Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A

Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.     

Segmental and suprasegmental features in speech perception in Cantonese‐speaking second graders: An ERP study

Using a multiple‐deviant oddball paradigm, this study examined second graders' brain responses to Cantonese speech. We aimed to address the question of whether a change in a consonant or lexical tone could be automatically detected by children. We measured auditory mismatch responses to place of articulation and voice onset time (VOT), reflecting segmental perception, as well as Cantonese lexical tones including level tone and contour tone, reflecting suprasegmental perception. The data showed that robust mismatch negativities (MMNs) were elicited by all deviants in the time window of 300–500 ms in second graders. Moreover, relative to the standard stimuli, the VOT deviant elicited a robust positive mismatch response, and the level tone deviant elicited a significant MMN in the time window of 150–300 ms. The findings suggest that Hong Kong second graders were sensitive to neural discriminations of speech sounds both at the segmental and suprasegmental levels.     

Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects

The etiology for the majority of congenital heart defects (CHD) is unknown. We identified a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle who harbored an ～0.3 Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first four exons of FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine whether FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD.     

Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010–2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study

Complicated skin and soft tissue infections (cSSTI) are common and frequently require treatment in hospital. Comprehensive current data on management practices in patients hospitalized with cSSTI are limited. REACH was a retrospective, observational cohort study designed to provide data on current clinical management of moderate to severe cSSTI in European hospitals. Data were collected via an electronic case report form from 129 sites in ten European countries. The study population comprised patients ≥18 years, hospitalized between March 2010 and February 2011 with cSSTI who received intravenous antibiotic treatment. Presented here is an analysis of the disease characteristics, treatment patterns during hospitalization and clinical outcomes identified by the study. The total population included 1995 patients (mean age 60.6 years; 57.7% male). Initial antibiotic treatment modification was reported in 39.6% (n = 791) of patients; it was more common in patients with co-morbidities (42.6%), those requiring surgical intervention (43.4%), those with more severe infections such as bacteraemia (51.6%) or with fascia affected (49.0%), those admitted to the intensive care unit (56.2%) and those with lesions > 50 cm² (44.3%). A switch to narrower-spectrum antibiotic treatment (streamlining) occurred in 5.6% of patients. Mean length of hospital stay was 18.5 days (±19.9; median 12.0) and the total mortality rate was 3.4%. The data collected in REACH give a comprehensive and current view of real-life clinical management of cSSTI in European hospitals and provide evidence of a high rate of initial antibiotic treatment modification.     

Clinical aspects of pelvic inflammatory disease

Pelvic inflammatory disease (PID) is a common and poorly managed condition. Untreated or inadequately treated, it leads to tubal infertility, ectopic pregnancy and chronic pelvic pain. Diagnostic difficulties are compounded by the wide variety of clinical presentations and the insensitivity and poor specificity of laboratory tests. Better recognition of mild and atypical disease needs a high index of suspicion whenever young, sexually active women present with gynaecological symptoms. Laparoscopy supplemented by microbiological tests and fimbrial minibiopsy should be regarded as the diagnostic 'gold standard' for research studies; new studies are required to identify techniques which might reduce under- and over-diagnosis. Early treatment reduces the risk of an adverse effect on fertility. Any therapeutic regimen selected should be effective against the common aetiological agents Chlamydia trachomatis, Neisseria gonorrhoeae, genital mycoplasmas and aerobic and anaerobic bacteria. Since at least 60% of cases of PID can be attributed to infection with a sexually transmitted organism, partner notification forms an essential part of management.      

Multimodality imaging of an appendiceal intussusception

Appendiceal intussusception is a rare entity. The majority of cases reported in the literature address surgical and colonoscopic approaches to treatment of the condition. The existing radiologic literature largely describes the sonographic and double-contrast enema findings of appendiceal intussusception. We present a case of appendiceal intussusception and describe the air-contrast enema, sonographic and CT findings.     

Mechanical efficiency during repetitive vertical jumping

The purpose of this study was to compare mechanical efficiency between repeated static jumps (SJ), countermovement jumps (CMJ), drop jumps from 75% of maximum CMJ jump height (75DJ) and drop jumps from 125% of maximum CMJ height (125DJ). Subjects included eight jump-trained males. All subjects completed 30 continuous repetitions in the SJ, CMJ, 75DJ, and 125DJ. Oxygen consumption, peak force and center of mass displacement for each repetition during the four jumping patterns were measured. ME was calculated from a combination of force-time curves, displacement-time curves and lactate-corrected oxygen consumption values. In addition, muscle activity was recorded from the vastus medialis, vastus lateralis and biceps femoris using surface electromyography (EMG). 125DJ and 75DJ resulted in significantly (P ≤ 0.05) greater ME in comparison to CMJ and SJ. CMJ resulted in significantly greater ME in comparison to SJ. In addition, braking phase muscle activity was significantly greater in 125DJ and 75DJ in comparison to CMJ. Negative work was significantly different between 125DJ, 75DJ and CMJ (125DJ > 75DJ > CMJ). There was a significant positive correlation (r = 0.68) between ME and negative work performed across 125DJ, 75DJ and CMJ. These findings suggest that stretch-shortening cycle movements, which include a strenuous braking phase combined with simultaneous high muscle activity, increase ME. This may be due to optimal muscle-tendon unit kinetics and usage of stored elastic energy.