small molecule pharmacotherapy and immunotherapies have accumulated a long list of failures. Considering that around 90 % of the circulating Aβ is bound to albumin, and that a dynamic equilibrium exists between peripheral and central Aβ, plasma exchange with albumin replacement has emerged as a new approach in a multitargeted AD therapeutic strategy (AMBAR Program). In plasma exchange, a patient’s plasma is removed by plasmapheresis to eliminate toxic endogenous substances, including Aβ and functionally impaired albumin. The fluid replacement used is therapeutic albumin, which acts not only as a plasma volume expander but also has numerous pleiotropic functions (e.g., circulating Aβ- binding capacity, transporter, detoxifier, antioxidant) that are clinically relevant for the treatment of AD. Positive results from the AMBAR Program (phase 1, 2, an 2b/3 trials), i.e., slower decline or stabilization of disease symptoms in the most relevant clinical efficacy and safety endpoints, offer a glimmer of hope to both AD patients and caregivers.