Matchmaking facilitates the diagnosis of an autosomal‐recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease–gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created “matching” platforms. We describe four individuals from three unrelated families “matched” by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease‐causing gene and interprets the variants as “pathogenic.” TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder.     

Taking a toll on the bones: regulation of bone metabolism by innate immune regulators

The interplay between the immune system and bone metabolism has been recognized as important for both of these systems. Various factors produced and released during immune responses markedly affect bone cells and bone metabolism. Meanwhile, niches for lymphocytes in bone also play an important role in the biology of these cells. Osteoimmunology, a new area of research focusing on associations between the immune and bone systems, is based on the concept that deeper investigation of the relationships between these systems will enhance our understanding of their biology and contribute to the discovery of novel therapeutic approaches for diseases of the two systems. Toll-like receptors (TLRs), the focus of this review, sense pathogen-derived molecules and initiate the inflammatory reactions of innate immune cells. TLRs are also expressed in bone cells, and their activation affects osteoclast differentiation and activity in a complex manner: TLR activation in early osteoclast precursors blocks the differentiation of those cells, while in cells that have already started their osteoclastic differentiation, it stimulates this process and increases the survival rates of mature osteoclasts (OCs). Activation of TLRs in osteoblasts (OBs) induces the production of osteoclastogenic cytokines, such as RANKL and TNF-alpha, thereby contributing to TLR ligand-induced osteoclastogenesis. These processes are the reason for the bone loss observed in variety of infectious diseases. The inhibition of osteoclastogenesis by TLR activation in early precursor cells may play a role in reducing the excessive bone loss caused by pathogenic infection and shifting the balance between the bone and immune systems during infection to recruit immune cells.     

Improved posterobasal segment function after thrombolysis is associated with decreased incidence of significant mitral regurgitation in a first inferior myocardial infarction

Objectives. This study was designed to investigate the association between wall motion abnormalities and the occurrence of ischemic mitral regurgitation in patients with a first inferior or posterior myocardial infarction and to reassess the role of thrombolytic treatment in these patients.

Background. We previously demonstrated that thrombolytic therapy reduces the incidence of significant mitral regurgitation in patients with a first inferior myocardial infarction, but the mechanisms responsible for this decrease were not clear.

Methods. Wall motion score on two-dimensional echocardiography (16 segments) and mitral regurgitation grade (0 to 3) on Doppler color flow imaging were assessed in 95 patients (in 47 after thrombolysis) at 24 h, 7 to 10 days and 1 month after myocardial infarction. Significant mitral regurgitation was defined as moderate or severe (grade 2 or 3).

Results. Multivariate analysis revealed that the presence of an advanced wall motion abnormality of the posterobasal segment of the left ventricle was the most significant independent variable associated with significant mitral regurgitation: odds ratio (OR) 15.0, 90% confidence interval (CI) 1.4 to 165.6 at 24 h; OR 2.8, CI 0.9 to 9.3 at 7 to 10 days; OR 4.2, CI 1.2 to 11.4 at 1 month. Thrombolysis reduced the prevalence of advanced wall motion abnormalities in the posterobasal segment at 24 h (55% vs. 75%, OR 0.5, CI 0.2 to 0.99), 7 to 10 days (44% vs. 73%, OR 0.3, CI 0.1 to 0.7) and 1 month (36% vs. 56%, OR 0.4, CI 0.2 to 0.9).

Conclusions. There is a strong association between advanced wall motion abnormalities in the posterobasal segment and significant mitral regurgitation. In this study group, thrombolysis reduced the prevalence of advanced wall motion abnormalities in the posterobasal segment and thereby reduced the incidence of significant mitral regurgitation.     

Clinical, sonographic, and epidemiologic features of second- and early third-trimester spontaneous antepartum uterine rupture: a cohort study

OBJECTIVE: To present prenatal findings and maternal and neonatal outcomes following second- and early third-trimester spontaneous antepartum uterine rupture events in our institute. METHOD: Charts of patients with full-thickness second- or early third-trimester symptomatic uterine ruptures locally treated between 1984 and 2007 were evaluated. RESULTS: There were seven events involving six women, all requiring emergency laparotomy, and cesarean section (CS). During the study period in our institute, there were 120 636 singleton deliveries (> or =22 weeks' gestation), including 5 of our cases, while in 2 cases, the rupture occurred earlier (<22 weeks' gestation). The rupture occurred after > or = 1 previous CSs in five cases. Six events were associated with abnormal placentation: placenta previa (n = 3), placenta percreta (n = 1), or both (n = 2). Other associated events included short, interpregnancy (IP) interval (n = 3) and past uterine rupture (n = 2). Pregnant women at gestational age > or = 22 weeks, who had the combination of placenta previa, and previous CS (n = 3), had a higher chance for spontaneous symptomatic antepartum uterine rupture when compared to women with placenta previa without a previous CS (OR 29.3, 95% CI 1.5-569.3, p = 0.007). There were no maternal deaths. Three of the five viable neonates survived. CONCLUSIONS: Spontaneous symptomatic second- or early third-trimester uterine rupture in nonlaboring women is a very rare, obstetric emergency, which is hard to diagnose. Maternal and neonatal outcomes can be optimized by awareness of risk factors, recognition of clinical signs and symptoms, and availability of ultrasound to assist in establishing diagnosis, and enabling prompt surgical intervention.     

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