Mechanical unfolding of spectrin reveals a super-exponential dependence of unfolding rate on force.

We investigated the mechanical unfolding of single spectrin molecules over a broad range of loading rates and thus unfolding forces by combining magnetic tweezers with atomic force microscopy. We find that the mean unfolding force increases logarithmically with loading rate at low loading rates, but the increase slows at loading rates above 1pN/s. This behavior indicates an unfolding rate that increases exponentially with the applied force at low forces, as expected on the basis of one-dimensional models of protein unfolding. At higher forces, however, the increase of the unfolding rate with the force becomes faster than exponential, which may indicate anti-Hammond behavior where the structures of the folded and transition states become more different as their free energies become more similar. Such behavior is rarely observed and can be explained by either a change in the unfolding pathway or as a reflection of a multidimensional energy landscape of proteins under force.

Patient Mortality in Geriatric Distal Femur Fractures.

OBJECTIVES: To estimate 1-year mortality rates in elderly patients who undergo operative treatment for distal femur fractures and identify potential risk factors for mortality. DESIGN: Retrospective chart review. SETTING: Level 1 and Level 2 trauma centers. PATIENTS/PARTICIPANTS: Two hundred eighty-three elderly patients (average age 76.0 years ± 9.8) who sustained distal femur fractures between 2002 and 2012. INTERVENTION: Fracture fixation of the distal femur. MAIN OUTCOME MEASURE: Survival up to 1 year after surgery. RESULTS: The 1-year mortality rate for distal femur fractures in elderly patients was 13.4%. There were no statistically significant differences in overall mortality between native bone and periprosthetic fractures, intramedullary nail or open reduction internal fixation, or across Orthopaedic Trauma Association fracture classifications. Overall patient mortality was significantly higher at 30 days (P = 0.036), 6 months (P = 0.019), and 1 year (P = 0.018), when surgery occurred more than 2 days from the injury. Mean Charlson Comorbidity Index scores were significantly lower in survivors versus nonsurvivors at all time intervals (30 days, P = 0.023; 6 months, P = 0.001 and 1 year P ≤ 0.001). A time to surgery of more than 2 days, regardless of baseline illness, did not result in improved survivability at 1 year. CONCLUSIONS: Overall mortality for distal femur fractures was 13.4% in the elderly population. A surgical treatment more than 2 days after injury was associated with increased patient mortality. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Early prediction of tibial and femoral fracture healing: Are we reliable?

INTRODUCTION: To evaluate the ability of orthopaedic trauma subspecialists to predict early bony union in femoral and tibia shaft fractures. MATERIALS AND METHODS: Eight orthopaedic trauma subspecialists prospectively predicted the probability of bony union at 6 and 12 weeks post-operatively for an aggregate of 48 femoral and tibial shaft fractures treated at a Level 1 trauma centre. An additional orthopaedic trauma subspecialist was blinded to treating surgeon and adjudicated healing at 18 weeks. The Squared-Error Skill Score (SESS) determined the likelihood of accurate forecasting for bony union. RESULTS: Nine patients were lost follow-up, resulting in 39 fractures (81.25% retention) including 20 femoral and 19 tibial fractures. Fourteen fractures were open, 15 were not-yet united at final follow-up. SESS values were 0.25-0.77. The ability to predict union (sensitivity) was 1.000. The ability to predict nonunions (specificity) was 0.330-0.500. The probability of a correct predicted union was 0.727 and correct predicted nonunion at final follow-up was 1.000. AO/OTA type A fractures pattern predictions were highly accurate. As body mass index increased, predictions trended toward decreased accuracy (p=0.06). Tobacco use, age, gender, associated injuries, open fractures, and surgeons' years in clinical practice were not associated with accuracy of predictions. CONCLUSIONS: At 12-weeks post-operatively orthopaedic trauma subspecialists can confidently predict the union state in this patient population. This data is most useful in the nonunion patient, directing early intervention, thereby decreasing patient disability and discomfort.

Prone and direct posterior approach for management of posterior column tibial plateau fractures.

INTRODUCTION: The three-column fixation concept is becoming popular in orthopedic practice. Posterior column fracture is an uncommon type of tibial plateau fracture. The supine position for the surgical approach is familiar to most surgeons; however, it is difficult to achieve good reduction and fixation in posterior column fracture. HYPOTHESES: The prone position and direct posterior approach can achieve proper reduction and fixation for posterior column tibial plateau fracture, yielding good functional outcome. MATERIALS AND METHODS: Between January 2010 and January 2012, 184 tibial plateau fractures were diagnosed and operated on in our institution. Sixteen posterior column tibial plateau fractures (10 male and 6 female patients, with a mean age of 41.5 ± 14.3 years) were diagnosed by preoperative plain films and CT scans. Ten patients presented with fracture-dislocation of the knee joint. A direct posterior approach in prone position was used to reduce the tibial condyle and fix it with an anti-glide buttress plate. Radiographic evaluation included reduction quality and bone union. Functional evaluation included Lysholm score and Tegner activity score. RESULTS: All fractures healed within 6 months, without secondary displacement. Ten knees had postoperative anatomic reduction (0mm step-off) and 6 had acceptable reduction (< 2mm step-off). At 34.4 ± 9.6 months, median extension was 3 (5-10) and flexion 135 (100-145). The mean Lysholm score was 95 (75-100) and the mean Tegner activity score was 6 (5-8). All patients were satisfied with the operation. No cases of post-traumatic osteoarthritis of the knee occurred during follow-up. CONCLUSIONS: The prone position and direct posterior approach has great advantages in terms of reduction and stable fixation, yielding good results.

Biomechanical analysis of augmented plate fixation for the treatment of vertical shear femoral neck fractures.

OBJECTIVES: To compare the strength of augmented versus nonaugmented fixation techniques for stabilizing vertical shear femoral neck fractures. METHODS: Two surgical screw constructs were tested with and without augmentation using 40 composite femurs: (1) 7.3-mm cannulated screws placed in an inverted triangular configuration and (2) 135-degree dynamic hip screw (DHS). The augmentation consisted of a 2.7-mm locking plate placed on the anterior-inferior femoral neck. Specimens in all 4 groups were tested with load to failure, while failure loads, energy absorbed to failure, and axial stiffness were determined. These data were then analyzed using a two-way (construct × augmentation) analysis of variance. RESULTS: There was no statistically significant interaction between screw construct and augmentation for load to failure (P = 0.11). Augmentation with the 2.7-mm locking plate increased failure loads in both constructs on average by 83% (2409 vs. 4417 N, P < 0.01). Femurs instrumented with cannulated screws had 26% higher loads to failure than those instrumented with DHS (3879 vs. 3087 N, P < 0.01). On average, the augmentation increased energy absorbed to failure by 183% and constructs' stiffness by 35%. CONCLUSIONS: The strength of surgical repairs of the vertical shear femoral neck fractures can be significantly augmented with the 2.7-mm locking plate. The construct with the cannulated screws was significantly stronger than the DHS construct.

Transmission and strain variation of Shigella flexneri 4a after mass prophylaxis in a long-stay psychiatric centre.

Shigella flexneri 4a caused sustained outbreaks in a large long-stay psychiatric centre, Taiwan, 2001-2006. Trimethoprim-sulphamethoxazole (SXT) prophylaxis was administered in 2004. We recovered 108 S. flexneri 4a isolates from 83 symptomatic (including one caregiver) and 12 asymptomatic subjects (11 contacts, one caregiver). The isolates were classified into eight antibiogram types and 15 genotypes (six clusters) by using antimicrobial susceptibility testing and pulsed-field gel electrophoresis of NotI-digested DNA, respectively. These characteristics altered significantly after SXT prophylaxis (P < 0·05), with concomitant emergence of SXT-resistant isolates in two antibiogram types. P01 (n = 71), the predominant epidemic genotype, caused infection in two caregivers and five patients under their care; two P01 isolates were recovered from the same patient 6 months apart. These results indicate the importance of sustained person-to-person transmission of S. flexneri 4a by long-term convalescent, asymptomatic or caregiver carriers, and support the emergence of SXT-resistant strains following selective pressure by SXT prophylaxis.

Appropriateness of patient transfer with associated orthopaedic injuries to a Level I trauma center.

OBJECTIVE: To prospectively evaluate the appropriateness, indications, risk factors, and epidemiology of patients with orthopaedic injuries transferred to a Level I trauma center. DESIGN: Prospective data were supplemented through chart review on all patients transferred to a Level I trauma center with orthopaedic injuries (n = 546) from January 1, 2007, to December 31, 2007. The accepting orthopaedic trauma surgeon evaluated the appropriateness of transfer by visual analog scale. SETTING: A Level I trauma center. PARTICIPANTS: Patients transferred to the trauma center requiring orthopaedic trauma service involvement. MAIN OUTCOME MEASUREMENTS: Demographics and visual analog scale appropriateness scores were collected on each patient. RESULTS: The authors considered 16.5% of the cohort inappropriate transfers, 49.3% appropriate, and the remaining 34.2% were designated as intermediate. The transfers came from an emergency department physician in 81% of cases, an orthopaedic surgeon in 14% of cases, and 5% by general surgeon or internist. One hundred forty-eight cases transferred primarily as a result of orthopaedic injuries had an available orthopaedic surgeon on-call at the original institution. Sixty percent were transferred as a result of orthopaedic injury complexity, but only 39% of the 148 were evaluated by an actual orthopaedic surgeon before transfer. Lack of orthopaedic coverage at the referring hospital accounted for 27% of transfers. CONCLUSIONS: A total of 16.5% of transfers were deemed completely inappropriate by the accepting orthopaedic traumatologist. Most transfers, both appropriate and inappropriate, were attributed to either complete lack of orthopaedic coverage or a lack of expertise at the referring center.

Zebrafish and medaka as models for bone research including implications regarding space-related issues.

Teleost fish develop bones directly from mesenchymal condensations and from cartilage precursors. At the cellular level, the involved cell populations share many features with their mammalian counterparts. In addition, several genes are already described in fish showing high homology in amino acid sequence and expression with the corresponding genes of tetrapods that are involved in bone metabolism. Therefore, analysis of the underlying molecular mechanism in fish, in particular zebrafish and medaka, will increase the knowledge in teleosts. Furthermore, it will help to identify novel genes and regulatory pathways of bone homeostasis and skeletal disorders also in higher vertebrates, including disorders caused by altered gravity.

Depression in orthopaedic trauma patients. Prevalence and severity.

BACKGROUND: There is a known connection between physical injury and disability and emotional distress. Several investigators have shown a relationship between trauma, depression, and poor outcomes. The literature on trauma and depression is limited with regard to clarifying the relationship between the degree of injury and depression and the relationship between physical function of patients with less severe injuries and depression. METHODS: One hundred and sixty-one patients who presented to our orthopaedic trauma services were enrolled in the study and interviewed. We obtained information about patient demographics and administered several self-reported outcome measures: the Beck Depression Inventory (BDI), the Short Musculoskeletal Function Assessment (SMFA), and the Physical Function-10 (PF-10) subset of the Short Form-36 (SF-36). We documented the nature and severity of the injury or injuries and calculated correlations between the outcome measures and the BDI. Injury-specific factors such as the AO Fracture Classification, the Abbreviated Injury Scale (AIS), the Injury Severity Score (ISS), and the Gustilo and Anderson grade of open fractures were also examined. RESULTS: Fifty-five percent of the patients had minimal depression, as measured with the BDI; 28% had moderate depression; 13% had moderate-to-severe depression; and 3.7% had severe depression. When the somatic elements of the BDI were removed, the prevalence of moderate, moderate-to-severe, or severe depression was 26%. The SMFA scores had a strong negative correlation with the BDI (-0.75; p < 0.001). Of the injury-specific factors, only open factures were found to have an impact on the presence of depression, with an odds ratio of 4.58 (95% confidence ratio, 1.57 to 12.35). CONCLUSIONS: The prevalence of clinically relevant depression approached 45% in a diverse cohort of orthopaedic trauma patients. Global disability is strongly correlated with depression. The presence of an open fracture may also increase the risk of depression. LEVEL OF EVIDENCE: Prognostic Level II.

The teleost fish medaka (Oryzias latipes) as genetic model to study gravity dependent bone homeostasis in vivo.

Long-term space flight and microgravity result in bone loss that can be explained by reduced activity of bone-forming cells (osteoblasts) and/or an increase in activity of bone resorbing cells (osteoclasts). Osteoprotegerin (OPG) has been shown to regulate the balance between osteoblast and osteoclast cell numbers and is involved in maintaining constant bone mass under normal gravitational conditions. The small bony fish medaka (Oryzias latipes) has attracted increasing attention as a genetic model system to study normal embryonic developmental and pathological processes. To analyze the molecular mechanisms of bone formation in this small vertebrate, we have isolated two opg genes, opgl and opg2, from medaka. Our phylogenetic analysis reveals that both genes originated from a common ancestor by fish-specific gene duplication and represent the orthologs of the mammalian opg gene. Both opg genes are differentially expressed during embryonic and larval development, in adult tissues and in cultured primary osteoblast-like cells. Furthermore, we have characterized the opg2 promoter region and identified consensus binding sites for the transcription factor core-binding-factor-1A (CBFA1). In mammals, CBFA1 has been shown to be a regulator of opg expression and to be essential for several steps during osteoblast differentiation. Here we show that sequence and expression domains of opg, cbfal and a member of the dlx gene family are highly conserved between medaka and higher vertebrates. This suggests that not only single genes but entire genetic networks for bone formation are conserved between teleosts and mammals. These findings will open medaka fish as a genetic model to monitor bone formation under different gravity conditions in a living whole animal allowing the identification of novel factors involved in bone homeostasis.

Mapping quantitative trait loci that influence femoral cross-sectional area in mice.

Size and shape are critical determinants of the mechanical properties of skeletal elements and can be anticipated to be highly heritable. Moreover, the genes responsible may be independent of those that regulate bone mineral density (BMD). To begin to identify the heritable determinants of skeletal geometry, we have examined femoral cross-sectional area (FCSA) in male and female mice from two inbred strains of mice with divergent FCSA (C57BL/6 [B6] and DBA/2 [D2]), a large genetically heterogeneous population (n = 964) of B6D2F2 mice and 18 BXD recombinant inbred (RI) strains derived from their F2 cross. Femora were harvested from 16-week-old mice and FCSA (bone and marrow space enclosed within the periosteum) was measured at the midshaft by digital image analysis. In all mouse populations examined, FCSA was positively correlated with body weight and weight-corrected FCSA (WC-FCSA) values were normally distributed in the BXD-RI and F2 populations, suggesting polygenic control of this trait. Genome-wide quantitative trait locus (QTL) analysis of the B6D2F2 population revealed regions on four different chromosomes that were very strongly linked to WC-FCSA (chromosomes 6, 8, 10, and X) in both genders. Evidence of gender-specific genetic influences on femoral geometry was also identified at three other chromosomal sites (chromosomes 2, 7, and 12). Supporting evidence for the WC-FCSA QTLs on chromosomes 2, 7, 8, 10, and 12 also was present in the RI strains. Interestingly, none of these WC-FCSA QTLs were identified in our previous QTL analysis of whole body BMD in the same B6D2F2 population. Thus, the genetic determinants of bone size appear to be largely, if not entirely, distinct from those that regulate BMD attainment. The identification of the genes responsible for geometric differences in bone development should reveal fundamentally important processes in the control of skeletal integrity.

Reliability and validity of depressive personality disorder.

OBJECTIVE: Depressive personality disorder was introduced into DSM-IV's appendix amid controversy. While that disorder appears to be a reliable and valid one, the authors offer new data about its relationship to major depression, dysthymic disorder, and other personality disorders. METHOD: The authors assessed 54 subjects with early-onset, long-standing mild depressive features for depressive personality disorder, axis I and axis II disorders, family history, and treatment history; they conducted follow-up interviews 1 year after the baseline assessment. Subjects with (N=30) and without (N=24) depressive personality disorder were characterized and compared in terms of those variables. RESULTS: Although depressive personality disorder and dysthymia co-occurred in some subjects, 63% of subjects with depressive personality disorder did not have dysthymia, and 60% did not have current major depression. Although subjects with depressive personality disorder were more likely than the mood disorder comparison group to have another personality disorder, 40% had no such disorder. Contrary to study hypotheses, mood disorder was not more common in first-degree relatives of subjects with depressive personality disorder than in relatives of the comparison group. Subjects with and without depressive personality disorder had similar rates of past treatment with medication and psychotherapy; however, the duration of psychotherapy was significantly longer for subjects with than for those without depressive personality. The depressive personality diagnosis was relatively stable over the 1-year follow-up period. CONCLUSIONS: Depressive personality disorder appears to be a relatively stable condition with incomplete overlap with axis I mood disorders and personality disorders. Further studies are needed to better characterize its treatment response and relationship to axis I mood disorders.

The Origin of Gravitational Lensing: A Postscript to Einstein's 1936 Science Paper

Gravitational lensing, now taken as an important astrophysical consequence of the general theory of relativity, was found even before this theory was formulated but was discarded as a speculative idea without any chance of empirical confirmation. Reconstruction of some of Einstein's research notes dating back to 1912 reveals that he explored the possibility of gravitational lensing 3 years before completing his general theory of relativity. On the basis of preliminary insights into this theory, Einstein had already derived the basic features of the lensing effect. When he finally published the very same results 24 years later, it was only in response to prodding by an amateur scientist.