Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6.

Histone deacetylase 6 (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.

Crystal structure of histone deacetylase 6 complexed with (R)-lipoic acid, an essential cofactor in central carbon metabolism.

The enzyme cofactor (R)-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of (R)-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of (R)-lipoic acid, (R)-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the complex between (R)-dihydrolipoic acid and HDAC6 catalytic domain 2 from Danio rerio, and we report a dissociation constant (KD) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn2+ coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of (R)-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn2+ ion and the aromatic crevice in the active site of HDAC6.

Structure and Function of Kdac1, a Class II Deacetylase from the Multidrug-Resistant Pathogen Acinetobacter baumannii.

Proteomics studies indicate that 10% of proteins in the opportunistic pathogen Acinetobacter baumannii are acetylated, suggesting that lysine acetyltransferases and deacetylases function to maintain and regulate a robust bacterial acetylome. As the first step in exploring these fascinating prokaryotic enzymes, we now report the preparation and characterization of the lysine deacetylase Kdac1. We show that Kdac1 catalyzes the deacetylation of free acetyllysine and acetyllysine tetrapeptide assay substrates, and we also report the X-ray crystal structures of unliganded Kdac1 as well as its complex with the hydroxamate inhibitor Citarinostat. Kdac1 is a tetramer in solution and in the crystal; the crystal structure reveals that the L1 loop functions to stabilize quaternary structure, forming inter-subunit hydrogen bonds and salt bridges around a central arginine residue (R30). Surprisingly, the L1 loop partially blocks entry to the active site, but it is sufficiently flexible to allow for the binding of two Citarinostat molecules in the active site. The L12 loop is also important for maintaining quaternary structure; here, a conserved arginine (R278) accepts hydrogen bonds from the backbone carbonyl groups of residues in an adjacent monomer. Structural comparisons with two other prokaryotic lysine deacetylases reveal conserved residues in the L1 and L12 loops that similarly support tetramer assembly. These studies provide a structural foundation for understanding enzymes that regulate protein function in bacteria through reversible lysine acetylation, serving as a first step in the exploration of these enzymes as possible targets for the development of new antibiotics.

Crystal Structure of Histone Deacetylase 6 Complexed with ( R )-Lipoic Acid, an Essential Cofactor in Central Carbon Metabolism.

The enzyme cofactor ( R )-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of ( R )-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of ( R )-lipoic acid, ( R )-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the HDAC6-( R )-dihydrolipoic acid complex, and we report a dissociation constant (K D ) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn 2+ coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of ( R )-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn 2+ ion and the aromatic crevice in the active site of HDAC6.

Macrocyclic Octapeptide Binding and Inferences on Protein Substrate Binding to Histone Deacetylase 6.

Histone deacetylases (HDACs) are essential for the regulation of myriad biological processes, and their aberrant function is implicated in cancer, neurodegeneration, and other diseases. The cytosolic isozyme HDAC6 is unique among the greater family of deacetylases in that it contains two catalytic domains, CD1 and CD2. HDAC6 CD2 is responsible for tubulin deacetylase and tau deacetylase activities, inhibition of which is a key goal as new therapeutic approaches are explored. Of particular interest as HDAC inhibitors are naturally occurring cyclic tetrapeptides such as Trapoxin A or HC Toxin, or the cyclic depsipeptides Largazole and Romidepsin. Even more intriguing are larger, computationally designed macrocyclic peptide inhibitors. Here, we report the 2.0 Å resolution crystal structure of HDAC6 CD2 complexed with macrocyclic octapeptide 1. Comparison with the previously reported structure of the complex with macrocyclic octapeptide 2 reveals that a potent thiolate-zinc interaction made by the unnatural amino acid (S)-2-amino-7-sulfanylheptanoic acid contributes to nanomolar inhibitory potency for each inhibitor. Apart from this zinc-binding residue, octapeptides adopt strikingly different overall conformations and make few direct hydrogen bonds with the protein. Intermolecular interactions are dominated by water-mediated hydrogen bonds; in essence, water molecules appear to cushion the enzyme-octapeptide interface. In view of the broad specificity observed for protein substrates of HDAC6 CD2, we suggest that the binding of macrocyclic octapeptides may mimic certain features of the binding of macromolecular protein substrates.

Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia.

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.

Aromatic Ring Fluorination Patterns Modulate Inhibitory Potency of Fluorophenylhydroxamates Complexed with Histone Deacetylase 6.

Bavarostat (EKZ-001) is a selective inhibitor of histone deacetylase 6 (HDAC6) that contains a meta-fluorophenylhydroxamate Zn2+-binding group. The recently determined crystal structure of its complex with HDAC6 from Danio rerio (zebrafish) revealed that the meta-fluoro substituent binds exclusively in an aromatic crevice defined by F583 and F643 rather than being oriented out toward solvent. To explore the binding of inhibitor C-F groups in this fluorophilic crevice, we now report a series of 10 simple fluorophenylhydroxamates bearing one or more fluorine atoms with different substitution patterns. Inhibitory potencies against human and zebrafish HDAC6 range widely from 121 to >30,000 nM. The best inhibitory potency is measured for meta-difluorophenylhydroxamate (5) with IC50 = 121 nM against human HDAC6; the worst inhibitory potencies are measured for ortho-fluorophenylhydroxamate (1) as well as fluorophenylhydroxamates 4, 7, 9, and 10, although there are some variations in activity trends against human and zebrafish HDAC6. These studies show that aromatic ring fluorination at the meta position(s) does not improve inhibitory activity against human HDAC6 relative to the nonfluorinated parent compound phenylhydroxamate (IC50 = 120 nM), but meta-fluorination does not seriously compromise inhibitory activity either. Crystal structures of selected zebrafish HDAC6-fluorophenylhydroxamate complexes reveal that the fluoroaromatic ring is uniformly accommodated in the F583-F643 aromatic crevice, so ring fluorination does not perturb the inhibitor binding conformation. However, hydroxamate-Zn2+ coordination is bidentate for some inhibitors and monodentate for others. These studies will inform design strategies underlying the design of 18F-labeled HDAC6 inhibitors intended for positron emission tomography.

Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.

Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC50 values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain.

Adherencia al tratamiento farmacológico del tabaquismo y factores predictores en un escenario no financiado / Adherence to pharmacological treatment of smoking and predictive factors in an unfunded scenario

Antecedentes y objetivo. Las intervenciones de des habituación basadas en el asesoramiento psicológicoy tratamiento farmacológico han demostrado ser las más eficaces para abandonar el tabaco. La terapia sustitutiva con nicotina, bupropión y vareniclina son lostratamientos farmacológicos de primera elección que han demostrado una mayor seguridad y eficacia, triplicando las posibilidades de cesación tabáquica. Sinembargo, en un escenario no financiado, el grado de adherencia a estos fármacos es bajo. Por todo ello, el objetivo del estudio es analizar la adherencia a dichosfármacos y los factores predictores de ella.Pacientes y métodos. Estudio transversal de una cohorte de 660 fumadores reclutados entre 2013 y 2017en un área sanitaria de Galicia incluidos en programas de deshabituación tabáquica. Se analizan las características de los pacientes y el porcentaje de adherenciaa los fármacos de cesación tabáquica.Resultados.Un 35% de los fumadores que acuden aconsultas de deshabituación tabáquica en nuestra áreasanitaria no retiran el fármaco previamente prescrito.Son factores predictores de adherencia a fármacos dedeshabituación tabáquica: estar en fase de preparación OR: 4,06 IC95% (1,58-6,39) p=0,003; realizarintentos previos de abandono en el último año OR:5,3 IC95% (1,3-7,1) p=0,016; uso de fármacos pre-viamente OR: 4,16 IC95 (1,7-6,2) p=0,0003; o elnúmero de consultas: OR: 1,6 IC95% (1,26-2,05)p=0,000.Conclusiones.La adherencia al tratamiento del tabaquismo es mejorable en nuestra área sanitaria. Lafase de abandono del fumador, los intentos previoscon tratamientos farmacológicos y la intensidad de la intervención son factores que se asocian a su implementación. (AU)

Backgrounds and objective. The smoking cessation interventions based on psychological advice and drugtreatment have been shown to be the most effectiveto stop smoking. Nicotine replacement therapy, bu-propion and varenicline are the drug treatments of first choice that have demonstrated better safety andefficacy, tripling the possibilities of smoking cessation.However, in an unfinanced setting, the degree of ad-herence to these drugs is low. Therefore, the objectiveof the study is to analyze adherence to said drugs andthe predictive factors of it.Patients and methods.Cross-sectional study of acohort of 660 smokers recruited between 2013 and2017 in a health care area of Galicia enrolled in smo-king cessation programs. The characteristics of thepatients and percentage of adherence to the smokingcessation drugs are analyzed.Results.A total of 35% of smokers who come to thesmoking cessation consultations in our health carearea do not obtain the previously prescribed drug.Predictive factors of adherence to smoking cessationdrugs are: being in the preparation phase: OR: 4.0695% CI (1.58-6.39) p=0.003, having made previousattempts to stop smoking in the last year: OR: 5.395% CI (1.3-7.1) p=0.016, previous use of drug: OR:4.16 95% CI (1.7-6.2) p=0.0003 or number of con-sultations: OR: 1.6 95% CI (1.26-2.05) p=0.000.Conclusions.Adherence to treatment of smoking ces-sation can be improved in our health care area. Thecessation phase of the smoker, previous attempts withdrug treatments and intensity of the intervention arethe factors associated to its implementation. (AU)

Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype.

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (Ki = 0.7 nM) and inhibits the enzyme function (IC50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn2+ and, uniquely, making a never seen before direct hydrogen bond with the Zn2+ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.

Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders.

Cornelia de Lange Syndrome (CdLS) and associated spectrum disorders are characterized by one or more congenital anomalies including distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms. The molecular genetic basis of CdLS is linked to defects in cohesin, a protein complex that functions in sister chromatid cohesion, chromatin organization, and transcriptional regulation. Histone deacetylase 8 (HDAC8) plays an important role in cohesin function by catalyzing the deacetylation of SMC3, which is required for efficient recycling of the cohesin complex. Missense mutations in HDAC8 have been identified in children diagnosed with CdLS spectrum disorders, and here we outline structure-function relationships for four of these mutations. Specifically, we report the 1.50 Å-resolution structure of the I45T HDAC8-suberoylanilide hydroxamic acid complex, the 1.84 Å-resolution structure of E66D/Y306F HDAC8 complexed with a peptide assay substrate, and the 2.40 Å-resolution structure of G320R HDAC8 complexed with the inhibitor M344. Additionally, we present a computationally generated model of D176G HDAC8. These structures illuminate new structure-function relationships for HDAC8 and highlight the importance of long-range interactions in the protein scaffold that can influence catalytic function.

An improved method for the heterologous production of soluble human ribosomal proteins in Escherichia coli.

Human ribosomal proteins play important structural and functional roles in the ribosome and in protein synthesis. An efficient method to recombinantly produce and purify these proteins would enable their full characterisation. However, the production of human ribosomal proteins can be challenging. The only published method about the recombinant production of human ribosomal proteins involved the recovery of proteins from inclusion bodies, a process that is tedious and may lead to significant loss of yield. Herein, we explored the use of different Escherichia coli competent cells and fusion protein tags for the recombinant production of human ribosomal proteins. We found that, by using thioredoxin as a fusion protein, soluble ribosomal protein could be obtained directly from cell lysates, thus leading to an improved method to recombinantly produce these proteins.

[Acetabular revision at 96 years old. Is the age a limiting factor in revision surgery for hip replacement?] / Revisión acetabular a los 96 años. ¿Es la edad un factor limitante en la cirugía de revisión de prótesis de cadera?

This is a case report of a 96 year old woman with pain and functional impotence in her left hip after fall. X rays were performed and loosening of the acetabular component was appreciated. After discussion of treatment options, it was decided to cement an acetabular component for a double mobility head. There was a high rate of medical and surgical complications in revision of hip arthroplasty in elderly patients. However, it can also offer important benefits in terms of independence and quality of life and even increase life expectancy in patients with less comorbidity. In our case after six months of follow-up the patient was able to walk alone using a walker. In the literature review, age does not appear as a limit for the surgical indication. Preoperative medical optimization of the patient as well as shorter operative time and blood loss, are important factors for good results of these cases.

Se presenta el caso clínico de una paciente de 96 años con dolor e impotencia funcional en cadera izquierda tras caída. En las radiografías se aprecia un aflojamiento del componente acetabular. Tras la discusión de las opciones de tratamiento se decide intervenirla colocando un cotilo cementado para cabeza de doble movilidad. La revisión de artroplastía en pacientes ancianos tiene un riesgo considerable. No obstante, también puede ofrecer importantes beneficios en términos de independencia y calidad de vida e incluso aumentar la esperanza de vida en aquellos pacientes con menos comorbilidad. En nuestro caso tras seis meses de seguimiento la paciente es capaz de deambular de forma autónoma con andador. En la revisión bibliográfica la edad no figura como límite para la indicación quirúrgica. Una adecuada optimización preoperatoria del paciente así como una cirugía con el menor tiempo quirúrgico y sangrado son factores destacados para la buena evolución de estos casos.

Revisión acetabular a los 96 años. ¿Es la edad un factor limitante en la cirugía de revisión de prótesis de cadera? / Acetabular revisión at 96 yeras old. Is the age a limiting factor in revision surgery for hip replacement?

Resumen: Se presenta el caso clínico de una paciente de 96 años con dolor e impotencia funcional en cadera izquierda tras caída. En las radiografías se aprecia un aflojamiento del componente acetabular. Tras la discusión de las opciones de tratamiento se decide intervenirla colocando un cotilo cementado para cabeza de doble movilidad. La revisión de artroplastía en pacientes ancianos tiene un riesgo considerable. No obstante, también puede ofrecer importantes beneficios en términos de independencia y calidad de vida e incluso aumentar la esperanza de vida en aquellos pacientes con menos comorbilidad. En nuestro caso tras seis meses de seguimiento la paciente es capaz de deambular de forma autónoma con andador. En la revisión bibliográfica la edad no Figura como límite para la indicación quirúrgica. Una adecuada optimización preoperatoria del paciente así como una cirugía con el menor tiempo quirúrgico y sangrado son factores destacados para la buena evolución de estos casos.

Abstract: This is a case report of a 96 year old woman with pain and functional impotence in her left hip after fall. X rays were performed and loosening of the acetabular component was appreciated. After discussion of treatment options, it was decided to cement an acetabular component for a double mobility head. There was a high rate of medical and surgical complications in revision of hip arthroplasty in elderly patients. However, it can also offer important benefits in terms of independence and quality of life and even increase life expectancy in patients with less comorbidity. In our case after six months of follow-up the patient was able to walk alone using a walker. In the literature review, age does not appear as a limit for the surgical indication. Preoperative medical optimization of the patient as well as shorter operative time and blood loss, are important factors for good results of these cases.

Measurements of metastatic renal cell tumours as determined by diffusion weighted imaging or computed tomography are in close agreement, a pilot study.

BACKGROUND: Diffusion weighted magnetic resonance imaging (DWI) provides both functional and anatomical information regarding tumours but can also be used for tumour detection. Today, tumour treatment response in clinical trials is mainly assessed on Computed Tomography (CT) using established criteria. Despite availability of dedicated software, CT still requires significant manual work for selection and measurement in treatment response evaluation of solid tumours. PURPOSE: To compare the maximum diameter of tumour lesions on CT with the corresponding measurements on diffusion weighted images. MATERIALS AND METHODS: In this prospective cohort, metastatic lesions were identified on CT and on DWI in five patients with metastatic renal cell carcinoma before and after three months of treatment with pazopanib. Two radiologists independently measured the same lesions on axial CT images and separately also on axial DWI images. The measurements were compared between CT and DWI with respect to the number of target lesions measured, size of the lesions, size reduction due to treatment and the inter-observer variability. Wilcoxon signed rank test, linear regression and Bland-Altman plots were used for statistical analyses. RESULTS: In this pilot study, there was no significant inter-observer variability in terms of numbers of lesion selected between CT and DWI. A significant reduction of lesion size was observed both for CT and DWI when post-treatment scans were compared to pre-treatment scans. There was no significant difference in measurement of lesion size on both pre- and post treatment scans between CT and DWI (p = 0.099 and p = 0.388 respectively). CONCLUSION: Measurement of the size of metastatic lesions on the basis of axial DWI images are in close agreement with measurement based on conventional axial CT images, the most often employed approach in clinical trials today. The results in this pilot study can be used to estimate sufficient sample size in a larger trial with adequate power, were the results can be confirmed in a wider range of cancers other than renal cell carcinoma.

Estudio prospectivo aleatorizado sobre la influencia del bloqueo distal del clavo Gamma 3 en el tratamiento de las fracturas pertrocantéreas de fémur / Randomized prospective study on the influence distal block and Gamma 3 nail on the treatment of intertrochanteric fractures of femur

Objetivo. El propósito de este estudio es valorar la necesidad de bloquear distalmente los clavos Gamma 3 (Stryker. Mahwah, New Jersey. USA) en fracturas pertrocantéreas de fémur 31-A1 y 31-A2 de la AO. Material y métodos. Desde junio de 2011 hasta enero de 2013 se recoge una muestra formada por 177 pacientes con fractura pertrocantérea de fémur tratados en nuestro centro mediante osteosíntesis con clavo Gamma 3 estándar. Es un estudio prospectivo y aleatorizado según el año de nacimiento de cada paciente, par con bloqueo o impar sin bloqueo distal del clavo, formando dos grupos de 90 y 87 fracturas respectivamente. Resultados. En los pacientes intervenidos mediante clavo con bloqueo distal se observó una mayor incidencia de complicaciones médicas, una menor incidencia de complicaciones biomecánicas y un aumento en el colapso del foco de fractura en comparación con el grupo control, siendo estas diferencias estadísticamente significativas (p < 0,05). También se observa en el grupo con bloqueo distal un mayor requerimiento transfusional y una mayor tasa de éxitus presentando diferencias estadísticamente significativas (p < 0,05), sin embargo esta significación desaparece al ajustar los resultados por otras características relacionadas con los pacientes. Conclusiones. Basándonos en los resultados hallados en este trabajo, el uso del tornillo de bloqueo distal en los clavos Gamma 3 debe restringirse a fracturas pertrocantéreas inestables tras reducción donde se requiera una estabilidad adicional al clavo intramedular, pudiendo así disminuir el riesgo de complicaciones derivadas de su uso (AU)

Objective. The purpose of this study is to assess the need to lock the Gamma 3 nail (Stryker, Mahwah New Jersey USA) distally for intertrochanteric fractures of femur 31-A1 and 31-A2 of the AO. Material and methods. Details were recorded on a sample of 177 patients with intertrochanteric femoral fractures treated in our hospital by a standard Gamma nail between June 2011 and January 2013. A prospective study was conducted by randomizing patients by year of birth, even numbers with, or odd number without, distal locking, forming two groups of 90 and 87 fractures, respectively. Results. The patients treated with a distal locking nail had an increased incidence of medical complications, a lower incidence of biomechanical complications, and an increase in the fracture collapse compared with the control group, with statistical significance (p < 0 .05). It is also observed in the group with distal locking increased transfusion requirement and a higher death rate, with statistically significant differences (p < 0 .05), but this significance disappears when adjusting for other patient-related characteristics. Conclusions. Based on the results found in this work, the use of distal locking screw in the Gamma 3 nails should be restricted to unstable trochanteric fractures after reduction where additional stability to the intramedullary nail is required, and may decrease the risk of complications from use (AU)

[Randomized prospective study on the influence distal block and Gamma 3 nail on the treatment of intertrochanteric fractures of femur]. / Estudio prospectivo aleatorizado sobre la influencia del bloqueo distal del clavo Gamma 3 en el tratamiento de las fracturas pertrocantéreas de fémur.

OBJECTIVE: The purpose of this study is to assess the need to lock the Gamma 3 nail (Stryker, Mahwah New Jersey USA) distally for intertrochanteric fractures of femur 31-A1 and 31-A2 of the AO. MATERIAL AND METHODS: Details were recorded on a sample of 177 patients with intertrochanteric femoral fractures treated in our hospital by a standard Gamma nail between June 2011 and January 2013. A prospective study was conducted by randomizing patients by year of birth, even numbers with, or odd number without, distal locking, forming two groups of 90 and 87 fractures, respectively. RESULTS: The patients treated with a distal locking nail had an increased incidence of medical complications, a lower incidence of biomechanical complications, and an increase in the fracture collapse compared with the control group, with statistical significance (p < 0.05). It is also observed in the group with distal locking increased transfusion requirement and a higher death rate, with statistically significant differences (p < 0.05), but this significance disappears when adjusting for other patient-related characteristics. CONCLUSIONS: Based on the results found in this work, the use of distal locking screw in the Gamma 3 nails should be restricted to unstable trochanteric fractures after reduction where additional stability to the intramedullary nail is required, and may decrease the risk of complications from use.

A novel controlled drug delivery system based on pH-responsive hydrogels included in soft gelatin capsules.

pH-sensitive hydrogels based on methacrylic acid (MAA) and poly(ethylene glycol) macromonomer (PEGMEMA) entrapping diltiazem hydrochloride (DIL·HCl) were synthesized inside soft gelatin capsules for use as a new dosage form for oral drug administration. Different monomer compositions were used to evaluate their swelling and release behavior in two media: at low pH, simulating the acid pH of the stomach, and at pH 7, simulating the higher pH environment of the intestine. Both the swelling process and DIL·HCl release strongly depended on pH and monomer composition. Hydrogels with intermediate compositions showed diminished DIL·HCl release at pH 1.2. This fact was related to the formation of an impermeable outer skin, observed by magnetic resonance imaging (MRI). At pH 7 similar shaped release profiles were found for the four hydrogel compositions under investigation. At this neutral pH slow protonation of the carboxylate groups of MAA led to a swelling front and a dry core, also observed by MRI. As a consequence of this anomalous swelling, release curves exhibited a long period of zero order kinetics. This shows that the system could be a suitable candidate to develop a zero order release dosage form for oral administration of DIL·HCl. The swelling and dissolution processes were analyzed by different mathematical approaches.

¿Cómo perciben los profesionales de paliativos las necesidades espirituales del paciente al final de la vida? / No disponible

Objetivo: obtener datos empíricos sobre la detección y atención de las necesidades espirituales en las unidades de cuidados paliativos españolas. Método: se ha diseñado un cuestionario anónimo ad hoc autoadministrado, del cual se han distribuido 1.200 ejemplares a través de la revista Medicina Paliativa a profesionales con experiencia paliativa de toda la geografía española. Los cuestionarios incluían cuestiones sobre la detección, valoración e intervención sobre necesidades espirituales de los pacientes al final de la vida. Se han recibido 202 cuestionarios cumplimentados correspondientes a una muestra de 72 médicos, 73 enfermeras y el resto psicólogos, trabajadores sociales, sacerdotes y voluntarios. Los datos han sido analizados cualitativamente mediante un análisis sistemático de contenido y cuantitativamente mediante análisis estadístico. Resultados: el ratio de retorno ha sido de un 17%. De los 202 cuestionarios analizados, un 31% de los participantes manifiesta tener bastante o mucha dificultad en la identificación de las expresiones de necesidades espirituales escuchadas a sus pacientes. El 28% expresa que todos o la mayoría de sus pacientes manifiestan preocupaciones espirituales, un 56% afirma que sólo una minoría de sus pacientes lo hace. Un 40% de los profesionales expresa que se siente con pocos o escasos recursos para responder a estas situaciones donde el enfermo expresa sufrimiento de origen espiritual. Un 23% manifiestan que los aspectos espirituales son tratados regularmente dentro de las sesiones de trabajo del equipo multidisciplinar, mientras que un 63% expone que los mismos no se abordan nunca o prácticamente nunca en las sesiones clínicas del equipo. El 39% de los participantes expresa que siempre o casi siempre habla de la muerte con sus pacientes, sin embargo un 43% indica que no lo hace nunca o prácticamente nunca. Del análisis cualitativo, se propone una taxonomía con 12 tipos de necesidades existenciales-espirituales, basadas en las 463 expresiones textuales de los propios pacientes tal y como son recogidas por sus cuidadores. Esta categorización empírica ofrece pistas para estructurar la atención a la dimensión espiritual en los pacientes al final de la vida. Conclusión: los datos encontrados sugieren que, en general, las necesidades existenciales-espirituales no están debidamente atendidas en las unidades de cuidados paliativos de nuestro país. Los profesionales sanitarios suelen mostrar un nivel de concienciación insuficiente respecto a la detección de las preocupaciones espirituales y, por tanto, se percibe una incapacidad de atención adecuada, y dificultad para abordar o discutir estas cuestiones en las sesiones clínicas de los equipos

Objective: to collect empirical evidence about the identification and care of spiritual needs for patients in palliative care units. Method: an anonymous questionnaire was designed and 1200 copies were distributed through the Medicina Paliativa journal to palliative care professionals all over Spain. Questionnaires included items on the detection, assessment, and care of spiritual needs in end-of-life patients. We received 202 completed questionnaires from 72 physicians, 73 nurses, and 57 psychologists, social workers, priests, and volunteers. Data were analyzed using a qualitative systematic content analysis and standard statistical quantitative procedures. Results: the return ratio was 17%. Among all 202 questionnaires analyzed, 31% of participants reported many difficulties in identifying spiritual concerns from sentences collected from their patients. Twenty-eight percent stated that nearly all of their patients expressed spiritual concerns, and 56% affirmed that only a minority of their patients did. Forty percent of all professionals interviewed expressed that they had little or very few abilities to respond to situations where patients showed spiritual suffering. Only 23% of professionals agreed that the spiritual needs of patients in their unit were taken into account regularly in the multidisciplinary team sessions, whereas 63% reported that such issues were never dealt with in clinical team sessions. Thirty-nine percent of professionals shared that they always or nearly always talked about death with their patients, whereas 43% said that they never or very rarely did so. From the content analysis of 463 literal expressions from patients, as collected by their carers, a taxonomy of 12 different types of existential-spiritual needs is proposed. This empirical categorization offers interesting clues about the rationale on which a model of spiritual care at the end of life should be based. Conclusion: data collected suggest that existential-spiritual needs are not properly cared for in most palliative care units in our country. Health professionals show an insufficient level of awareness in identifying spiritual distress in their patients. Additionally, our survey detected an inability to deliver appropriate care, and difficulties to discuss such issues in clinical team sessions