The emerging relevance of the cysteine protease Cathepsin S in disease

Cathepsin S is a lysosomal cysteine protease that has been shown to play a key role in MHC class II antigen presentation. Consequently, it has been extensively evaluated as a therapeutic target in autoimmune diseases, such as rheumatoid arthritis and psoriasis. Additionally, clinical and mechanistic evidence is emerging, revealing its inappropriate expression and secretion in a wide range of disease states including atherosclerosis and tumourigenesis. This review covers the known role and consequences of cathepsin S activity in these pathological disorders, highlighting various studies that have demonstrated its utility as a therapeutic target. This review also examines challenges that exist towards the development of agents that specifically target this protease and discusses the studies to date that have applied cathepsin S inhibitors in disease models.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

FINDINGS: We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).

INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

FUNDING: Cancer Research UK, Medical Research Council.

The Middle Stone Age of Eastern Africa

The Middle Stone Age (MSA) covers the evolution, emergence, and dispersal of Homo sapiens. This article focuses on archaeological data and on published material from key stratified sites with some form of geochronological control from across eastern Africa. The MSA is often characterised by a shift from handaxe production towards discoidal and Levallois techniques. Although evidence for the controlled use of fire remains minimal, it seems likely that MSA hominins used it, as well as being highly skilled in working stone and probably bone and wood. MSA hominins appear to have exploited a range of different ecozones and many MSA sites are focused on ecotones, maximising access to resources. Over time, use of rockshelters and caves also seems to have increased. Although much work remains, the MSA is presently one of the most exciting and dynamic periods in the study of human evolution.

Classifying cerebral palsy: are we nearly there?

BACKGROUND: Cerebral palsy (CP) is the most common cause of physical disability in childhood in developed countries and encompasses a wide range of clinical phenotypes. Classification of CP according to movement disorder or topographical distribution is widely used. However, these classifications are not reliable nor do they accurately predict musculoskeletal pathology. More recently, the Gross Motor Function Classification System (GMFCS) has been introduced and its validity, reliability, and clinical utility have been confirmed. In 2005 it was suggested that children should be described and classified according to the GMFCS in all outcome studies involving children with CP, in the Journal of Pediatric Orthopaedics (JPO). This study aimed to describe utilization of the GMFCS in 3 journals: Journal of Bone and Joint Surgery (JBJS Am), JPO, and Developmental Medicine and Child Neurology (DMCN), over a 7-year period (2005 to 2011), and any relationship to the journal's impact factor. A secondary aim was to establish if differences in methodological quality existed between those studies utilizing GMFCS and those that did not.

METHODS: A targeted literature search of the 3 selected journals using the term "cerebral palsy" was conducted using the Medline database. Utilization of the GMFCS was assessed using report of these data in the methods or results section of the retrieved papers. The Methodological Index for Non-Randomized Studies (MINORS) was employed to evaluate the quality of papers published in JPO.

RESULTS: One hundred and fifty-four studies met the inclusion criteria and in 85 (68%) the GMFCS was used. Of these, 112 were published in JPO, of which 51 (46%) utilized the GMFCS, compared with 72% for JBJS Am, and 88% for DMCN. In the JPO, utilization of the GMFCS improved from 13% to 80%, over the 7-year study period.

CONCLUSIONS: Utilization of the GMFCS has increased rapidly over the past 7 years in the JPO but there is room for further improvement.

LEVEL OF EVIDENCE: Not applicable.