First Metatarsophalangeal Joint Arthroscopy of 36 Consecutive Cases.

PURPOSE OF THE STUDY In this study, we retrospectively reviewed a consecutive case series of first metatarsophalangeal (MTP) joint arthroscopies performed in our department over a span of six years. This study aimed to evaluate the efficacy and safety of arthroscopic treatment for various first MTP joint pathologies. MATERIAL AND METHODS A total of 36 patients that underwent first MTP joint arthroscopy between January 2014 and December 2019 were reviewed. The mean age at the time of surgery was 38.3 years (range, 14-65), with no gender predominance (19 males). All arthroscopies were performed by a single surgeon using a 2.7 mm arthroscope with a 30° viewing angle as well as other standard instruments with a diameter equal to or smaller than 3.5 mm. Postoperative results were assessed by a satisfaction questionnaire obtained during the telephone interview. For patients with sesamoid bone pathology ability to return to sports activities was also evaluated. RESULTS The far most common indication, in even twenty-nine patients, was hallux rigidus, five patients were treated for nonunion of sesamoid bone fracture, one patient had an osteochondral defect of the first metatarsal head and one was treated due to the development of arthrofibrosis following the open corrective procedure of hallux valgus. The mean follow-up was 31.2 months. Thirty-four patients responded to the satisfaction questionnaire. Thirty patients (88.2%) were either satisfied or very satisfied with the procedure and thirty-one (91.2%) of them stated that they would undergo the same procedure again. The satisfaction rate for patients with early stages of hallux rigidus (grade 1 and 2) was 90.4%. Only one patient in this group (2.8%) required open revision surgery due to recurrence of pain and joint stiffness. All patients with nonunion of sesamoid bone fracture were very satisfied with the procedure, and three out of four patients (75%) who were also competitive athletes resumed their sports activity at the same or improved level after the arthroscopy. Regarding arthroscopy-related complications we observed four cases (11.1%) of iatrogenic injury to dorsal sensory nerves of the great toe, resulting in only one permanent sensory impairment. DISCUSSION Considering the high satisfaction rate and low rate of complications in our study, as well as those published in the literature, we can suggest that arthroscopy of the first MTP joint is a safe and effective procedure. CONCLUSIONS Arthroscopy of the first MTP joint certainly has a place in the treatment of some pathological conditions of the first MTP joint, and in our opinion, it should be first-line surgical therapy for the initial stages of hallux rigidus and sesamoid bone pathology. Key words: arthroscopy, metatarsophalangeal joint, great toe, hallux rigidus, cheilectomy, sesamoid bone, sesamoidectomy.

Involving research participants in a pan-European research initiative: the EPAD participant panel experience.

BACKGROUND: Including participants in patient and public involvement activities is increasingly acknowledged as a key pillar of successful research activity. Such activities can influence recruitment and retention, as well as researcher experience and contribute to decision making in research studies. However, there are few established methodologies of how to set up and manage participant involvement activities. Further, there is little discussion of how to do so when dealing with collaborative projects that run across countries and operate in multiple linguistic and regulatory contexts. METHODS: In this paper we describe the set-up, running and experiences of the EPAD participant panel. The EPAD study was a pan-European cohort study with the aim to understand risks for developing Alzheimer's disease and build a readiness cohort for Phase 2 clinical trials. Due to the longitudinal nature of this study, combined with the enrolment of healthy volunteers and those with mild cognitive impairments, the EPAD team highlighted participant involvement as crucial to the success of this project. The EPAD project employed a nested model, with local panels meeting in England, France, Scotland, Spain and The Netherlands, and feeding into a central study panel. The local panels were governed by terms of reference which were adaptable to local needs. RESULTS: The impact of the panels has been widespread, and varies from feedback on documentation, to supporting with design of media materials and representation of the project at national and international meetings. CONCLUSIONS: The EPAD panels have contributed to the success of the project and the model established is easily transferable to other disease areas investigating healthy or at-risk populations.

Measurements of the Thermal Resistivity of InAlAs, InGaAs, and InAlAs/InGaAs Superlattices.

Thermal management efforts in nanoscale devices must consider both the thermal properties of the constituent materials and the interfaces connecting them. It is currently unclear whether alloy/alloy semiconductor superlattices such as InAlAs/InGaAs have lower thermal conductivities than their constituent alloys. We report measurements of the crossplane thermal resistivity of InAlAs/InGaAs superlattices at room temperature, showing that the superlattice resistivities are larger by a factor of 1.2-1.6 than that of the constituent bulk materials, depending on the strain state and composition. We show that the additional resistance present in these superlattices can be tuned by a factor of 2.5 by altering the lattice mismatch and thereby the phonon-mode mismatch at the interfaces, a principle that is commonly assumed for superlattices but has not been experimentally verified without adding new elements to the layers. We find that the additional resistance in superlattices does not increase significantly when the layer thickness is decreased from 4 to 2 nm. We also report measurements of 250-1000 nm thick films of undoped InGaAs and InAlAs lattice-matched to InP substrates, for there is no published thermal conductivity value for the latter, and we find it to be 2.24 ± 0.09 at 22 °C, which is ∼2.7 times smaller than the widely used estimates.

Guidelines for the use of cell lines in biomedical research.

Cell-line misidentification and contamination with microorganisms, such as mycoplasma, together with instability, both genetic and phenotypic, are among the problems that continue to affect cell culture. Many of these problems are avoidable with the necessary foresight, and these Guidelines have been prepared to provide those new to the field and others engaged in teaching and instruction with the information necessary to increase their awareness of the problems and to enable them to deal with them effectively. The Guidelines cover areas such as development, acquisition, authentication, cryopreservation, transfer of cell lines between laboratories, microbial contamination, characterisation, instability and misidentification. Advice is also given on complying with current legal and ethical requirements when deriving cell lines from human and animal tissues, the selection and maintenance of equipment and how to deal with problems that may arise.

Quantitative determination of contributions to the thermoelectric power factor in Si nanostructures.

We report thermoelectric measurements on a silicon nanoribbon in which an integrated gate provides strong carrier confinement and enables tunability of the carrier density over a wide range. We find a significantly enhanced thermoelectric power factor that can be understood by considering its behavior as a function of carrier density. We identify the underlying mechanisms for the power factor in the nanoribbon, which include quantum confinement, low scattering due to the absence of dopants, and, at low temperatures, a significant phonon-drag contribution. The measurements set a target for what may be achievable in ultrathin nanowires.

Evaluation of cell substrates for the production of biologicals: Revision of WHO recommendations. Report of the WHO Study Group on Cell Substrates for the Production of Biologicals, 22-23 April 2009, Bethesda, USA.

Evaluating cell substrates for producing vaccines and other biologicals is one of the critical aspects in assuring quality and safety of these products. As part of its mission in setting standards for biological products, WHO provides recommendations for manufacturing and evaluating biologicals. Regular updates of the guidance documents are important to manufacturers and regulators worldwide. WHO Expert Committee on Biological Standardization (ECBS) identified a need for revising the requirements for cell substrates (WHO TRS 878, annex 1). In response, WHO established a Study Group (SG) in 2006 that prepared an updated set of recommendations for using cell substrates for the production of biologicals. A summary of the proposed changes that the SG made in 2007 is available at WHO web site (http://www.who.int/biologicals/publications/meetings/areas/vaccines/cells/en/index.html). Draft revised recommendations were circulated to regulators, manufacturers and other experts for comments in April 2009. The SG held its third meeting on 22-23 April 2009 to review progress in the revision and to propose further improvements. In addition, the experts discussed the need for reference preparations, reference cell banks, and standardization of testing methodologies. The SG proposed clarifications of the rationale for in vivo testing as well as the potential for applying new methods for in vitro testing for detecting microbial agents. In line with this, WHO should conduct review of the current manufacturers' practice in using tests for microbial agents and interpreting these results. Additionally, WHO should take a lead in developing an International Standard for nucleic acid amplification test (NAT) for detecting mycoplasma contamination in cell substrates. WHO Collaborating Centers will lead this initiative, involving other relevant institutions in this area. Finally, advice on the replacement of the WHO Vero reference cell bank 10-87 with respect to the source of cells and re-characterization of the bank was provided. The intended use of the replacement cell bank would be the same as for the current cell bank, which is to serve as a source of well-characterized cells for establishing master cell banks for the production of biologicals. The SG will report outcomes of its discussion to the ECBS at its next meeting in October 2009 for further considerations and advice regarding the proposed course of action.

Challenges in the evaluation and licensing of new pneumococcal vaccines, 7-8 July 2008, Ottawa, Canada.

The introduction of seven valent pneumococcal conjugate vaccine (7vPnC) into immunization programmes has led to a significant reduction in invasive disease due to Streptococcus pneumoniae. New conjugate pneumococcal vaccine formulations containing additional serotypes are at advanced stages of clinical development and are expected to be available in the near future. There are also a number of on-going initiatives to facilitate the introduction of pneumococcal conjugate vaccines into the immunization programmes of developing countries. These initiatives are dependent upon the vaccines being satisfactorily licensed and subsequently pre-qualified by the WHO for use by UN agencies. Recommendations for the production and control of pneumococcal conjugate vaccines were established by WHO in 2003 and have served as a basis for national requirements for the evaluation and licensing of these products. Much progress has been made since that time and a consultation held in Ottawa, Canada, in July 2008 aimed to provide regulators and manufacturers with further guidance on the criteria for evaluating and licensing of new pneumococcal conjugate vaccines taking account of recent developments. The principal conclusion of the meeting was that the current WHO recommendations, in which the demonstration of immunological non-inferiority to the licensed 7vPnC vaccine is proposed as the main basis for approval, continue to provide a solid basis for the evaluation of pneumococcal conjugate vaccines and may be referred to when assessing new vaccines for licensure and pre-qualification. Uncertainties regarding serological criteria for assessing the efficacy of new conjugate vaccines against invasive pneumococcal disease were discussed in detail and proposals made for handling complex data. In particular, it was emphasized that all relevant immunological data should be taken into account when comparing new pneumococcal conjugate vaccines with licensed 7vPnC vaccine. These include the measurement of the total amount of anticapsular IgG as well as the demonstration of functionality of vaccine-induced antibodies, by verifying their ability to opsonize and promote the killing of pneumococcal serotypes, and the demonstration of immunological priming. It was agreed that new information on assay performance and on the effectiveness of currently licensed 7vPnC vaccine, as assessed in routine mass immunization programmes, should both be included in any update of the WHO recommendations. A detailed meeting report is available at the WHO web site for biologicals: http://www.who.int/biologicals/publications/meetings/areas/vaccines/pneumococcal/en/index.html.

Neurologic recovery after prolonged circulatory arrest in surgery for aortic dissection.

BACKGROUND: Brain injury manifested by subtle, transient neurologic and neuropsychologic dysfunctions occurs in about a quarter of patients who are subjected to periods of deep hypothermia and circulatory arrest (DHCA). We describe a patient who sustained minimal neurologic damage despite prolonged DHCA. METHODS: The patient was a previously healthy 62-year-old woman with acute type A aortic dissection that involved the ascending aorta. During surgery we established retrograde cerebral perfusion and DHCA to provide cerebral protection, and during the procedure the patient underwent 3 separate DHCA periods with a total circulatory arrest time of 91 minutes. Because of tubing damage, retrograde cerebral perfusion was not used during the final period (59 minutes). The patient's head was packed in ice to facilitate maintenance of brain hypothermia. Her average systemic temperature during the third period of circulatory arrest was 22.5 degrees C. RESULTS: Extensive neuropsychologic testing, which was performed to assess the patient's cognitive functions and abilities at 4-month follow-up, showed an absence of global cognitive decline and only a moderate impairment of attentional capacity. Overall cognitive functioning was within the normal range and did not interfere with everyday activities or quality of life. CONCLUSION: Although the total arrest time vastly exceeded the recommended safe period, our patient survived and sustained minimal neurologic damage. The combination of neuroprotective measures used may have contributed to this beneficial outcome.

BHK-21 cell culture rabies vaccine: immunogenicity of a candidate vaccine for humans.

Veterinary rabies vaccines produced in BHK-21/C13 permanent cell cultures have been used for a long period of time and have been proven as efficacious and safe. A candidate vaccine for human use (YU BHK Rabivak) was developed at the Pasteur Institute, Novi Sad, Serbia on the basis of the fixed rabies virus strain "L. Pasteur 2061/Vero 15 pas" using BHK 21/C13 as a cell substrate for vaccine production. To test the vaccine immunogenicity, a clinical trial was conducted involving 164 subjects between 18 and 60 years of age, immunized either with the YU BHK Rabivak vaccine candidate orwith a commercially available vaccine (Rabipur). Three groups of subjects were immunized with either vaccine by intramuscular administration in the deltoid region, following a pre-exposure regimen on days 0, 7 and 21, or the Essen or Zagreb post-exposure regimens. Rabies virus neutralizing antibodies (VNA) titres were determined by rapid fluorescent focus inhibition test (RFFIT) 21 and 30-45 days post vaccination. A protective titre of VNAs (>0.5 IU/ml) was found in all subjects vaccinated. Dynamics of the immune response showed that 96.4% of the subjects developed protective VNA titres after two doses, 99.3% after three doses and 100% after four and five doses of the candidate YU BHK Rabivak vaccine. There was a low reactogenicity without serious adverse events indicating a satisfactory safety profile in humans. Results obtained in this study indicate that BHK 21 cells offer the possibility of producing an efficacious and safe cell-culture rabies vaccine for humane use.

WHO Working Group meeting on standardization of acellular pertussis vaccines: Potency assay Beijing, China, 7-9 November 2007.

New acellular pertussis vaccines have recently been developed in China and India. In this context, potency testing and potential improvements of the protective animal models with inclusion of a reference material were recognized as critical issues in the quality assessment of acellular pertussis vaccines. One of these models, namely Modified Intracerebral Challenge Assay (MICA), is currently used as a potency assay in Japan, China and Korea. A collaborative study comparing whole cell references, a candidate acellular pertussis vaccine reference (JNIH-3) and various acellular pertussis products was undertaken in 2006. The results of the collaborative study showed that MICA worked reliably and gave consistent results between laboratories. JNIH-3 was found to give similar dose-response lines to a variety of acellular pertussis vaccines and DTaP formulations, irrespective of the differences in acellular pertussis components. The WHO Working Group agreed that proposal for establishing JNIH-3 as the First International Standard for acellular pertussis vaccine in MICA should be submitted to the Expert Committee on Biological Standardization at its meeting in October 2008.

WHO Study Group on cell substrates for production of biologicals, Geneva, Switzerland, 11-12 June 2007.

For many years, the World Health Organization (WHO) has provided global leadership in defining technical specifications for quality assurance and safety of biological medicines produced in cell substrates. Current WHO requirements for the use of animal cells as substrates for production of vaccines and other biologicals were adopted by the WHO Expert Committee on Biological Standardization in 1996 (WHO TRS 878). Since then, significant progress especially in the development of vaccines in novel continuous cell lines of mammalian origin as well as in insect cells has been made and consequently there is an increasing need for the re-evaluation of existing criteria for the acceptability of such cell lines. In addition there is also a need to consider new issues in cell substrate safety arising from these new cell types and developments in technology and scientific knowledge. In response to these demands, the WHO Study Group on Cell Substrates was formed in 2006 to initiate revision of WHO requirements and to address the need for further research in this area. At its second meeting on 11-12 June 2007, the Study Group reviewed scientific data that would form the basis for new recommendations and made a number of proposals for further investigations. The Study Group is working on the preparation of a revised WHO document, and a broad consultation with regulators, manufacturers, and other relevant parties is planned for 2008.

WHO working group on standardisation and control of acellular pertussis vaccines--report of a meeting held on 16-17 March 2006, St. Albans, United Kingdom.

This report reflects the discussion and conclusions of a WHO group of experts from national regulatory authorities, national control laboratories, vaccine industry and other relevant institutions involved in standardisation and control of acellular pertussis vaccines, held on 16-17 March 2006, in St. Albans, UK. Following previous discussions (Bethesda, 2000; Ferney-Voltaire, 2003; Geneva, 2005) and collection of relevant data for quality control, on the one hand, and clinical evaluation of acellular pertussis vaccines, on the other, this meeting was intended to review the scientific basis for the revision of WHO guidelines adopted in 1996 [Guidelines for the production and control of the acellular pertussis component of monovalent or combined vaccines. In: WHO Expert Committee on Biological Standardisation. Forty-seventh report. Geneva, World Health Organisation, 1998 (WHO Technical Report Series, No. 878), Annex 2]. The discussion on animal protection models, immunogenicity and toxicity testing was focused on three main aspects: value of the assay for the purpose of licensing and/or lot release; validity criteria and potential optimisation of the assays. The group agreed that establishment of JNIH-3 as a potential International Standard (IS) for modified intra-cerebral challenge assay should be under consideration. It was suggested that the inclusion of a reference vaccine, such as JNIH-3 in the intra-nasal challenge model could improve the standardisation of this assay. It was proposed that the development of stable reference vaccines for immunogenicity testing should be encouraged. Further collection of the data from the countries with established lot release of acellular pertussis vaccines will be undertaken to prepare a solid basis for recommendations on toxicity tests. In the context of recommendations for clinical assessment of new vaccines, the group emphasised the importance of comparability studies with antigens that have already undergone efficacy trials in the past. The outline for the section on clinical evaluation of acellular pertussis vaccines was presented and after the consultation further additions were made. Post-marketing surveillance was recognised as an important part of overall vaccine evaluation and a unique opportunity to understand vaccine performance in the population and to establish a link with quality control.

Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail.

Following platelet aggregation, integrin alpha(IIb)beta(3) becomes associated with the platelet cytoskeleton. The conserved NPLY sequence represents a potential beta-turn motif in the beta(3) cytoplasmic tail and has been suggested to mediate the interaction of beta(3) integrins with talin. In the present study, we performed a double mutation (N744Q/P745A) in the integrin beta(3) subunit to test the functional significance of this beta-turn motif. Chinese hamster ovary cells were co-transfected with cDNA constructs encoding mutant beta(3) and wild type alpha(IIb). Cells expressing either wild type (A5) or mutant (D4) alpha(IIb)beta(3) adhered to fibrinogen; however, as opposed to control A5 cells, adherent D4 cells failed to spread, form focal adhesions, or initiate protein tyrosine phosphorylation. To investigate the role of the NPLY motif in talin binding, we examined the ability of the mutant alpha(IIb)beta(3) to interact with talin in a solid phase binding assay. Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin. Additionally, purified talin failed to interact with peptides containing the AKWDTANNPLYK sequence indicating that the talin binding domain in the integrin beta(3) subunit does not reside in the NPLY motif. In contrast, specific binding of talin to peptides containing the membrane-proximal HDRKEFAKFEEERARAK sequence of the beta(3) cytoplasmic tail was observed, and this interaction was blocked by a recombinant protein fragment corresponding to the 47-kDa N-terminal head domain of talin (rTalin-N). In addition, RGD affinity purified platelet alpha(IIb)beta(3) bound dose-dependently to immobilized rTalin-N, indicating that an integrin-binding site is present in the talin N-terminal head domain. Collectively, these studies demonstrate that the NPLY beta-turn motif regulates post-ligand binding functions of alpha(IIb)beta(3) in a manner independent of talin interaction. Moreover, talin was shown to bind through its N-terminal head domain to the membrane-proximal sequence of the beta(3) cytoplasmic tail.

Alterations in optic canal following resection of nerve in rats.

The authors have studied relations between bony optic canal and nerve elements resulting from lesion in the optic nerve. Experimental animals were divided in two groups: young adults and old adult rats; the non-operated sides of rat skulls were used as a control group. At the same time in control samples the changes in osseous openings resulting from ageing were studied. Four months after surgery the animals were sacrificed, their skulls macerated and morphometric measurements taken by photometric and planimetric techniques. The obtained results show no significant difference in size of bony openings between the operated and non-operated sides. A significant difference has been found in the size of optic canal between the young and the old rats, regardless of the operated side. The authors have thus come to the conclusion that the size of bony canals in adult animals depends on their age in the first place. Narrowing of bony canaliculi, observed in the course of ageing, is most probably caused by primary osseous apposition, while atrophy of nerve elements may be considered as a secondary event.

Immunogenicity of BHK-rabies vaccine in human volunteers.

The production of rabies vaccine on baby hamster kidney (BHK-21) cells for human use is discussed. Long term experience in application of this vaccine in animals, without any noticeable complications and findings of inactivation of contaminated DNA from the cell substrate by beta-propiolactone have justified its recommendation for human use. Preliminary results of applying this simple, adjuvant vaccine in volunteers, confirmed its good tolerability and immunogenicity.

Direct binding of the platelet integrin alphaIIbbeta3 (GPIIb-IIIa) to talin. Evidence that interaction is mediated through the cytoplasmic domains of both alphaIIb and beta3.

As a consequence of platelet activation and fibrinogen binding, glycoprotein (GP)IIb-IIIa (integrin alphaIIbbeta3) becomes associated with the cytoskeleton. Although talin has been suggested to act as a linkage protein mediating the attachment of GPIIb-IIIa to actin filaments, direct binding of GPIIb-IIIa to this cytoskeletal protein has not been demonstrated. In the present study, we examined the interaction of GPIIb-IIIa with purified talin using a solid-phase binding assay. Soluble GPIIb-IIIa bound in a time- and dose-dependent manner to microtiter wells coated with talin but not with BSA. Time course studies demonstrated that steady-state binding was achieved after 4-5 h incubation at 37 degrees C. Binding isotherms with varying concentrations of GPIIb-IIIa showed that half-saturation binding was achieved at approximately 15 nM GPIIb-IIIa. At saturation, there was 211 +/- 8 fmol of GPIIb-IIIa bound per well containing 117 +/- 10 fmol of immobilized talin. Besides binding to immobilized talin, GPIIb-IIIa also bound to talin captured by the anti-talin monoclonal antibody 8d4. Moreover, the interaction of GPIIb-IIIa to 8d4-captured talin was blocked by mAb10B2, a monoclonal antibody raised against a synthetic peptide encompassing the entire cytoplasmic sequence of GPIIb. The interaction of talin with the cytoplasmic domain of GPIIb-IIIa was further investigated using peptide-coated wells. Purified talin was found to bind to both synthetic peptides corresponding to the cytoplasmic sequences of GPIIb (P2b) and GPIIIa (P3a). As expected, the binding of talin to P2b-coated wells was specifically blocked by mAb10B2. Thus, these results demonstrate direct binding of GPIIb-IIIa to talin and suggest a role of the cytoplasmic sequences of both GPIIb and GPIIIa in mediating this interaction.