FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation

The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.     

Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband

Comprehensive genetic screening programs have led to the identification of pathogenic methyl-CpG-binding protein 2 (MECP2) mutations in up to 95% of classical Rett syndrome (RTT) patients. This high rate of mutation detection can partly be attributed to specialised techniques that have enabled the detection of large deletions in a substantial fraction of otherwise mutation-negative patients. These cases would normally be missed by the routine PCR-based screening strategies. Here, we have identified large multi-exonic deletions in 12/149 apparently mutation-negative RTT patients using multiplex ligation-dependent probe amplification (MLPA). These deletions were subsequently characterised using real-time quantitative PCR (qPCR) and long-range PCR with the ultimate aim of defining the exact nucleotide positions of the breakpoints and rearrangements. We detected an apparent deletion in one further patient using MLPA; however, this finding was contradicted by subsequent qPCR and long-range PCR results. The patient group includes an affected brother and sister with a large MECP2 deletion also present in their carrier mother. The X chromosome inactivation pattern of all female patients in this study was determined, which, coupled with detailed clinical information, allowed meaningful genotype-phenotype correlations to be drawn. This study reaffirms the view that large MECP2 deletions are an important cause of both classical and atypical RTT syndrome, and cautions that apparent deletions detected using high-throughput diagnostic techniques require further characterisation.     

Gastrointestinal bleeding and obstructive jaundice:Think of hepatic artery aneurysm

Hemobilia is an uncommon and potential life-threatening condition mainly due to hepato-biliary tree traumatic or iatrogenic injuries.Spontaneously ruptured aneurysm of the hepatic artery is seldom described.We report the case of an 89-year-old woman presenting with abdominal pain,jaundice and gastrointestinal bleeding,whose ultrasound and computed tomography revealed a non-traumatic,spontaneous aneurysm of the right hepatic artery.The oeso-gastro-duodenoscopy and colonoscopy did not reveal any bleeding at the ampulla of Vater,nor anywhere else.Selective angiography confirmed the diagnosis of hepatic artery aneurysm and revealed a full hepatic artery originating from the superior mesenteric artery.The patient was successfully treated by selective embolization of microcoils.We discuss the etiologies of hemobilia and its treatment with selective embolization,which remains favored over surgical treatment.Although aneurysm of the hepatic artery is rare,especially without trauma,a high index of suspicion is needed in order to ensure appropriate treatment.     

Inferior subluxation of the fibular head following tibial lengthening with a unilateral external fixator

BACKGROUND: Inferior subluxation of the proximal part of the fibula has been reported to occur with distraction osteogenesis of the tibia; however, the clinical sequelae of this subluxation are unknown. The purpose of this study was to evaluate inferior subluxation of the proximal part of the fibula and its possible clinical implications in patients who had undergone tibial lengthening by distraction osteogenesis with use of a unilateral external fixator. METHODS: Thirty tibiae in seventeen patients with a variety of conditions underwent tibial lengthening by distraction osteogenesis with use of a unilateral external fixator and were followed clinically and radiographically for a mean of two years and ten months (range, two to four years). Ten patients were female and seven were male. Their mean age at the time of the surgery was seventeen years (range, eight to twenty-five years). The mean tibial lengthening was 8.1 cm (range, 3.5 to 13 cm). RESULTS: An inferior shift of the fibular head in relation to the tibia was evident in all cases. The shift, which ranged from 0.4 to 3.3 cm, was proportionally related to the amount of tibial lengthening. This type of subluxation is probably attributable to the tension that is exerted by the intact interosseous membrane during the distraction as well as to the tension of the regenerated bone of the fibula and the fact that the fibula itself is not fixed or directly lengthened by the external fixator. CONCLUSIONS: It appears that inferior subluxation of the fibula is a common phenomenon in patients undergoing tibial lengthening by distraction osteogenesis with use of a unilateral external fixator. However, no clinical symptoms or findings related to the inferior subluxation of the fibula were found in our series.     

Proctalgia Fugax in Patients with the Irritable Bowel, Peptic Ulcer, or Inflammatory Bowel Disease

One hundred forty-eight patients with gastrointestinal disease, 50 patients with the irritable bowel syndrome (IBS) and 49 each with peptic ulcer and inflammatory bowel disease, were interviewed to determine if they had proctalgia fugax (PF) and if the symptom was associated with the IBS. One-third of the patients had PF. It occurred in 51% of females and 12% of males (p less than 0.001). When corrected for sex, PF was no more prevalent in IBS than in peptic ulcer or inflammatory bowel disease. Only two of six previously described IBS symptoms were more prevalent in the PF patients. Attacks occurred in the day in 94%, and one-third of sufferers related them to defecation. The pain was localized in the anus in 90%, occurred less than five times a year in 51%, and lasted less than 1 min in 57%. In most, activity was not interrupted by this pain and only 20% had ever reported it to a physician. PF is very common among patients with abdominal symptoms, but is not related to the IBS. Since it is infrequent, benign, and transient, PF is usually not mentioned to the physician.     

A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13

We have constructed a contig of non-chimaeric yeast artificialchromosomes (YACs) across the candidate region for childhoodautosomal recessive spinal muscular atrophy (SMA) In 5q13. Anovel microsatellite reduces the candidate region to approximately400kb of DNA distal to D5S435. The candidate region containsblocks of chromosome 5 specific repeats which have copies on5p as well as elsewhere on 5q. Restriction mapping of the YACsreveals at least one CpG island In the SMA gene region. TheYAC maps indicate that the contig contains minimal rearrangementsor deletions. The data show the value of screening several YAClibraries simultaneously in order to construct a set of overlappingsequences suitable for candidate gene searches and direct genomicsequencing.     

Quality of life in Greek family members living with leg ulcer patients

Leg ulcers have been shown to have a significant impact on a patient's quality of life (QoL). Little is known, however, about the secondary impact of the disease on the QoL of the relatives and partners of patients with leg ulcers. The aim of this study was to explore the impact of chronic leg ulcers on the lives of both patients and their family members. Two hundred sixteen patients with leg ulcers and their family members were recruited. All patients entered were evaluated for QoL using the Dermatology Life Quality Index (DLQI) scale, and family members were similarly evaluated using the Family Dermatology Life Quality Index (FDLQI).The study included 56 female and 52 male patients, and 50 female and 58 male family members. The FDLQI score for the latter group was 14.37 ± 2.46 with over 96% of family members reporting a large effect on their QoL due to their relative's disease. The DLQI score in patients with leg ulcers was 13.18 ± 2.88. A significant positive and high correlation between DLQI and FDLQI scores (r = 0.71, p < 0.001) was documented, while DLQI contributed significantly to the prediction of FDLQI (standardized β = 0.71, p < 0.001). Our study results indicate that the QoL of the family was also affected by the patient's condition of chronic leg ulcers and clearly associated with that of the patients.     

Ipsilateral atrophy of paraspinal and psoas muscle in unilateral back pain patients with monosegmental degenerative disc disease

Objectives

The aim of this study was to assess the cross-sectional area (CSA) of both paraspinal and psoas muscles in patients with unilateral back pain using MRI and to correlate it with outcome measures.

Methods

40 patients, all with informed consent, with a minimum of 3 months of unilateral back pain with or without sciatica and one-level disc disease on MRI of the lumbosacral spine were included. Patients were evaluated with self-report measures regarding pain (visual analogue score) and disability (Oswestry disability index). The CSA of multifidus, erector spinae, quadratus lumborum and psoas was measured at the disc level of pathology and the two adjacent disc levels, bilaterally. Comparison of CSAs of muscles between the affected vs symptomless side was carried out with Student''s t-test and correlations were conducted with Spearman''s test.

Results

The maximum relative muscle atrophy (% decrease in CSA on symptomatic side) independent of the level was 13.1% for multifidus, 21.8% for erector spinae, 24.8% for quadratus lumborum and 17.1% for psoas. There was significant difference (p<0.05) between sides (symptomatic and asymptomatic) in CSA of multifidus, erector spinae, quadratus lumborum and psoas. However, no statistically significant correlation was found between the duration of symptoms (average 15.5 months), patient''s pain (average VAS 5.3) or disability (average ODI 25.2) and the relative muscle atrophy.

Conclusion

In patients with long-standing unilateral back pain due to monosegmental degenerative disc disease, selective multifidus, erector spinae, quadratus lumborum and psoas atrophy develops on the symptomatic side. Radiologists and clinicians should evaluate spinal muscle atrophy of patients with persistent unilateral back pain.Paraspinal and trunk muscles play an important role in the kinetics and balance of the lumbar spine. They are considered as dynamic stabilisers applying their working force by providing stability to the spine–pelvis complex and motion to the spinal units. In addition, psoas is a significant hip flexor. Any decrease in the cross-sectional diameter (CSA) of these muscles could lead to loss of proper biomechanics and may be accompanied by the appearance of back pain [1-5]. Some authors have proposed that pain leads to a sedentary lifestyle and, furthermore, this creates extra muscle atrophy and pain, thus beginning a vicious cycle [6,7].In athletes with regular physical training, an increase in CSA of the paraspinal and trunk muscles has been demonstrated that reflects the improvement of muscle force and endurance [8]. In contrast, prolonged bed rest results in selective atrophy of the multifidus muscle whereas trunk muscles increase their CSA. The latter is probably the effect of shortening of muscle fibres or overactivity during bed rest [9].Many studies on paraspinal musculature have focused on the multifidus muscle because of its unique and segmental innervation [10]. A multifidus bundle''s unisegmental innervation always arises purely from the root exiting below the spinous process from which the fascicles originate, whereas in the other paraspinal muscles innervation is multisegmental. Several studies have demonstrated atrophy of multifidus following trauma, disc herniation or spinal nerve lesion by electromyographic, histological or radiographic measurements [1,11,12]. None of these studies focused on monosegmental degenerative disc disease.This study aims to examine the CSA of all muscles around the lumbar spine in patients with persistent unilateral back pain caused by monosegmental degenerative disc disease and correlate this with their symptoms and period of pain.     

Intimate Partner Violence and Food Insecurity Predict Early Behavior Problems Among South African Children over 5-years Post-Birth

Households experiencing intimate partner violence (IPV) and food insecurity are at high risk of lifelong physical and behavioral difficulties. Longitudinal data from a perinatal home-visiting cluster-randomized controlled intervention trial in South Africa townships were used to examine the relationships between household settings and mothers’ histories of risk and children’s behavior problems at 3 and 5 years of age. IPV, food insecurity, maternal depressed mood, and geriatric pregnancy (at age of 35 or older) were consistently associated with children’s internalizing and externalizing behavior problems. Aggressive behavior was more prevalent among 3- and 5-year olds boys, and was associated with maternal alcohol use. The effects of these factors on child behavior were more prominent than maternal HIV status. There is a continuing need to reduce IPV and household food insecurity, as well as supporting older, depressed, alcohol using mothers in order to address children’s behavioral needs.