Segmental Aging Underlies the Development of a Parkinson Phenotype in the AS/AGU Rat.

There is a paucity of information on the molecular biology of aging processes in the brain. We have used biomarkers of aging (SA ß-Gal, p16Ink4a, Sirt5, Sirt6, and Sirt7) to demonstrate the presence of an accelerated aging phenotype across different brain regions in the AS/AGU rat, a spontaneous Parkinsonian mutant of PKCγ derived from a parental AS strain. P16INK4a expression was significantly higher in AS/AGU animals compared to age-matched AS controls (p < 0.001) and displayed segmental expression across various brain regions. The age-related expression of sirtuins similarly showed differences between strains and between brain regions. Our data clearly show segmental aging processes within the rat brain, and that these are accelerated in the AS/AGU mutant. The accelerated aging, Parkinsonian phenotype, and disruption to dopamine signalling in the basal ganglia in AS/AGU rats, suggests that this rat strain represents a useful model for studies of development and progression of Parkinson's disease in the context of biological aging and may offer unique mechanistic insights into the biology of aging.

SIRT2: tumour suppressor or tumour promoter in operable breast cancer?

PURPOSE: Sirtuins comprise a family of genes involved in cellular stress, survival and damage responses. They have been implicated in a range of diseases including cancer, with most information pertaining to their function in tumourigenesis being derived from in vitro studies, or model organisms. Their putative roles as tumour suppressors or tumour promoters remain to be validated in vivo. Little is known about their role in breast tumourigenesis. We sought to evaluate the seven sirtuin family members (SIRT1-7) in a human breast cancer cohort, in relation to clinico-pathological features and outcome of the disease. MATERIALS AND METHODS: Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in 392 oestrogen receptor (ER+ve) and 153 ER-ve breast tumour samples. SIRT1-7 transcriptional levels were assessed in normal (n=25), non-malignant (n=73) and malignant (n=70) breast tissue using Relative Quantitative Real Time PCR. Statistical analyses determined if SIRT1-7 transcription or protein expression was associated with clinical parameters or outcome. RESULTS: In ER-ve tumours, high protein levels of nuclear SIRT2 were associated with reduced time to recurrence and disease-specific death. This association was only observed in Grade 3 tumours. In the ER+ve cohort, high SIRT2 nuclear levels were associated with shorter disease-free survival and time to recurrence whilst on Tamoxifen, in patients with Grade 3 tumours. Conversely, in Grade 2 tumours, high SIRT2 levels were associated with increased time to recurrence. CONCLUSIONS: Our data suggest that SIRT2 is the sirtuin predominantly involved in breast tumourigenesis and prognosis. It indicates that SIRT2 acts as a tumour suppressor or tumour promoter dependent upon breast tumour grade.

Comparative analysis of the structural properties of the collateral ligaments of the human knee.

STUDY DESIGN: Controlled laboratory study. BACKGROUND: Varus knee instability arising from lateral collateral ligament (LCL) injury increases stress on cruciate ligament grafts, potentially leading to failure of reconstructed ligaments. In contrast to the medial collateral ligament (MCL), little is known about the structural properties of the LCL. OBJECTIVES: To compare the tensile properties of the LCL and MCL complex of the human knee joint. METHODS: Ten fresh-frozen cadaveric knees (mean ± SD age, 81 ± 11 years), free of gross musculoskeletal pathology, were obtained. Following dissection, the length, width, and thickness of the ligaments were measured using calipers, and bone-ligament-bone preparations were mounted in a uniaxial load frame. After preconditioning, specimens were extended to failure at a rate of 500 mm/min (approximately 20%/s). Force and crosshead displacement were used to calculate structural properties, including stiffness, yield strength, ultimate tensile strength, and failure energy. RESULTS: The fan-shaped MCL was significantly longer (60%; P<.001), wider (680%; P<.001), and thinner (19%; P = .009) than the cord-like LCL. The LCL failed at either the fibular attachment (n = 6) or midsubstance (n = 4), while failure of the MCL primarily occurred at the femoral attachment (n = 7). Although the ultimate tensile strength of the MCL (mean ± SD, 799 ± 209 N) was twice that of the LCL (392 ± 104 N; P<.001), there was no significant difference in stiffness of the ligaments (MCL, 63 ± 14 N/mm; LCL, 59 ± 12 N/mm). CONCLUSIONS: Despite differences in geometry and strength, there was no significant difference in stiffness of the MCL and LCL when tested in vitro.

Topographic anatomy of the nerve to masseter: an anatomical and clinical study.

BACKGROUND: The use of the motor nerve to masseter has proved to be a reliable and sensible solution in facial reanimation as a donor for free muscle transfer. In this paper we describe the topographic anatomy of the nerve to masseter and our original technique for its quick and safe harvesting. METHODS: This anatomical study is based on the dissection of the nerve to masseter in 17 embalmed cadaverous sites and is focused on the anatomical relations between the nerve and the surrounding structures. Also buccal and zygomatic branches of the facial nerve were dissected and assessed and the resulting data are compared. RESULTS: The nerve to masseter has a predictable track inside the muscle which can be identified topographically within a square area under the zygomatic arch. This area is different between males and females and its accuracy has been tested on six patients at the Canniesburn Unit. CONCLUSIONS: The nerve to masseter emerges in a very predictable point from the mandibular notch - immediately below the zygomatic arch - to run within the muscle belly. The approach here described allows safer and faster harvesting of the nerve to masseter with minimal dissection through the muscle.

Pancreatic-derived pathfinder cells enable regeneration of critically damaged adult pancreatic tissue and completely reverse streptozotocin-induced diabetes.

We demonstrate that intravenous delivery of human, or rat, pancreas-derived pathfinder (PDP) cells can totally regenerate critically damaged adult tissue and restore normal function across a species barrier. We have used a mouse model of streptozotocin (STZ)-induced diabetes to demonstrate this. Normoglycemia was restored and maintained for up to 89 days following the induction of diabetes and subsequent intravenous delivery of PDP cells. Normal pancreatic histology also appeared to be restored, and treated diabetic animals gained body weight. Regenerated tissue was primarily of host origin, with few rat or human cells detectable by fluorescent in situ hybridization (FISH). Crucially, the insulin produced by these animals was overwhelmingly murine in origin and was both types I and II, indicative of a process of developmental recapitulation. These results demonstrate the feasibility of using intravenous administration of adult cells to regenerate damaged tissue. Critically, they enhance our understanding of the mechanisms relating to such repair and suggest a means for novel therapeutic intervention in loss of tissue and organ function with age.

Reliability of frames of reference used for tibial component rotation in total knee arthroplasty.

This study evaluated seven different frames of reference used for tibial component rotation in total knee arthroplasty (TKA) to determine which ones showed good reliability between bone specimens. An optoelectronic system based around a computer-assisted surgical navigation system was used to measure and locate 34 individual anatomical landmarks on 40 tibias. Each particular frame of reference was reconstructed from a group of data points taken from the surface of each bone. The transverse axis was used as the baseline to which the other axes were compared, and the differences in angular rotation between the other six reference frames and the transverse axis were calculated. There was high variability in the tibial rotational alignment associated with all frames of reference. Of the references widely used in current TKA procedures, the tibial tuberosity axis and the anterior condylar axis had lower standard deviations (6.1° and 7.3°, respectively) than the transmalleolar axis and the posterior condylar axis (9.3° for both). In conclusion, we found high variability in the frames of reference used for tibial rotation alignment. However, the anterior condylar axis and transverse axis may warrant further tests with the use of navigation. Combining different frames of reference such as the tibial tuberosity axis, anterior condylar axis and transverse axis may reduce the range of errors found in all of these measurements.

The anatomic and radiologic basis of the circumflex scapular artery perforator flap.

Microsurgical development has recently focused upon the perforator paradigm and primary thinning. Existing perforator flaps may require intramuscular dissection or lack reliable surface markings, whereas traditional scapular/parascapular flaps have low donor morbidity and reliable anatomy, but can be excessively bulky. Clinical application of a new flap based on a perforator from the circumflex scapular axis (CSA) has recently been published, but the vessel's anatomy has not been adequately characterized. The CSA was dissected in 115 sites in 69 cadavers. The number, external vessel diameter, and site of origin of perforators were measured relative to the CSA bifurcation. Color Doppler ultrasound was used to delineate the CSA and its perforators bilaterally in 40 volunteers. The number, origin relative to CSA bifurcation, diameter, length, and flow velocity of cutaneous perforators were determined. A CSA perforator was always present, running into the subdermal plexus, arising within 2.4 cm of the bifurcation. Cadaver studies: mean perforator diameter, 1.3 mm (SD, 0.66); 13% arose at bifurcation, 36% arose proximal (mean, 1.1 mm; SD, 0.63), and 52% distal to bifurcation (mean, 1.5 mm; SD, 0.88). Ultrasound: mean perforator diameter, 1.18 mm (SD, 0.41); mean flow velocity, 16.3 cm/s (SD, 3.65); perforator arose in 36% proximal, in 40% distal to bifurcation, and in 24% from the bifurcation. We definitively describe the anatomy of the perforator from the circumflex scapular artery upon which a new flap has been based. Its origin and dimensions are anatomically and radiologically reliable. The flap has certain potential benefits over existing perforator flaps.