RESUMEN
The paenilamicins are a group of hybrid non-ribosomal peptide-polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here, we have determined structures of the paenilamicin PamB2 stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site tRNAs. In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms utilized by P. larvae. We could further demonstrate that PamB2 interferes with the translocation of mRNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a new class of context-specific translocation inhibitors.
RESUMEN
The ribosome is a major target for clinically used antibiotics, but multidrug resistant pathogenic bacteria are making our current arsenal of antimicrobials obsolete. Here we present cryo-electron-microscopy structures of 17 distinct compounds from six different antibiotic classes bound to the bacterial ribosome at resolutions ranging from 1.6 to 2.2 Å. The improved resolution enables a precise description of antibiotic-ribosome interactions, encompassing solvent networks that mediate multiple additional interactions between the drugs and their target. Our results reveal a high structural conservation in the binding mode between antibiotics with the same scaffold, including ordered water molecules. Water molecules are visualized within the antibiotic binding sites that are preordered, become ordered in the presence of the drug and that are physically displaced on drug binding. Insight into RNA-ligand interactions will facilitate development of new antimicrobial agents, as well as other RNA-targeting therapies.
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Antibacterianos , Ribosomas , Antibacterianos/farmacología , Antibacterianos/química , Ribosomas/metabolismo , Bacterias/metabolismo , Sitios de Unión , ARN/metabolismoRESUMEN
The proline-rich antimicrobial peptide (PrAMP) drosocin is produced by Drosophila species to combat bacterial infection. Unlike many PrAMPs, drosocin is O-glycosylated at threonine 11, a post-translation modification that enhances its antimicrobial activity. Here we demonstrate that the O-glycosylation not only influences cellular uptake of the peptide but also interacts with its intracellular target, the ribosome. Cryogenic electron microscopy structures of glycosylated drosocin on the ribosome at 2.0-2.8-Å resolution reveal that the peptide interferes with translation termination by binding within the polypeptide exit tunnel and trapping RF1 on the ribosome, reminiscent of that reported for the PrAMP apidaecin. The glycosylation of drosocin enables multiple interactions with U2609 of the 23S rRNA, leading to conformational changes that break the canonical base pair with A752. Collectively, our study reveals novel molecular insights into the interaction of O-glycosylated drosocin with the ribosome, which provide a structural basis for future development of this class of antimicrobials.
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Antiinfecciosos , Glicopéptidos , Procesamiento Proteico-Postraduccional , Animales , Antibacterianos/química , Drosophila/metabolismo , Glicopéptidos/química , Glicosilación , Procesamiento Proteico-Postraduccional/genéticaRESUMEN
Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent.
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Mycobacterium tuberculosis , Myxococcales , Antibacterianos/química , Ribosomas/metabolismo , Biosíntesis de ProteínasRESUMEN
HflX is a ubiquitous bacterial GTPase that splits and recycles stressed ribosomes. In addition to HflX, Listeria monocytogenes contains a second HflX homolog, HflXr. Unlike HflX, HflXr confers resistance to macrolide and lincosamide antibiotics by an experimentally unexplored mechanism. Here, we have determined cryo-EM structures of L. monocytogenes HflXr-50S and HflX-50S complexes as well as L. monocytogenes 70S ribosomes in the presence and absence of the lincosamide lincomycin. While the overall geometry of HflXr on the 50S subunit is similar to that of HflX, a loop within the N-terminal domain of HflXr, which is two amino acids longer than in HflX, reaches deeper into the peptidyltransferase center. Moreover, unlike HflX, the binding of HflXr induces conformational changes within adjacent rRNA nucleotides that would be incompatible with drug binding. These findings suggest that HflXr confers resistance using an allosteric ribosome protection mechanism, rather than by simply splitting and recycling antibiotic-stalled ribosomes.
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Listeria monocytogenes , Listeria monocytogenes/genética , Proteínas de Unión al GTP/genética , Farmacorresistencia Microbiana , Ribosomas/genética , Ribosomas/metabolismo , Lincosamidas/farmacología , Antibacterianos/farmacología , Antibacterianos/metabolismoRESUMEN
Argyrins are a family of naturally produced octapeptides that display promising antimicrobial activity against Pseudomonas aeruginosa. Argyrin B (ArgB) has been shown to interact with an elongated form of the translation elongation factor G (EF-G), leading to the suggestion that argyrins inhibit protein synthesis by interfering with EF-G binding to the ribosome. Here, using a combination of cryo-electron microscopy (cryo-EM) and single-molecule fluorescence resonance energy transfer (smFRET), we demonstrate that rather than interfering with ribosome binding, ArgB rapidly and specifically binds EF-G on the ribosome to inhibit intermediate steps of the translocation mechanism. Our data support that ArgB inhibits conformational changes within EF-G after GTP hydrolysis required for translocation and factor dissociation, analogous to the mechanism of fusidic acid, a chemically distinct antibiotic that binds a different region of EF-G. These findings shed light on the mechanism of action of the argyrin-class antibiotics on protein synthesis as well as the nature and importance of rate-limiting, intramolecular conformational events within the EF-G-bound ribosome during late-steps of translocation.
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Antibacterianos , Factor G de Elongación Peptídica , Antibacterianos/metabolismo , Ácido Fusídico/farmacología , Humanos , Oligopéptidos , Factor G de Elongación Peptídica/metabolismo , Ribosomas/metabolismo , Translocación GenéticaRESUMEN
Paenilamicins are a group of complex polycationic peptide secondary metabolites with antibacterial and antifungal activities produced by the devastating honey bee brood pathogen Paenibacillus larvae causing the lethal brood disease American Foulbrood (AFB). Here, we report the convergent total synthesis and structural revision of paenilamicin B2. Specific stereoisomers of paenilamicin B2 were synthesized for unambiguous confirmation of the natural product structure and for evaluation of biological activities. These studies revealed the N-terminal fragment of paenilamicin as an important pharmacophore. Infection assays using bee larvae and the insect pathogen Bacillus thuringiensis demonstrated that paenilamicins outcompete bacterial competitors in the ecological niche of P. larvae. Finally, we show first data that classifies paenilamicins as potential ribosome inhibitors. Hence, our synthesis route is a further step for understanding the pathogenicity of P. larvae and for thorough structure-activity-relationship as well as mode-of-action studies in the near future.
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Paenibacillus larvaeRESUMEN
Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Cryo-EM structural analysis showed that the macrolide telithromycin binds in the tunnel of the engineered eukaryotic ribosome. Genome-wide analysis of cellular translation and biochemical studies demonstrated that the drug inhibits eukaryotic translation by preferentially stalling ribosomes at distinct sequence motifs. Context-specific action markedly depends on the macrolide structure. Eliminating macrolide-arrest motifs from a protein renders its translation macrolide-tolerant. Our data illuminate the prospects of adapting macrolides for protein-selective translation inhibition in eukaryotic cells.
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Antibacterianos/farmacología , Macrólidos/farmacología , Ribosomas/efectos de los fármacos , Antibacterianos/química , Sitios de Unión , Microscopía por Crioelectrón , Células Eucariotas/efectos de los fármacos , Células Eucariotas/metabolismo , Humanos , Macrólidos/química , Modelos Moleculares , Mutación , Unión Proteica , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/química , Inhibidores de la Síntesis de la Proteína/farmacología , ARN de Hongos/genética , ARN Ribosómico/genética , Ribosomas/genética , Ribosomas/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/biosíntesis , Relación Estructura-ActividadRESUMEN
INTRODUCTION: Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC. METHODS: Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy. RESULTS: One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%. CONCLUSIONS: Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.
RESUMEN
Soft tissue defects in the genito-perineal region are predominantly because of trauma, infections, neoplasms or iatrogenic causes. As a result of the region's urological, reproductive and gastrointestinal function, defects in this area may cause devastating physical and psychological consequences as well as diminished sexual functioning. The purpose of this study was to examine the efficacy of implementing a medial thigh lift for defect coverage in the perineal region. A retrospective analysis of all medial thigh lift procedures for defect coverage in the genito-perineal region between November 2010 and March 2015 was conducted at three institutions. Ten consecutive patients underwent a medial thigh lift for defect coverage in the genito-perineal region. Nine patients were male, and one was female. The causative factors were Fournier's gangrene in eight patients, one patient had a straddle injury, and one suffered from extramammary Paget's disease. The mean follow-up time was 19·8 months. The average total defect size was 11·1 × 11 cm (length × width). The medial thigh lift procedure is a safe, technically easy and reliable technique with discrete scars. Outstanding aesthetic and functional outcomes result in a high rate of patient satisfaction. Through immediate wound closure, a reduction of recovery time can be achieved.
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Enfermedades de los Genitales Femeninos/cirugía , Genitales/cirugía , Perineo/cirugía , Procedimientos de Cirugía Plástica/métodos , Colgajos Quirúrgicos/cirugía , Muslo/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Gangrena de Fournier/cirugía , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Paget Extramamaria/cirugía , Satisfacción del Paciente , Estudios RetrospectivosRESUMEN
Moyamoya disease is an extremely rare cerebrovascular condition that predisposes affected patients to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches. To our knowledge, this is the first report of a lethal complication due to moyamoya disease after septorhinoplasty. A 25-year-old female Caucasian patient presented to our outpatient clinic with impaired nasal breathing for septorhinoplasty. Regrettably the patient died 6 days postoperatively due to progressive infarct series affecting all major cerebral vessels. Despite a thorough knowledge of possible local complications after septorhinoplasty, it is of utmost importance to consider rare general complications like moyamoya disease. Although cerebral infarctions are very rare in young people, it is crucial to identify and correctly interpret underlying typical symptoms.
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Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/terapia , Neoplasias Faciales/diagnóstico , Neoplasias Faciales/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Carcinoma Basocelular/patología , Neoplasias Faciales/patología , Humanos , Invasividad Neoplásica , Piel/patología , Neoplasias Cutáneas/patología , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/patología , Úlcera Cutánea/terapiaRESUMEN
Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.
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Anomalías Múltiples/genética , Ensamble y Desensamble de Cromatina/genética , Cara/anomalías , Deformidades Congénitas del Pie/genética , Deformidades Congénitas de la Mano/genética , Hipotricosis/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Eliminación de Secuencia/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Proteínas Portadoras/genética , Niño , Preescolar , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Exoma/genética , Cara/patología , Facies , Femenino , Deformidades Congénitas del Pie/patología , Deformidades Congénitas de la Mano/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipotricosis/patología , Lactante , Recién Nacido , Discapacidad Intelectual/patología , Cariotipificación , Masculino , Micrognatismo/patología , Mutación Missense , Cuello/patología , Proteínas Represoras , Proteína SMARCB1 , Factores de Transcripción/genéticaRESUMEN
We present two previously unreported and unrelated female patients, one with the tentative diagnosis of acromegaloid facial appearance (AFA), the other with the tentative diagnosis of hypertrichosis with acromegaloid facial appearance (HAFF) with or without gingival hyperplasia. Main clinical features of HAFF were generalized hypertrichosis terminalis and coarse facial features. In both patients, pregnancy was complicated by polyhydramnios, and both had hyperbilirubinemia and persistent fetal circulation. Development was normal in one patient and slightly delayed in the other. At 13 years, both had round faces with full cheeks, thick scalp hair and eyebrows, a low frontal hairline, hirsutism, hyperextensible joints and deep palmar creases. One of them additionally showed gingival hypertrophy and epicanthus, the other one was macrocephalic at birth and at the age of 13 years and suffered from repeated swelling of the soft tissue. Array analysis excluded a 17q24.2-q24.3 microdeletion, which has been reported in patients with hypertrichosis terminalis with or without gingival hyperplasia. Sequencing of the mutational hotspots of the ABCC9 gene revealed two different de novo missense mutations in the two patients. Recently, identical mutations have been found recurrently in patients with Cantú syndrome. Therefore, we propose that ABCC9 mutations lead to a spectrum of phenotypes formerly known as Cantú syndrome, HAFF and AFA, which may not be clearly distinguishable by clinical criteria, and that all patients with clinical signs belonging to this spectrum should be revisited and offered ABCC9 mutation analysis.
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Transportadoras de Casetes de Unión a ATP/genética , Anomalías Múltiples/diagnóstico , Acromegalia/diagnóstico , Cardiomegalia/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Hipertricosis/diagnóstico , Deformidades Congénitas de las Extremidades/diagnóstico , Osteocondrodisplasias/diagnóstico , Canales de Potasio de Rectificación Interna/genética , Receptores de Droga/genética , Anomalías Múltiples/genética , Acromegalia/genética , Adolescente , Cardiomegalia/genética , Análisis Mutacional de ADN , Facies , Femenino , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Hipertricosis/genética , Deformidades Congénitas de las Extremidades/genética , Técnicas de Diagnóstico Molecular , Mutación Missense , Osteocondrodisplasias/genética , Fenotipo , Receptores de SulfonilureasRESUMEN
PURPOSE: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. PATIENTS AND METHODS: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. RESULTS: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. CONCLUSION: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
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Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias/epidemiología , Neoplasias/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Mutación , Países Bajos/epidemiología , Proteínas Nucleares/genética , Sistema de Registros , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Reconstructed mechanically stressed zones of the lower extremity frequently suffer from problems such as hyperkeratotic edges or chronic ulcerations in the transition zone between conventional thigh skin grafts and normal skin. Defect coverage with skin grafts harvested from the instep region and placed on muscle flaps is not yet an established alternative. METHODS: This is a retrospective study of a series of 12 clinical applications of soft tissue reconstruction at mechanically exposed zones of the lower extremity. Locally transposed or transplanted muscle flaps were covered with meshed instep skin instead of meshed thigh skin for the purpose to gain a superior stable skin surface and transition zones adjacent to normal skin. RESULTS: There is no ulceration found at follow-up from 6 to 72 months. Only one case presented with delayed graft take. Different thicknesses of the corneal layers of the healed instep versus thigh skin grafts were verified histologically. Instep skin grafts showed substantial durability as well as advantageous aesthetic appearance with respect to texture and coloring. All donor sites healed without notable scars or sensitivity disorders. CONCLUSIONS: The instep split skin graft is particularly well suited for defect coverage of muscle flaps transposed or transplanted to mechanically stressed zones of the foot or lower leg. The paramount advantage of transplanted instep skin as compared to thigh skin is given by the feasibility to create a durable graft with a thick horny layer and a stable transition zone at its periphery that is bordering normal skin.
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Muñones de Amputación/cirugía , Extremidad Inferior/cirugía , Procedimientos de Cirugía Plástica/métodos , Trasplante de Piel , Piel/patología , Colgajos Quirúrgicos , Heridas y Lesiones/cirugía , Adolescente , Adulto , Amputación Quirúrgica , Femenino , Humanos , Extremidad Inferior/lesiones , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.
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Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Heterocigoto , Mutación , Adulto , Edad de Inicio , Anciano , Neoplasias de la Mama/epidemiología , Etnicidad/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Persona de Mediana Edad , Linaje , Fenotipo , Factores de RiesgoRESUMEN
Standardized psychological assessment of candidates for reconstructive hand transplantation (RHT) is a new approach in transplantation medicine. Currently, international guidelines and standardized criteria for the evaluation are not established. Patients suffering from the loss of a hand or an upper extremity have to cope with multiple challenges. For a selected group of patients, RHT represents an option for restoring natural function and for regaining daily living independence. The identification of at-risk patients and those requiring ongoing counseling due to poor coping or limited psychological resources are the primary focus of the psychological assessment. We have developed the 'Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT-PSP)' which utilizes a semi-structured interview and standardized psychological screening procedures and continuous follow-up ratings. Between January 2011 and October 2011, four candidates were evaluated using the iRT-PSP. Psychological impairments including social withdrawal, embarrassment, reduced self-esteem, and a depressive coping style were identified and poor quality of life was reported. The motivation for transplantation was diverse, depending on many factors such as bi- or unilateral impairment, native or accidental loss of hand, and social integration.