Antimicrobial activities of doripenem and other carbapenems against Pseudomonas aeruginosa, other nonfermentative bacilli,and Aeromonas spp.

The in vitro activity of doripenem against prevalent nonfermentative Gram-negative bacilli and Aeromonas spp. was evaluated. The collection comprised 14979 nonduplicate clinical isolates submitted during a global Doripenem Surveillance Program conducted from 2003 through 2007. Susceptibility tests were performed using the Clinical and Laboratory Standards Institute reference broth microdilution method and the susceptibility criteria of the US Food and Drug Administration. Doripenem (MIC₉₀, 8 and 4 μg/mL) was 2-fold more potent than imipenem (MIC₉₀, >8 and 8 μg/mL) and meropenem (MIC₉₀, >8 and 8 μg/mL) against Pseudomonas aeruginosa and other Pseudomonas spp., covering 77.2% and 82.9% of the isolates, respectively, at the breakpoint of ≤2 μg/mL. Against Acinetobacter spp., including Acinetobacter baumannii, imipenem showed slightly greater activity and potency (2-fold) than other carbapenems, though only 41.8% of A. baumannii were susceptible at breakpoint. Doripenem, imipenem, and meropenem exhibited similar and near-complete coverage (98.2–98.8% at ≤4 μg/mL) against Aeromonas spp. Rates of susceptibility to doripenem among P. aeruginosa isolates varied by geographic region, being highest in North America and lowest in Latin America (84.9% and 67.2% inhibited at ≤2 μg/mL, respectively). Infections caused by nonfermentative Gram-negative bacilli and Aeromonas spp. often occur in severely debilitated patients and may be associated with poor clinical outcomes; moreover, these organisms have a significant capacity to develop resistance. Given the limited treatment choices available, doripenem appears to offer potency and an enhanced spectrum of activity usable against these troublesome pathogens, particularly against P. aeruginosa.     

Length-dependent truncal Aδ-fiber dysfunction in hereditary transthyretin amyloidosis: An intra-epidermal electrical stimulation study

ObjectiveTo elucidate Aδ-fiber dysfunction at the trunk in patients with hereditary transthyretin (ATTRm) amyloidosis using intra-epidermal electrical stimulation (IES).MethodsIn 16 patients with ATTRm amyloidosis and 18 healthy subjects, sensory thresholds using IES and cooling detection thresholds using the Computer-Aided Sensory Evaluation (CASE IV) system, were assessed to investigate Aδ-fiber functions at the Th10 level of the anterior, lateral, and posterior trunk. Furthermore, evoked potentials (EPs) following electrical stimulation using IES at the anterior and posterior trunk were evaluated.ResultsIn patients with ATTRm amyloidosis, both IES and CASE IV sensory thresholds tended to be higher at the anterior trunk than at the lateral and posterior trunks. The amplitudes of EPs following electrical stimulation at the anterior trunk were lower than those at the posterior trunk. Aδ-fiber dysfunction at the anterior trunk was conspicuous in patients with more intense polyneuropathy at the limbs. In healthy subjects, there were no differences in both sensory thresholds and EP amplitudes among any examination sites. Sensory thresholds with IES and CASE IV were correlated.ConclusionsEvaluation using IES demonstrated length-dependent Aδ-fiber dysfunction at the trunk in patients with ATTRm amyloidosis.SignificanceIES may be a useful clinical tool for investigating Aδ-fiber dysfunction at various parts of the body in patients with neuropathy.     

A novel ATTR L32V mutation causes familial amyloid polyneuropathy in a Bolivian family

We report a new transthyretin (ATTR) gene c.272C>G mutation and variant protein, p.Leu32Val, in a kindred of Bolivian origin with a rapid progressive peripheral neuropathy and cardiomyopathy. Three individuals from a kindred with peripheral nerve and cardiac amyloidosis were examined. Analysis of the TTR gene was performed by Sanger direct sequencing. Neuropathologic examination was obtained on the index patient with mass spectrometry study of the ATTR deposition. Direct DNA sequence analysis of exons 2, 3, and 4 of the TTR gene demonstrated a c.272 C>G mutation in exon 2 (p.L32V). Sural nerve biopsy revealed massive amyloid deposition in the perineurium, endoneurium and vasa nervorum. Mass spectrometric analyses of ATTR immunoprecipitated from nerve biopsy showed the presence of both wild‐type and variant proteins. The observed mass results for the wild‐type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. The ATTR L32V is associated with a severe course. This has implications for treatment of affected individuals and counseling of family members.     

Aging and transthyretin-related amyloidosis: Pathologic examinations in pulmonary amyloidosis

Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 ± 8.75 vs. 39.75 ± 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M.     

河北省5岁以下儿童生长发育Z评分及营养状况评价

【目的】 应用Z评分法对河北省5岁以下儿童生长发育及营养状况进行评价和分析,为做好儿童保健工作提供科学依据。 【方法】 采用分层随机整群抽样法,抽取河北省24个县、3个城市5岁以下儿童15 930人为研究对象,对其进行身高、体重测量,采用WHO Anthroplus 2007软件计算Z评分值。 【结果】 生长发育迟缓(HAZ<2)患病率11.41％(1 818/15 930)、低体重(WAZ<2)患病率7.06%(1 125/15 930)、消瘦(WHZ<2)患病率2.58%(411/15 930),且城乡差异显著,尤其是生长发育迟缓农村患病率12.35%,约是城市的3.2倍;儿童年龄别身高Z评分(HAZ)、年龄别体重Z评分(WAZ)以及身高别体重Z评分(WHZ)均值分别为0.96±1.08、0.51±1.32和0.08±1.68。其中城市分别为0.18±1.37、0.19±1.12和0.52±1.11,农村分别为1.23±1.40、0.63±1.21和0.12±1.24。仅城市WAZ和WHZ为正值,其余均为负值,且平均Z评分随年龄增长呈下降趋势。 【结论】 河北省儿童生长发育水平与WHO推荐的参考标准有一定差距,且城乡差异显著,农村儿童营养状况欠佳。     

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU.

Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov.

Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.     

Evaluation of a panel of in vitro methods for assessing thyroid receptor β and transthyretin transporter disrupting activities

We developed a thyroid testing panel to assess endocrine disrupting chemicals (EDCs) capacities to bind either the thyroid receptor β (TRβ) or the thyroid hormones transporter transthyretin (TTR). We first stably transfected a human U2OS cell line with TRβ and a luciferase reporter construct to develop the TRβ CALUX® reporter gene assay to assess chemicals’ potential to interact with TRβ. Secondly, we combined a TTR-binding assay with the TRβ CALUX (TTR-TRβ CALUX) and optimized the system to evaluate the competitive properties of EDCs towards T4 for TTR binding. Both systems were evaluated with a range of known thyroid-disrupting compounds. The agonistic/antagonistic TRβ CALUX successfully predicted 9/9 and 9/12 test compounds, respectively. The TTR-TRβ CALUX predicted 9/9 compounds and demonstrated competitive activities when analyzing waste water samples. We concluded that the proposed test battery is a promising screening method able to efficiently generate data on thyroid hormone interferences by chemicals.     

A Patient With Hereditary ATTR and a Novel AGel p.Ala578Pro Amyloidosis

Hereditary amyloidosis represents a group of diseases in which mutant proteins are deposited in various organs leading to their dysfunction. Correct identification of the amyloid-causing protein is critical because this will determine the optimal therapy for the patient. The most common type of hereditary amyloidosis is due to mutant transthyretin (ATTRm) deposition and often presents with heart failure or peripheral neuropathy. We report the first known case of a patient who had amyloidosis both due to a mutant transthyretin (p.Val122Ile) and due to a novel variant in the gelsolin gene (p.Ala578Pro). Both mutant proteins were identified by mass spectrometry analysis of amyloid deposits as well as sequencing of the genes. Molecular dynamic simulations suggest that the gelsolin p.Ala578Pro variant is likely amyloidogenic.