αv integrins play an important role in myofibroblast differentiation

Transforming growth factor-beta1 is a potent mediator of the differentiation of fibroblasts into myofibroblasts, which is characterized by the appearance of the cytoskeletal protein alpha-smooth muscle actin. The aim of this study was to investigate the role of integrin extracellular matrix receptors in transforming growth factor-beta1-induced myofibroblast differentiation. We show that blockade of the alphav and/or beta1 integrins prevents the transforming growth factor-beta1-induced myofibroblast differentiation, seen by the increased expression of alpha-smooth muscle actin and enhanced collagen gel contraction in three human fibroblast cell lines (from the mouth, skin, and kidney). Further, blockade of alphav specific integrins alphavbeta5 and alphavbeta3 suppressed myofibroblast differentiation in fibroblasts from the mouth and skin; however, in the kidney cells, the prevention of differentiation was seen only with blockade of alphavbeta5 integrin but not alphavbeta3. A possible reason for this result may be different degrees of responsiveness to transforming growth factor-beta1 treatment seen from different anatomical origins of the cell lines. These data indicate a novel role for alphav integrins in the differentiation of human fibroblasts from the mouth, skin, and kidney into myofibroblasts and suggest that there is a common differentiation pathway.     

Brain‐derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells

We used cultured adult mouse retinae as a model system to follow and quantify the retraction of dendrites using diolistic labelling of retinal ganglion cells (RGCs) following explantation. Cell death was monitored in parallel by nuclear staining as ‘labelling’ with RGC and apoptotic markers was inconsistent and exceedingly difficult to quantify reliably. Nuclear staining allowed us to delineate a lengthy time window during which dendrite retraction can be monitored in the absence of RGC death. The addition of brain‐derived neurotrophic factor (BDNF) produced a marked reduction in dendritic degeneration, even when application was delayed for 3 days after retinal explantation. These results suggest that the delayed addition of trophic factors may be functionally beneficial before the loss of cell bodies in the course of conditions such as glaucoma.     

Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals

We present two cases of recurrent progressive multifocal leukoencephalopathy (PML) in patients with long standing virally suppressed human immunodeficiency virus (HIV) and normal CD4+ T cell count who were taking stable regimens of highly active antiretroviral therapy (HAART). This has significant implications for other patients with a past history of PML, not just those with HIV but also those on medications such as natalizumab or fumarates.     

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue‐specific lesions associated with local double‐inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre‐expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1^flox/flox and Nf1^flox/? mice. The effects of the presence of Nf1^null cells were extensively examined. Cultured Nf1^null‐committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein‐2 (rhBMP‐2) treatment. Similarly, Nf1^null‐inducible osteoprogenitors obtained from Nf1 mouse muscle were also unresponsive to rhBMP‐2. In both closed and open fracture models in Nf1^flox/flox and Nf1^flox/? mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1^flox/flox and Nf1^flox/? mice. Histological analyses showed invasion of the Nf1^null fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10‐fold in Nf1^null fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1^null fractures, tartrate‐resistant acid phosphatase–positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. © 2012 American Society for Bone and Mineral Research     

Efficacy and safety of emergency non-invasive pelvic ring stabilisation

BackgroundUrgent non-invasive pelvic ring stabilisation (pelvic binding, PB) in shocked patients is recommended by state and institutional guidelines regardless of the fracture pattern. The purpose of this study was to determine the adherence to the guidelines, efficacy of the technique and identification of potential adverse effects associated with PB.Patients and methodsA 41-month retrospective analysis of the prospective pelvic fracture database was undertaken at a level 1 trauma centre. High-energy pelvic fractures were included in the analysis with exclusion of the A type injuries (AO/OTA classification) and patients who were dead on arrival. Collected data included patient demographics, injury severity score, fracture classification, application and timing of PB, associated injuries, physiological parameters, resuscitation fluids and outcomes. Pre and post-PB radiographs were reviewed. The potential effects of the PB on soft tissue (femoral vessel, bladder and rectal injury) complications were assessed by independent experts.Results115 patients with high-energy B and C type pelvic ring injuries were included. Thirty-six (31%) patients presented in haemorrhagic shock on arrival. A total of 43 pelvic bindings were performed, 18 of them on shocked patients. The adherence to the guidelines was 50% (18/36) overall. Analysing fracture types of shocked patients the adherence was: B1 80%, B2 20%, B3 20%, C1 66%, C2 86%, C3 33%. The alignment of the pelvis was improved or perfect on post-PB radiographs in 68% and had not changed in 21%. In some cases of B2 and B3 type injuries the PB increased the deformity after application (11%). There were 10 deaths (8.7%) in the study group, with 4 deaths attributed to acute pelvic bleeding. Two of these had PB applied and two were identified as potential for improvement. One femoral artery injury, four bladder injuries and three rectum injuries were identified in patients who had PB applied. Association between the PB and these injuries is unlikely.ConclusionThe adherence to the guidelines should be improved with further education and system development. The good effect of the technique was evident on radiographs. Although in some lateral compression fracture patterns the deformity increased, no hazards were associated with the use of PB.     

Grade progression and regression in recurrent urothelial cancer

PURPOSE: Recurrent urothelial cancers are reported to have characteristics similar to those of the primary tumor, with 10% to 25% of low grade tumors recurring as high grade disease. We determined how often grade progression and regression occur and whether abnormalities in p53 protein expression in original tumors are preserved in recurrences. MATERIALS AND METHODS: Two groups of patients treated for recurrent stages Ta/T1 urothelial bladder cancers with at least 1 tumor-free examination between the index and recurrent tumors were reviewed. Group 1 included 115 patients in whom the first available tumor was compared with the last recurrence and group 2 included 42 in whom the initial tumor was compared with the first recurrence. Immunohistochemical analysis of p53 expression was performed on a subset of 34 tumor pairs. RESULTS: In group 1, 33 grade 3 tumors (45%) recurred as grade 1 or 2 tumors, while 9 of 82 grades 1 and 2 tumors (11%) recurred as grade 3 tumors. Five of 7 group 2 grade 3 tumors (71%) recurred as grade 1 or 2 disease, while 1 of 35 grades 1 and 2 tumors (3%) recurred as grade 3 disease. In the 34 pairs studied immunohistochemically 6 of 14 grade 3 tumors recurred at lower grades. Nuclear p53 over expression occurred in 21 index tumors (12 of 14 grade 3, 8 of 17 grade 2 and 1 of 3 grade 1) and in 9 recurrences (6 of 10 grade 3, 2 of 17 grade 2 and 1 of 7 grade 1). Only 7 of 21 p53 positive and 2 of 12 p53 negative index tumors were p53 positive on recurrence. CONCLUSIONS: While progression from low to high grade occurred in less than 15% of patients, grade regression was observed in almost 50%. The loss of p53 positivity in regressing tumors indicates that these recurrences are molecularly distinct from the corresponding initial tumor.     

Hemispheric specialization for processing auditory nonspeech stimuli

The left hemisphere specialization for speech perception might arise from asymmetries at more basic levels of auditory processing. In particular, it has been suggested that differences in "temporal" and "spectral" processing exist between the hemispheres. Here we used functional magnetic resonance imaging to test this hypothesis further. Fourteen healthy volunteers listened to sequences of alternating pure tones that varied in the temporal and spectral domains. Increased temporal variation was associated with activation in Heschl's gyrus (HG) bilaterally, whereas increased spectral variation activated the superior temporal gyrus (STG) bilaterally and right posterior superior temporal sulcus (STS). Responses to increased temporal variation were lateralized to the left hemisphere; this left lateralization was greater in posteromedial HG, which is presumed to correspond to the primary auditory cortex. Responses to increased spectral variation were lateralized to the right hemisphere specifically in the anterior STG and posterior STS. These findings are consistent with the notion that the hemispheres are differentially specialized for processing auditory stimuli even in the absence of linguistic information.     

Discrepancy between training,competition and laboratory measures of maximum heart rate in NCAA division 2 distance runners

A percentage of either measured or predicted maximum heart rate is commonly used to prescribe and measure exercise intensity. However, maximum heart rate in athletes may be greater during competition or training than during laboratory exercise testing. Thus, the aim of the present investigation was to determine if endurance-trained runners train and compete at or above laboratory measures of ''maximum'' heart rate. Maximum heart rates were measured utilising a treadmill graded exercise test (GXT) in a laboratory setting using 10 female and 10 male National Collegiate Athletic Association (NCAA) division 2 cross-country and distance event track athletes. Maximum training and competition heart rates were measured during a high-intensity interval training day (TR HR) and during competition (COMP HR) at an NCAA meet. TR HR (207 ± 5.0 b·min^-1; means ± SEM) and COMP HR (206 ± 4 b·min^-1) were significantly (p < 0.05) higher than maximum heart rates obtained during the GXT (194 ± 2 b·min^-1). The heart rate at the ventilatory threshold measured in the laboratory occurred at 83.3 ± 2.5% of the heart rate at VO₂ max with no differences between the men and women. However, the heart rate at the ventilatory threshold measured in the laboratory was only 77% of the maximal COMP HR or TR HR. In order to optimize training-induced adaptation, training intensity for NCAA division 2 distance event runners should not be based on laboratory assessment of maximum heart rate, but instead on maximum heart rate obtained either during training or during competition.

Key points

• A percentage of maximum heart rate is commonly used to prescribe and measure exercise intensity. However, maximum heart rate may be greater during competition or training than during laboratory exercise testing.
• Heart rates during training and competition were significantly higher than maximum heart rates obtained during laboratory exercise testing.
• To optimize training-induced adaptation, training intensity for NCAA division 2 distance event runners should not be based on laboratory assessment of maximum heart rate, but instead on maximum heart rate measure obtained either during training or during competition.

Key words: Competition, heart rate, laboratory, performance, running, training     

Volume of Physical Activity and Injury Occurrence in Young Basketball Players

Participation in organised, competitive physical activity by young athletes is increasing rapidly. This is concurrent with an increase in sporting injuries in the young population. This pilot study aimed to compare the weekly volume and types of physical activity in young basketball players injured and not injured during the season. Detailed physical activity and injury data were prospectively collected in 46 school-level basketball players aged 14 to 18 years. Participants completed physical activity logs which documented the type of physical activity undertaken, what the activity consisted of (i.e. training, competition) and the level at which it was played on a daily basis. Allied health staff completed a weekly injury form. Results showed that injured and uninjured athletes participated in a similar volume of total weekly physical activity over the season. However, injured athletes (p = 0.04) and athletes who specifically sustained overuse injuries (p = 0.01) participated in a greater amount of basketball refereeing than uninjured athletes. Based on these findings it was concluded that greater participation in running-type physical activity such as refereeing, as an addition to training and competition, may predispose the young basketball player to increased injury risk. Future research using larger sample sizes are required to further investigate the role of participation volume and type on injury occurrence in adolescent athletes.

Key points

• Basketball players participating in larger amounts of running-type physical activity, in addition to regular training and competition, may be predisposed to overuse injury
• Future studies using larger sample sizes are required to investigate the precise volumes of physical activity that increase injury risk
• This would assist in the development of participation guidelines to decrease the current injury rates observed in the young athletic population.

Key words: Adolescent, sport injury, overuse, workload     

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging

Objective:

Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features.

Methods:

A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined.

Results:

Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy–Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC).

Conclusion:

The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making.

Advances in knowledge:

The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.