Red flags in patients with hereditary transthyretin amyloidosis at diagnosis in a non-endemic area of Spain.

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as "red flags," have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy. MATERIAL AND METHODS: We analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients. RESULTS: The frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags. CONCLUSION: Red flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset.

COVID-19 convalescent plasma as long-term therapy in immunodeficient patients?

OBJECTIVES: The patients with hematological malignancies are a vulnerable group to COVID-19, due to the immunodeficiency resulting from the underlying disease and oncological treatment that significantly impair cellular and humoral immunity. Here we report on a beneficial impact of a passive immunotherapy with convalescent plasma to treat a prolonged, active COVID-19 infection in a patient with a history of nasopharyngeal diffuse large B-cell lymphoma treated with the therapy inducing substantial impairment of particularly humoral arm of immune system. The specific aim was to quantify SARS-CoV2 neutralizing antibodies in a patient plasma during the course of therapy. MATERIALS AND METHODS: Besides the standard of care treatment and monitoring, neutralizing antibody titers in patient's serum samples, calibrated according to the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin (human), were quantified in a time-dependent manner. During the immunotherapy period peripheral blood flow cytometry immunophenotyping was conducted to characterize lymphocyte subpopulations. RESULTS: The waves of clinical improvements and worsening coincided with transfused neutralizing antibodies rises and drops in the patient's systemic circulation, proving their contribution in controlling the disease progress. Besides the patient's lack of own humoral immune system, immunophenotyping analysis revealed also the reduced level of helper T-lymphocytes and immune exhaustion of monocytes. CONCLUSION: Therapeutic approach based on convalescent plasma transfusion transformed a prolonged, active COVID-19 infection into a manageable chronic disease.

Red flags in patients with hereditary transthyretin amyloidosis at diagnosis in a non-endemic area of Spain. / «Red flags¼ en pacientes con polineuropatía amiloidótica familiar relacionada con transtiretina (hATTR) en el momento del diagnóstico en un área no endémica de España.

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as "red flags," have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy. MATERIAL AND METHODS: We analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients. RESULTS: The frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags. CONCLUSION: Red flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset.

Incidental Skin Cancer Detection in a Hospital Department: A Prospective Study. / Evaluación de la tasa de detección incidental de cáncer cutáneo: estudio prospectivo en un servicio hospitalario.

BACKGROUND AND OBJECTIVES: Skin cancer is a common cause for referral to dermatology, but it may also be an incidental finding during examination of patients referred for other reasons. The objective of the study was to compare the characteristics of skin cancer lesions (squamous skin carcinoma, basal cell carcinoma, melanoma) diagnosed at a dermatology department over 1 year between patients referred for suspected skin cancer and those referred for another reason but in whom skin cancer was detected as an incidental finding. Pearson's χ2 test was used to compare different study variables between the 2 groups. RESULTS: Data were collected from 433 patients with a mean age of 72 years; 233 (51.3%) of the patients were female. The most common skin types were Fitzpatrick types II and III. Basal cell carcinoma was the most frequent cancer in all the analyses and accounted for 68.4% of all cancers diagnosed (296/433). Twenty-six percent of the malignant skin tumors were detected incidentally. Statistical analysis revealed that these tumors tended to be located in nonvisible areas and were smaller and of more recent onset than tumors initially suspected to be malignant. CONCLUSIONS: The high rate of skin cancer diagnosed incidentally by dermatologists highlights the need to carry out thorough examinations of patients in order to facilitate early detection and treatment.

Histological changes in the rat brain and spinal cord following prolonged intracerebroventricular infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients are similar to those caused by the disease. / La infusión intracerebroventricular prolongada de líquido cefalorraquídeo procedente de pacientes con esclerosis lateral amiotrófica provoca cambios histológicos en el cerebro y la médula espinal de la rata similares a los hallados en la enfermedad.

INTRODUCTION: Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons. MATERIAL AND METHODS: We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery. RESULTS: Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatinC, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins. CONCLUSION: Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease.

Microstructure and in vitro behaviour of 45S5 bioglass coatings deposited by high velocity suspension flame spraying (HVSFS).

The high-velocity suspension flame spraying technique (HVSFS) was employed in order to deposit 45S5 bioactive glass coatings onto titanium substrates, using a suspension of micron-sized glass powders dispersed in a water + isopropanol mixture as feedstock. By modifying the process parameters, five coatings with different thickness and porosity were obtained. The coatings were entirely glassy but exhibited a through-thickness microstructural gradient, as the deposition mechanisms of the glass droplets changed at every torch cycle because of the increase in the system temperature during spraying. After soaking in simulated body fluid, all of the coatings were soon covered by a layer of hydroxyapatite; furthermore, the coatings exhibited no cytotoxicity and human osteosarcoma cells could adhere and proliferate well onto their surfaces. HVSFS-deposited 45S5 bioglass coatings are therefore highly bioactive and have potentials as replacement of conventional hydroxyapatite in order to favour osseointegration of dental and prosthetic implants.

[Cell therapy in amyotrophic lateral sclerosis: science and controversy]. / Terapia celular en la esclerosis lateral amiotrófica: ciencia y controversia.

Stem cell therapy is seen as a possible alternative for the treatment of different degenerative diseases, among which includes amyotrophic lateral sclerosis (ALS). Despite there being basic research works with this therapy in ALS, the mechanism of action of the implanted cells are still unclear. It is also unclear which type of cells to use (bone marrow, fat, dental pulp, etc.), or the most ideal administration route. Furthermore, clinical trials with mesenchymal stem cells are not very conclusive, therefore it has not been convincingly established as an alternative therapy in ALS or any other neurodegenerative disease. Despite the scientific evidence, several clinical trials have been conducted in the last few years that offer stem cell treatments for neurodegenerative diseases, giving rise to what is known as "cellular tourism". This phenomenon has set off alarms and reactions in the scientific community. The application of these therapies must be performed following the good clinical practice guidelines in research, evidence based methodology and international ethical and scientific recommendations.

Use of fully covered self-expanding metal stents for the management of benign biliary conditions.

BACKGROUND AND AIM: biliary self-expanding metal stents (SEMS) have the advantage of being inserted undeployed with very small sizes and provide, when fully opened, large diameters for biliary drainage. However, their use in benign conditions has been very limited, mainly because of difficulty in their extraction. We present our initial experience with a fully covered SEMS (Wallflex) for the management of benign problems of the bile duct. PATIENTS AND METHODS: in a prospective study, stents of 8 mm in diameter and 4, 6 or 8 cm long were inserted by means of ERCP. These SEMS were chosen when according to medical judgement it was thought that diameters greater than 10 French (3.3 mm) were needed for proper biliary drainage. Stents were extracted also endoscopically, several months later when deemed clinically appropriate. RESULTS: twenty biliary SEMS were inserted. Reasons for insertion were: large intrahepatic biliary fistula after hydatid cyst surgery (1), perforation of the papillary area following endoscopic sphincterotomy (2), coaxial insertion to achieve patency in obstructed uncovered stents inserted in benign conditions (3), benign strictures (7), multiple and large common bile duct stones that could not be extracted because of tapering and stricturing of the distal common bile duct (7). In all cases, successful biliary drainage was achieved and there were no complications from insertion. Stents were easily extracted after a mean time of 132 days (36-270) in place. Complete resolution of biliary problems was obtained in 14 patients (70%). CONCLUSIONS: in our initial experience, the fully covered Wallflex biliary stent was removed without any complication after being in place in the common bile duct for a mean time of over four months. Therefore, it could be used in the management of benign biliary conditions.

[The clinical application of intensity-modulated radiation therapy]. / Aplicación clínica de la radioterapia de intensidad modulada.

Intensity-modulated radiation therapy (IMRT) represents one of the greatest technical innovations in modern radiotherapy. Its capacity of achieving treatments with the dose conforming largely to the irradiated area makes it possible to treat volumes close to organs at risk with great safety These characteristics make it an ideal technique for studies, whether for reducing toxicity in organs at risk, or for intensifying dosages to improve the control of the disease. The first part of the article considers what is understood by IMRT and its peculiar dosimetric characteristics, as well the types of IMRT; the second part deals with the clinical evidence in some localisations such as tumours of the head and neck, prostate and breast.

[Radiotherapy of mobile tumors]. / Radioterapia en tumores móviles.

In this article we detail some questions related to managing the treatment of mobile tumors, that is, those tumors that shift with respiratory movements, integrating movement into the plan of treatment. This fact complicates the administration of high doses of radiotherapy since, in such cases, the radiation margin must be wider than that required by the tumor itself, representing a greater risk to surrounding healthy tissue. However, the new technologies offer an alternative in these cases, such as tracking and respiratory gating in radiotherapy (RT), that is, the synchronization of treatment with respiratory movement. In gating we capture the tumor and other organs at risk at a specific moment in the breathing cycle, while in tracking we trace the tumor and the organs at risk throughout the breathing cycle. It is therefore essential to obtain good images and to correlate them with each phase of the breathing cycle. The tumors with which these strategies have been most employed are those of the lung, breast and lymphomas, and less frequently with some abdominal tumors such as pancreas, liver and prostate.

[Image-guided brachytherapy]. / Braquiterapia guiada por imagen.

Brachytherapy consists in the administration of radiation in intimate contact with the tumour, with a low exposure of neighbouring healthy tissues. Its use began in the early XX century and it has developed since then: different radioisotopes, systems of remote treatment, computer programs making individual dose calculation possible. In recent years there have been changes affecting two aspects of brachytherapy. In the first place, the incorporation of imaging techniques such as echography, computerised tomography (CT) and magnetic resonance (MR), indispensable for diagnosis and tumoural staging. Their use when the implant is being done helps in guiding and carrying out the operation with greater precision. In the second place, the use of CT, MR and echography makes better coverage of the tumour possible, or reduces the dose to healthy organs. They are used in inverse planning systems, which carry out dose calculation on the basis of the doses to be administered to the tumour and healthy organs. In these planning programs it is possible to make calculations more rapidly, taking account of the placement of the source at each moment in time. This technique, called real-time planning, is starting to show advantages in the treatment of prostate cancer. Incorporation of imaging techniques and improvements in calculation systems mean that brachytherapy is currently playing an important role in treating cancer of the prostate, cervix, breast, head and neck tumours, bronchial tubes or oesophagus.

[Interaction of radiotherapy and new agents with molecular targets]. / Interacción de la radioterapia con los nuevos agentes con dianas moleculares.

Radiochemotherapy represents one of the greatest achievements in cancer treatment in recent decades, although it involves significant toxicity for patients. Research developed recently in the molecular biology of cancer has enabled understanding of the genetic and molecular changes that determine malign cellular transformation, which has led to the identification of key molecules, converting them into molecular targets that have led to a revolution in radiobiological concepts of cellular response to radiations and radioresistance. The new agents against molecular targets possess greater specificity and less adverse effects, making them more attractive than chemotherapy for combination with radiotherapy. They can act by inhibiting intracellular transduction signals, modulating the cellular cycle, apoptosis or inhibiting angiogenesis. The effect of radiotherapy can be strengthened through inhibition of cellular repopulation, improvement of tumour oxygenation, redistribution of the cellular cycle, inhibition of invasion and metastasis, and increase of radiosensitivity. The available data support its efficacy and applicability in preclinical and clinical studies in different tumour models and open up a promising path in cancer treatment.

Tubular epithelial cells transfected with hHGF counteracts monocyte chemotactic protein-1 up-regulation after hypoxia/reoxygenation insult.

Acute kidney injury (AKI) which is mainly produced by nephrotoxic or ischemic insults is correlated with a high mortality and morbidity. Proximal tubular epithelial cells (PTEC) play a major role. They are the main target of ischemia/reperfusion injury. PTECs have also been proposed as the effectors of AKI reversibility, but also as the creator of the inflammatory milieu: cytokine, chemokine, and complement expression. An important chemokine implicated in this process is monocyte chemotactic protein-1 (MCP-1) due to its ability to recruit and activate monocytes. Hepatocyte growth factor (HGF) is a pleiotropic factor with mitogenic, anti-apoptotic, and proliferative effects which has recently been studied for its anti-inflammatory and antifibrogenic effects. Our aim was to evaluate the potential inflammatory effect of hypoxia and reoxygenation on rat PTECs. We created a stable human HGF (hHGF) expressing PTEC line that emulated in vivo transfection and analyzed the role of this cell type in the induction and reversibility of AKI. Our results showed the efficiency of transfection with the hHGF gene to promote sustained expression of the protein in the medium (7627.13 +/- 1144.078 to 8211.3 +/- 795.37 pg/mL). When rat PTECs were under a hypoxia/reoxygenation insult, MCP-1 was highly overexpressed (4479.3 +/- 154.3 pg/mL of protein and 5.099 +/- 1.23 times control gene expression). Transfected cells abrogated this effect (288.7 +/- 13.5 pg/mL and 1.169 +/- 0.0759 times control). In conclusion, we observed that the hypoxia/reoxygenation insult stimulated MCP-1 protein secretion in PTECs and that PTECs which were stably transfected and overexpressing hHGF abrogated the inflammatory reaction mediated by hypoxia/reoxygenation, being a suitable model for later studies.

[Palliative management of malignant gastric outlet obstruction with endoscopically inserted self-expanding metal stents].

AIM AND BACKGROUND: the insertion of self-expanding metal stents to palliate malignant gastric outlet obstruction is a minimally invasive procedure that is being increasingly used. We discuss experience with this technique in a level-II hospital in the Spanish National Health System. PATIENTS AND METHODS: a retrospective five-year study (2003-2007) was conducted in 23 patients who underwent 27 procedures aimed at resolving malignant gastric outlet obstruction (mean, 0.45 procedures per month) using endoscopically inserted noncovered stents (Wallstent and Wallflex). RESULTS: insertion was technically feasible in all 27 (100%) attempts, with satisfactory clinical results in 25 cases (92.5%). Endoscopy alone was used 10 times (37%), and both endoscopy and fluoroscopy on 17 (63%) occasions. After stent insertion, one patient was intervened for treatment, and a patient with an unsuccessful prosthesis received a palliative surgical bypass. Four stents became obstructed by tumoral ingrowth, and patency was reestablished by inserting a new stent. Obstructive jaundice caused by stents covering the papilla of Vater occurred in three cases. There were no other complications or mortality due to the procedure. Mean survival was 104 days (range 28-400, SD +/- 94). CONCLUSIONS: in our experience endoscopic insertion of self-expanding metal stents appears to be a safe and efficient palliative method for malignant gastric outlet obstruction, and can be performed successfully in a center with our characteristics.

Clinical practices in neonatal oxygenation: where have we failed? What can we do?

INTRODUCTION: Oxygen is among the most frequently used therapies in neonates worldwide. Nevertheless, many times it is used unnecessarily. Neonatal practices have changed over the last several years; treatments originally believed to be beneficial have been discarded. STUDY DESIGN: Oxygen utilized 'just in case' or 'prophylactically' can lead to great damage previously ignored and/or unseen by healthcare providers. It is imperative to improve education on neonatal oxygenation and saturation monitoring. It is also important not to depend on old assumptions, which were not based on evidences. The potential for unseen damage at the cellular and tissue levels cannot be ignored. Therapies that prove to be outdated or even dangerous must be eliminated while further research and confirmation of the best practices are determined. Freedom to choose can come at a price.

Macrophage involvement in the kidney repair phase after ischaemia/reperfusion injury.

Macrophage infiltration is a common feature of the early phase of renal ischaemia/reperfusion injury. Indeed, it is generally regarded as the cause of tissue injury in this phase, although it is also clear that it can lead to tissue repair in other phases. In order to ascertain whether macrophages are directly involved in the repair/late phase, which follows the pro-inflammatory and injury process of renal ischaemia/reperfusion, we used two different approaches based on macrophage depletion. Firstly, we produced renal ischaemia in mice that were previously treated with clodronate liposome. Secondly, during reperfusion we re-injected RAW 264.7 to macrophage-depleted mice 24 h prior to sacrifice. The results showed that regeneration, as evaluated by stathmin and PCNA markers, was macrophage-dependent: it was blocked when macrophage depletion was provoked and recovered with macrophage re-injection. The cytokine profile revealed the influence of the inflammatory environment on kidney repair: pro-inflammatory cytokines (MCP-1, MIP-1alpha) increased during the early stages of reperfusion, coinciding with low regeneration, and the anti-inflammatory cytokine IL-10 increased during the longer periods of reperfusion when regeneration was more evident. We conclude that macrophages induce renal regeneration after ischaemia/reperfusion, depending on the inflammatory milieu.

[First SIBEN clinical consensus: diagnostic and therapeutic approach to patent ductus arteriosus in premature newborns]. / Primer consenso clínico de SIBEN: enfoque diagnóstico y terapéutico del ductus arterioso permeable en recién nacidos pretérmino.

OBJECTIVE: To report the process and results of the first neonatal clinical consensus of the Ibero-American region. DESIGN AND METHODS: Two recognized experts in the field (Clyman and Van Overmeire) and 45 neonatologists from 23 countries were invited for active participation and collaboration. We developed 46 questions of clinical-physiological relevance in all aspects of patent ductus arteriosus (PDA). Guidelines for consensus process, literature search and future preparation of educational material and authorship were developed, reviewed and agreed by all. Participants from different countries were distributed in groups, and assigned to interact and work together to answer 3-5 questions, reviewing all global literature and local factors. Answers and summaries were received, collated and reviewed by 2 coordinators and the 2 experts. Participants and experts met in Granada, Spain for 4.5 h (lectures by experts, presentations by groups, discussion, all literature available). RESULTS: 31 neonatologists from 16 countries agreed to participate. Presentations by each group and general discussion were used to develop a consensus regarding: general management, availability of drugs (indomethacin vs. ibuprofen), costs, indications for echo/surgery, etc. Many steps were learnt by all present in a collaborative forum. CONCLUSIONS: This first consensus group of Ibero-American neonatologists SIBEN led to active and collaborative participation of neonatologists of 16 countries, improved education of all participants and ended with consensus development on clinical approaches to PDA. Furthermore, it provides recommendations for clinical care reached by consensus. Additionally, it will serve as a useful foundation for future SIBEN Consensus on other topics and it could become valuable as a model to decrease disparity in care and improve outcomes in this and other regions.