Minimally invasive surgery for severe hallux valgus in 106 feet.

BACKGROUND: There is widespread variation in the optimal procedure for correction of severe hallux valgus deformity defined as hallux valgus angle (HVA) (≥40°) and/or 1-2 intermetatarsal angle (IMA) (≥20°). There is limited evidence investigating the clinical or radiological outcomes following treatment of severe hallux valgus deformity with third-generation minimally invasive chevron and Akin osteotomies (MICA). METHODS: This was a prospective observational single surgeon series of consecutive patients who underwent primary third-generation MICA with screw fixation for severe hallux valgus. The primary outcome was a validated patient reported outcome measure (PROM), the Manchester-Oxford Foot Questionnaire (MOXFQ), assessed minimum 2 years following MICA. Secondary outcomes were radiographic deformity correction (assessed 6 weeks post-operatively), complication rates and other quality of life PROMs (EQ-5D and Visual Analogue Pain Scale). RESULTS: Between September 2014 and November 2018, 106 consecutive feet (n = 78 patients; 73 female, 5 male) met the inclusion criteria. Prospectively collected pre-operative and 2 year PROM MOXFQ data was available for 86 feet (81.1%). At two years following surgery, the MOXFQ score significantly improved for the Pain, Walking and Standing and Social Interaction domains from 39.2 to 7.5, 38.2 to 5.9 and 48.6 to 5.5, respectively (p < 0.001). Pre- and 6 week post-operative radiographic data was available for all 106 feet. Mean IMA improved from 18.2° to 6.3° (p < 0.001) whilst mean HVA improved from 45.3° to 10.9° (p < 0.001). The complication rate was 18.8% and the screw removal rate was 5.6%. CONCLUSION: This study has demonstrated third-generation MICA for the treatment of severe hallux valgus deformity enables substantial deformity correction and is associated with significant improvements in clinical PROMs 2 years following surgery.

Time to maximum clinical improvement following minimally invasive chevron and Akin osteotomies (MICA) in hallux valgus surgery.

BACKGROUND: There is increasing evidence of positive improvement in clinical and radiological outcomes following minimally invasive hallux valgus deformity correction surgery (MIS). This study investigated the rate of improvement in clinical patient reported outcome measures (PROMs) following MIS as this is not well understood. METHODS: Between July 2014 and July 2019, data was prospectively collected from consecutive patients pre-operatively and at 6, 12, and 24 months following third-generation minimally invasive chevron and Akin osteotomies (MICA). Radiographic deformity and correction was assessed using weight-bearing radiographs pre-operatively and 6 weeks post-operatively. The primary outcome measure was the change in Manchester Oxford Foot Questionnaire (MOXFQ) score at each time point. Secondary outcomes include radiographic deformity correction, health-related quality of life PROMs and exploration of cases where PROMs did not improve. RESULTS: There were 202 feet with complete PROM data for every time point. There was a statistically significant improvement in MOXFQ Index score at each time point (p < 0.05) following MICA surgery. The majority of the improvement occurred within the first 6 months. A subgroup of 17 feet (8.4%) were identified which had worse MOXFQ Index scores 6 months following MICA. For 14 feet in this subgroup (82.4%), the MOXFQ Index score subsequently improved over time such that by two years, their score had significantly improved compared to their pre-operative score. CONCLUSION: The majority of PROM improvement with MICA is gained by 6 months post-operatively but further significant improvement can be seen up to 2 years. Those patients who have not improved at 6 months, are likely to do so with time. LEVEL OF EVIDENCE: IV.

The impact of hallux valgus on function and quality of life in females.

BACKGROUND: The effect of hallux valgus (HV) on health-related quality of life (HRQOL) and the relationship between radiographic severity of deformity and patient reported outcome measures (PROMs) is poorly understood. The aim of this study was to compare the HRQOL of female patients with HV to the UK population. The secondary aim was to assess the correlation between PROMs, including HRQOL, with radiographic severity of deformity. METHODS: Weight bearing radiographic data (hallux valgus (HVA) angle; intermetatarsal (IM) angle) were measured in consecutive female patients presenting with HV. Each patient prospectively completed the Euroqol EQ-5D-5L questionnaire (EQ-5D), Visual Analogue Scale for Pain (VAS-Pain) and Manchester Oxford Foot Questionnaire (MOXFQ). Data were stratified into age ranges and compared with an EQ-5D United Kingdom general population reference dataset. Pearson R correlation values were calculated for the PROMs and radiographic deformity. RESULTS: Between July 2015 and March 2020, 425 consecutive female patients presented with HV for consideration for surgery. EQ-5D-5L data were prospectively collected for 396 of these patients (93.2%). Females less than 65 years with HV had a statistically significantly worse quality of life compared with females of the same age group in the general population. Above the age of 65, there was no statistically significant difference in EQ-5D-5L Index score between the two groups. Younger females reported higher VAS-Pain scores compared to older patients with 91% of patients reporting some degree of pain symptoms. There was a moderate correlation with MOXFQ Index score and EQ-5D-5L Index (R = -0.51, p < 0.001) and VAS-Pain scores (R = 0.54, p < 0.001). There was no correlation between radiographic HV deformity and HRQOL measures or MOXFQ scores although it was noted that there was a trend of increasing HVA/IMA with age. CONCLUSION: Female patients presenting with HV deformity have a significantly reduced quality of life compared with the UK general population. The radiographic severity of deformity did not correlate with HRQOL measures or foot and ankle specific PROMs. Foot and ankle specific clinical PROMsmoderately correlate with HRQOL and may be a better marker of the negative effect of symptomatic hallux valgus deformity on quality of life. LEVEL OF EVIDENCE: III.

Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells.

Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. However, despite the well-established role of EWS-FLI1 in tumor initiation, the development of models of Ewing sarcoma in human cells with defined genetic elements has been challenging. Here, we report a novel approach to model the initiation of Ewing sarcoma tumorigenesis that exploits the developmental and pluripotent potential of human embryonic stem cells. The inducible expression of EWS-FLI1 in embryoid bodies, or collections of differentiating stem cells, generates cells with properties of Ewing sarcoma tumors, including characteristics of transformation. These cell lines exhibit anchorage-independent growth, a lack of contact inhibition and a strong Ewing sarcoma gene expression signature. Furthermore, these cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth, which is a hallmark of Ewing sarcoma tumors.

The outcome at 15 years of endoscopic anterior cruciate ligament reconstruction using hamstring tendon autograft for 'isolated' anterior cruciate ligament rupture.

The purpose of this study was to report the outcome of 'isolated' anterior cruciate ligament (ACL) ruptures treated with anatomical endoscopic reconstruction using hamstring tendon autograft at a mean of 15 years (14.25 to 16.9). A total of 100 consecutive men and 100 consecutive women with 'isolated' ACL rupture underwent four-strand hamstring tendon reconstruction with anteromedial portal femoral tunnel drilling and interference screw fixation by a single surgeon. Details were recorded pre-operatively and at one, two, seven and 15 years post-operatively. Outcomes included clinical examination, subjective and objective scoring systems, and radiological assessment. At 15 years only eight of 118 patients (7%) had moderate or severe osteo-arthritic changes (International Knee Documentation Committee Grades C and D), and 79 of 152 patients (52%) still performed very strenuous activities. Overall graft survival at 15 years was 83% (1.1% failure per year). Patients aged < 18 years at the time of surgery and patients with > 2 mm of laxity at one year had a threefold increase in the risk of suffering a rupture of the graft (p = 0.002 and p = 0.001, respectively). There was no increase in laxity of the graft over time. ACL reconstructive surgery in patients with an 'isolated' rupture using this technique shows good results 15 years post-operatively with respect to ligamentous stability, objective and subjective outcomes, and does not appear to cause osteoarthritis.

Male breast cancer in World War II aviation: a case report and review.

Increased incidence of malignancies within aviators is well documented. Commercial female flyers have been found to have a higher risk of developing breast cancer. However, there has not been any report of male breast cancer related to flying either alone or where malignant melanoma and other primary cancers are also associated. We report two male World War II, British Royal Air Force pilots with primary breast carcinoma associated with two other primary cancer sites.

Cross-suturing as an aid to wound closure: a prospective randomised trial using the forearm flap donor site as a model.

Direct closure of a full thickness skin defect by suturing is the simplest and best solution in most cases. When suturing is not possible, then a skin graft may be the next choice for reconstruction. It is usual for the graft to be applied to the unaltered defect, accepting the size of the wound as the area to be grafted. This approach ignores the potential contribution of the elastic properties of the wound edges, which are so readily used to advantage in direct closure. A simple technique, which makes skin defects substantially smaller prior to skin grafting, is described. This technique benefits the primary defect by minimising the area of scar produced, as well as minimising the size of skin graft required and thus the graft donor site. The secondary defect of the radial forearm flap was used as a model wound in a prospective randomised trial to assess the use of this technique. Twenty successive patients undergoing free radial forearm flap surgery were entered into the trial. The technique consisted of preliminary cross-suturing of the wound prior to skin grafting. Half of the cases received cross-wound suturing and half of the cases had grafts applied to the unaltered area of the defect. Measurements of the forearm flap donor defects were taken using templates made at the time of surgery and at later intervals. A statistically significant reduction in the flap donor defects was achieved using the cross-suturing technique. Fewer complications such as skin graft failure and tendon adherence to graft were seen with the new technique. This technique is recommended not only for minimising morbidity in the radial forearm flap donor site, but also for reducing the size of any full thickness skin defect prior to skin grafting.

Design and characterization of a membrane permeable N-methyl amino acid-containing peptide that inhibits Abeta1-40 fibrillogenesis.

Alzheimer's disease, Huntington's disease and prion diseases are part of a growing list of diseases associated with formation of beta-sheet containing fibrils. In a previous publication, we demonstrated that the self-association of the Alzheimer's beta-amyloid (Abeta) peptide is inhibited by peptides homologous to the central core domain of Abeta, but containing N-methyl amino acids at alternate positions. When these inhibitor peptides are arrayed in an extended, beta-strand conformation, the alternating position of N-methyl amino acids gives the peptide two distinct faces, one exhibiting a normal pattern of peptide backbone hydrogen bonds, but the other face having limited hydrogen-bonding capabilities due to the replacement of the amide protons by N-methyl groups. Here, we demonstrate, through two-dimensional NMR and circular dichroic spectroscopy, that a pentapeptide with two N-methyl amino acids, Abeta16-20m or Ac-K(Me)LV(Me)FF-NH2, does indeed have the intended structure of an extended beta-strand. This structure is remarkably stable to changes in solvent conditions and resists denaturation by heating, changes in pH (from 2.5 to 10.5), and addition of denaturants such as urea and guanindine-HCl. We also show that this peptide, despite its hydrophobic composition, is highly water soluble, to concentrations > 30 mm, in contrast to the nonmethylated congener, Abeta16-20 (Ac-KLVFF-NH2). The striking water solubility, in combination with the hydrophobic composition of the peptide, suggested that the peptide might be able to pass spontaneously through cell membranes and model phospholipid bilayers such as unilamellar vesicles. Thus, we also demonstrate that this peptide is indeed able to pass spontaneously through both synthetic phospholipid bilayer vesicles and cell membranes. Characterization of the biophysical properties of the Abeta16-20m peptide may facilitate the application of this strategy to other systems as diverse as the HIV protease and chemokines, in which there is dimerization through beta-strand domains.

Inhibition of beta-amyloid(40) fibrillogenesis and disassembly of beta-amyloid(40) fibrils by short beta-amyloid congeners containing N-methyl amino acids at alternate residues.

A potential goal in the prevention or therapy of Alzheimer's disease is to decrease or eliminate neuritic plaques composed of fibrillar beta-amyloid (Abeta). In this paper we describe N-methyl amino acid containing congeners of the hydrophobic "core domain" of Abeta that inhibit the fibrillogenesis of full-length Abeta. These peptides also disassemble preformed fibrils of full-length Abeta. A key feature of the inhibitor peptides is that they contain N-methyl amino acids in alternating positions of the sequence. The most potent of these inhibitors, termed Abeta16-22m, has the sequence NH(2)-K(Me-L)V(Me-F)F(Me-A)E-CONH(2). In contrast, a peptide, NH(2)-KL(Me-V)(Me-F)(Me-F)(Me-A)-E-CONH(2), with N-methyl amino acids in consecutive order, is not a fibrillogenesis inhibitor. Another peptide containing alternating N-methyl amino acids but based on the sequence of a different fibril-forming protein, the human prion protein, is also not an inhibitor of Abeta40 fibrillogenesis. The nonmethylated version of the inhibitor peptide, NH(2)-KLVFFAE-CONH(2) (Abeta16-22), is a weak fibrillogenesis inhibitor. Perhaps contrary to expectations, the Abeta16-22m peptide is highly soluble in aqueous media, and concentrations in excess of 40 mg/mL can be obtained in buffers of physiological pH and ionic strength, compared to only 2 mg/mL for Abeta16-22. Analytical ultracentrifugation demonstrates that Abeta16-22m is monomeric in buffer solution. Whereas Abeta16-22 is susceptible to cleavage by chymotrypsin, the methylated inhibitor peptide Abeta16-22m is completely resistant to this protease. Circular dichroic spectroscopy of Abeta16-22m indicates that this peptide is a beta-strand, albeit with an unusual minimum at 226 nm. In summary, the inhibitor motif is that of alternating N-methyl and nonmethylated amino acids in a sequence critical for Abeta40 fibrillogenesis. These inhibitors appear to act by binding to growth sites of Abeta nuclei and/or fibrils and preventing the propagation of the network of hydrogen bonds that is essential for the formation of an extended beta-sheet fibril.

A review of 100 consecutive free tissue transfers.

Following the introduction of microsurgical techniques the availability of free tissue transfer has radically transformed reconstructive possibilities for both oncological and surgical defects. This study is a review of 100 consecutive free tissue transfers (free flaps), carried out in 96 patients over a period of 25 months in our unit. The indications for surgery in this series mainly resulted from malignancy, trauma, chronic osteomyelitis, burns and congenital abnormalities. The tissues transferred included various combinations of skin, fat, fascia, muscle, bone and several free digits. Fourteen cases required re-exploration, of which 12 were salvaged, and the overall success rate was 96%.

Basal cell carcinoma in aplasia cutis congenita.

A case of multilocal basal cell carcinoma in a 45-year-old man is reported.

Familial British dementia: expression and metabolism of BRI.

Vidal et al. (1999. Nature 399: 776-778) discovered that the underlying genetic lesion in familial British dementia (FBD) is a T-A transversion at the termination codon of a membrane protein, termed BRI. The mutation creates an arginine codon; translational read-through generates a novel protein, termed BRI-L, that is extended by 11 amino acids at the carboxyl-terminus. BRI-L is the precursor of the ABri peptide, a component of amyloid deposits in FBD brain. We demonstrate that both BRI and its mutant counterpart are constitutively processed by furin, resulting in the secretion of carboxyl-terminal peptide derivatives that correspond to all, or part of, ABri. Notably, elevated levels of peptides are generated from the mutant BRI precursor, suggesting that subtle conformational alterations at the carboxyl-terminus may influence furin-mediated processing. We have examined BRI/BRI-L processing by other members of the prohormone convertase (PC) family (PACE4, LPC, PC 5/6) and found that these enzymes also process BRI, albeit inefficiently. Moreover, BRI-L processing by the other PC members is severely compromised. Finally, our electron microscopic studies reveal that synthetic ABri peptides assemble into insoluble beta-pleated fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates amyloidogenic peptides that initiate the pathogenesis of FBD.

Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia.

The genetic lesion underlying familial British dementia (FBD), an autosomal dominant neurodegenerative disorder, is a T-A transversion at the termination codon of the BRI gene. The mutant gene encodes BRI-L, the precursor of ABri peptides that accumulate in amyloid deposits in FBD brain. We now report that both BRI-L and its wild-type counterpart, BRI, were constitutively processed by the proprotein convertase, furin, resulting in the secretion of carboxyl-terminal peptides that encompass all or part of ABri. Elevated levels of peptides were generated from the mutant BRI precursor. Electron microscopic studies revealed that synthetic ABri peptides assembled into irregular, short fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates fibrillogenic peptides that initiate the pathogenesis of FBD.

Firework related injury and legislation: the epidemiology of firework injuries and the effect of legislation in Northern Ireland.

The efficacy of legislation in reducing firework associated injuries is uncertain as is the nature of the problem within the United Kingdom (UK). In September 1996 the legislation governing firework sale in Northern Ireland was relaxed thus equalling that of the rest of the UK. For the 2 years following the change in legislation we prospectively assessed those patients who were admitted with a firework injury over the Halloween period. We then compared these results with retrospective data for the 3 years prior to the change in firework law. In the pre-legislation series the mean number of patients admitted annually was 0.38 per 100,000 while in the post-legislation series the mean was 0.43 per 100,000. Blast injury to the hand was the commonest injury accounting for 53% of cases in both series. Burn injuries were the second commonest form of injury comprising 30% of all admissions. Of those admitted with a hand injury 47% had at least one finger terminalised and nearly half of those patients admitted with burns (44%) required skin grafting. We conclude that early evidence suggests that liberalisation of the law on firework sale has not resulted in a significant increase in firework related injuries requiring hospital admission.

Consequences of premature discontinuation of the developmental test of visual-motor integration: can these tests be salvaged?

The administration of many neuropsychological tests includes discontinuation criteria that are often complex and time-consuming. As a result, it is not uncommon for an examiner to unintentionally discontinue the administration of a test prematurely. This investigation of 56 correctly scored Developmental Test of Visual-Motor Integration protocols was conducted to determine how the premature termination of this particular test significantly affects its overall score, and thus, its interpretation. These data indicate that premature discontinuation of this test results in a minimal loss of points overall, and thus, does not invalidate the interpretation of its score.

Factors affecting high-density lipoproteins.

Although it is well established that a low-circulating level of high-density lipoprotein (HDL) cholesterol is strongly associated with the likelihood of developing atherosclerotic coronary heart disease (CHD), the causal nature of this association has not been shown. Low levels of HDL cholesterol frequently are associated with other CHD risk factors, whose correction, often by hygienic means, may reduce CHD risk with minimal risk of adverse side-effects. However, other recommended hygienic interventions may lower HDL cholesterol levels. Specific safe and effective drugs for correcting a low HDL cholesterol level are not available and the potential value of specific pharmacologic treatment of this condition in the treatment or prevention of CHD remains unproven. Thus, while HDL measurement should be incorporated routinely in risk-assessment, intervention efforts should focus primarily on lowering low-density lipoprotein cholesterol.

Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

OBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.