An inulin and doxorubicin conjugate for improving cancer therapy.

Chemotherapy is one of the primary treatment mechanisms for treating cancer. Current chemotherapy is systemically delivered and causes significant side effects; therefore the development of new chemotherapeutic agents or enhancing the effectiveness of current chemotherapeutic could prove vital to patients and cancer care. The purpose of this research was to develop a new conjugate composed of doxorubicin (chemotherapeutic) and inulin (polysaccharide chain) and evaluate its potential as a new therapeutic agent for cancer treatment. The synergistic effect of inulin conjugated to doxorubicin has allowed the same cytotoxic response to be maintained or improved at lower doses as compared to doxorubicin. Supporting results include cytotoxicity profiles, calf thymus DNA binding studies, confocal microscopy, and transport studies.

Clinical-epidemiological profile of the patient attended in a fracture liaison service (FLS) of a regional hospital in north-west of Spain. / [Artículo traducido] Perfil clínico-epidemiológico del paciente atendido en una unidad multidisciplinar de fractura de cadera de un hospital de primer nivel en el noroeste de España.

INTRODUCTION: Hip fractures constitute a capital public health issue associated with aging and frailty because of its impact on both quality of life and morbidity and mortality in older people. Fracture liaison services (FLS) have been proposed as tools to minimize this emergent problem. MATERIAL AND METHODS: A prospective observational study was conducted with 101 patients treated for hip fracture by the FLS of a regional hospital between October 2019 and June 2021 (20 months). Epidemiological, clinical, surgical, and management variables were collected during admission and up to 30 days after discharge. RESULTS: Mean age of patients was 87.6 ± 6.1 years and 77.2% were female. Some degree of cognitive impairment was detected at admission in 71.3% of patients using the Pfeiffer questionnaire, and 13.9% were nursing home residents, and 76.24% could walk independently before the fracture. Fractures were more commonly pertrochanteric (45.5%). Patients were receiving antiosteoporotic therapy in 10.9% of cases. The median surgical delay from admission was 26 h (RIC 15-46 h), the median length of stay was 6 days (RIC 3-9 days) and in-hospital mortality was 10.9%, and 19.8% at 30 days, with a readmission rate of 5%. DISCUSSION: Patients treated in our FLS at the beginning of its activity were similar to the general picture in our country in terms of age, sex, type of fracture, and proportion of patients treated surgically. A high mortality rate was observed, and low rates of pharmacological secondary prevention were followed at discharge. Clinical results of FLS implementation in regional hospitals should be assessed prospectively in order to decide their suitability.

Fungal sensitization in nasal polyposis.

BACKGROUND: There are indications that polyposis is somehow related to allergic phenomena. Fungal sensitization in substantial proportions of patients has been cited as a trigger of inflammatory mechanisms involving either an immunoglobulin (Ig) E-mediated reaction to fungal colonization or fungal invasion of tissues. OBJECTIVE: To confirm whether fungi were involved in the development of polyposis by examining sensitivity to fungal allergens and potential local contamination by fungal species. METHODS: We performed a study of 190 patients with polyposis and 190 controls in which we compared the results of skin prick tests to 12 fungi, total IgE, and specific IgE to 15 fungal extracts and nasal fungal cultures. RESULTS: The specific fungi eliciting a reaction from the largest proportion of patients in the skin prick tests were Fusarium solani (13.7%), Penicillium frequentans (12.6%), Trichophyton mentagrophytes (11.1%), and Candida albicans (8.4%) (P < .001). The proportion of individuals that tested positive for fungal-specific IgE was 22.4% (38/170) for patients and 10.1% (19/189) for controls (P = .04). The respective proportions of positive responses to fungal cultures were 58.7% and 60%. Furthermore, no significant differences between patients and controls were found for the results of in vitro tests with cultured fungal allergens. CONCLUSIONS: Although the patients with polyposis exhibited sensitization to fungal allergens, we found that nasal colonization by fungi was similar in patients and the general population. We were also unable to find a correlation between a positive response to the cultures and the presence of fungal allergen-specific IgE. It therefore seems that nasal colonization by fungi does not induce fungal sensitization.

Allergenic profile of nasal polyposis.

BACKGROUND: Nasal polyposis is highly prevalent in the general population. Its exact origin is unknown, although several factors are involved in the etiology and development of this condition. Clinical patterns, a history of atopy, environmental exposure, eosinophil-mediated inflammation, the presence of inflammatory mediators, and sensitization to some allergens indicate that nasal polyposis is associated with allergic phenomena. The aim of this study was to identify the association between nasal polyposis and allergic factors by examining hypersensitivity reactions to common allergens and environmental exposure that could lead to the development of atopy. METHODS: We conducted a comparative study of 190 patients with nasal polyposis and 190 healthy individuals. The study included clinical and epidemiological variables, environmental exposure factors, and an allergology workup using skin prick tests with 18 inhaled allergens. RESULTS: A total of 121 patients (63.7%) of the 190 were male; 62.1% had a family history of allergy. The incidence of asthma was 48.9% among the patients and only 2.3% among the controls (P < .001). The factor most frequently involved in the patients' symptoms was weather changes (67.4%). Skin prick tests were positive in 63.2% of the patients and 31.1% of the controls. The allergens that most frequently elicited a reaction from the patients in the prick tests were Dermatophagoides pteronyssinus (27.7%), Dermatophagoides farinae (21.3%), and Olea europaea (21.1%). The difference between these results and those of the controls was statistically significant. CONCLUSIONS: Patients with nasal polyposis are sensitive to the most common allergens in our environment and exhibit a clear-cut correlation with other allergic factors, as confirmed by personal and family histories, the presence of chronic rhinitis, and the results of in vivo tests.

Upper Airway Video Endoscopy: Assessment of the response to positive pressure ventilation and mechanical in-exsufflation.

Upper airways (UA) include the nasal cavities, pharynx, and larynx, and its main function is to warm and filter the inspired air. UA dysfunction is in the pathogenesis of various disorders, such as obstructive sleep apnea syndrome (OSAS) and vocal cord dysfunction. In addition, in some neurodegenerative diseases (e.g. Amyotrophic Lateral Sclerosis - ALS), UA dysfunction may also compromise the effective use of ventilatory support (VS). In this context, the endoscopic evaluation of UA may be useful in understanding the OSAS mechanisms, in determining the causes for treatment-induced airway obstruction and even in helping to titrate noninvasive ventilation (NIV) in ALS patients with bulbar or pseudo-bulbar (spastic) dysfunction. Specifically, in OSAS patients, when residual obstructive events persist, although an optimal ventilatory mode has been apparently achieved, along with interface and equipment, the endoscopic evaluation of UA seems to be a valuable tool in understanding its mechanisms, even assisting adjustments to NIV parameters. In addition, it has also been described as being useful in laryngeal response to mechanical in-exsufflation (MI-E) and Exercise-Induced Laryngeal Obstruction (EILO). However, no protocol has yet been published or validated for this. For this reason, a literature review was conducted on UA function and its response to positive pressure and MI-E. Special emphasis has also been given to the current indication for video endoscopy in chronically ventilated patients.

COPD and Cardiovascular Disease.

COPD is one of the major public health problems in people aged 40 years or above. It is currently the 4th leading cause of death in the world and projected to be the 3rd leading cause of death by 2020. COPD and cardiac comorbidities are frequently associated. They share common risk factors, pathophysiological processes, signs and symptoms, and act synergistically as negative prognostic factors. Cardiac disease includes a broad spectrum of entities with distinct pathophysiology, treatment and prognosis. From an epidemiological point of view, patients with COPD are particularly vulnerable to cardiac disease. Indeed, mortality due to cardiac disease in patients with moderate COPD is higher than mortality related to respiratory failure. Guidelines reinforce that the control of comorbidities in COPD has a clear benefit over the potential risk associated with the majority of the drugs utilized. On the other hand, the true survival benefits of aggressive treatment of cardiac disease and COPD in patients with both conditions have still not been clarified. Given their relevance in terms of prevalence and prognosis, we will focus in this paper on the management of COPD patients with ischemic coronary disease, heart failure and dysrhythmia.

The inverse relationship between chronic HBV and HCV infections among injection drug users is associated with decades of age and drug use.

Infection with hepatitis C virus (HCV) may suppress co-infection with hepatitis B virus (HBV) during acute or chronic HBV infection. We examined relationships between HBV infection, HCV infection and other factors among injection drug users (IDUs) with antibodies to both viruses. Participants enrolled in a cross-sectional study during 1998-2000 were considered to have been infected with HBV if they had core antibody, to be chronically infected if they had hepatitis B surface antigen (HBsAg), to have been infected with HCV if they had HCV antibody and to be chronically infected if they had HCV RNA. Among 1694 participants with antibody to both viruses, HBsAg prevalence decreased with increasing age among those positive for HCV RNA [from 4.55% in those 18-29 years to 1.03% in those >or=50 years old (P(trend) = 0.02)], but not among those who were negative for HCV RNA. Chronic HBV infection was less common overall among those with chronic HCV infection (odds ratio [OR], 0.25; P < 0.0001), but this inverse relationship was much stronger in the oldest (>50 years; OR = 0.15) than the youngest (18-29 years; OR = 0.81) participants (P(trend) = 0.03). Similar results were obtained when duration of injection drug use was substituted for age (P(trend) = 0.05). Among IDUs who have acquired both HBV and HCV, chronic HBV infection is much less common among those with chronic HCV infection, but this inverse relationship increases markedly with increasing years of age and injection drug use. Co-infection with HCV may enhance the resolution of HBsAg during the chronic phases of these infections.

Body mass index and airway hyper-responsiveness in individuals without respiratory disease.

BACKGROUND: Overweight and obesity are major health issues in Western societies. They are related with a higher risk of different co-morbidities but their relationship with airway hyperresponsiveness (AHR) is still under discussion. Nevertheless, they are related to higher severity in asthma and other respiratory diseases. The aim of the study was to analyze the AHR in individuals with normal lung function without respiratory disorders, according to body mass index (BMI) calculation. METHODS: We performed clinical observation and basal lung function tests (LFT) in 595 consecutive individuals in order to exclude respiratory disease. 377 individuals fulfilled the criteria of normal values according international guidelines. They were submitted to standardized treadmill exercise test followed by bronchodilator test. FVC, FEV1, FEF 25/75, RV and Raw were obtained at different conditions according to BMI groups (I: lean; II: normal; III: overweight; IV obese). RESULTS: 55.2% of the sample was overweight or obese, and a signficant relationship was found with female gender and older ages (p=0.0046 and p<0.0001 respectively). The positive response to exercise test or bronchodilator beta2 agonists was not significantly frequent compared with the other groups. In obese individuals the exercise markedly reduced basal Raw and increased FEF 25/75. Lean individuals showed higher basal values of RV that was reduced upon exercise. Response to 12 agonists showed no differences according to weight biotypes. CONCLUSION: BMI hampers lung function in normal individuals, and seems not to be related to AHR. Regular exercise should be encouraged in overweight and obese individuals, since it increases their bronchial permeability as shown in lower frequency of positive exercise tests. The same is advisable for lean individuals for different reasons. Their increased basal RV and Raw improve upon exercise. Despite overweight and obesity are being related to a low-grade of basal systemic inflammation, there was no association with a higher basal bronchial hyperresponsiveness in these individuals.

Portuguese consensus document for the management of alpha-1-antitrypsin deficiency.

Alpha-1-antitrypsin deficiency (AATD) is a genetic autosomal codominant disorder caused by mutations in SERPINA1 gene. It is one of the most prevalent genetic disorders, although it remains underdiagnosed. Whereas at international level there are several areas of consensus on this disorder, in Portugal, inter-hospital heterogeneity in clinical practice and resources available have been adding difficulties in reaching a diagnosis and in making therapeutic decisions in this group of patients. This raised a need to draft a document expressing a national consensus for AATD. To this end, a group of experts in this field was created within the Portuguese Pulmonology Society - Study group on AATD, in order to elaborate the current manuscript. The authors reviewed the existing literature and provide here general guidance and extensive recommendations for the diagnosis and management of AATD that can be adopted by Portuguese clinicians from different areas of Medicine. This article is part of a supplement entitled "Portuguese consensus document for the management of alpha-1-antitrypsin deficiency" which is sponsored by Sociedade Portuguesa de Pneumologia.

TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor.

The extracellular region of the nerve growth factor (NGF) receptor, TrkA, contains two immunoglobulin (Ig)-like domains that are required for specific ligand binding. We have investigated the possible role of these two Ig-like domains in receptor dimerization and activation by using different mutants of the TrkA extracellular region. Deletions of each Ig-like domain, of both, and of the entire extracellular region were made. To probe the structural constraints on ligand-independent receptor dimerization, chimeric receptors were generated by swapping the Ig-like domains of the TrkA receptor for the third or fourth Ig-like domain of c-Kit. We also introduced single-amino-acid changes in conserved residues within the Ig-like domains of TrkA. Most of these TrkA variants did not bind NGF, and their expression in PC12nnr5 cells, which lack endogenous TrkA, promoted ligand-independent neurite outgrowth. Some TrkA mutant receptors induced malignant transformation of Rat-1 cells, as assessed by measuring proliferation in the absence of serum, anchorage-independent growth, and tumorigenesis in nude mice. These mutants exhibited constitutive phosphorylation and spontaneous dimerization consistent with their biological activities. Our data suggest that spontaneous dimerization of TrkA occurs when the structure of the Ig-like domains is altered, implying that the intact domains inhibit receptor dimerization in the absence of NGF.

Incidence of tumoral pathology according to study using capsule endoscopy for patients with obscure gastrointestinal bleeding.

BACKGROUND: Capsule endoscopy has involved a significant advance in techniques for imaging of the small bowel. Its most frequent indication is for studying patients with obscure gastrointestinal bleeding (OGIB). Small bowel tumors are infrequent, representing only 1% to 3% of all malignant gastrointestinal tumors. This study aimed to assess retrospectively the occurrence and characteristics of tumoral pathology diagnosed by means of capsule endoscopy in patients with OGIB. METHODS: A retrospective review analyzed the first 320 patients submitted to capsule endoscopy because of OGIB (166 with obscure overt bleeding and 154 with obscure occult bleeding) at a single center. The patients with a tumor diagnosis were analyzed in terms of incidence, characteristics, and treatment of OGIB pathology. RESULTS: Tumor incidence was of 7.18% (23/320), with 65.2% of the cases supported with histologic confirmation (15/23). Obscure overt bleeding was the most frequent form of presentation, with the jejunum as the most frequent location (65.2%). For 16 patients, an intervention was conducted with a healing intent. Capsule endoscopy allowed the diagnosis of two cecal adenocarcinomas missed by colonoscopy. CONCLUSIONS: Small bowel tumors are not an infrequent cause of OGIB. Capsule endoscopy, even if it does not allow determination of the benign or malignant nature or the histologic type of the tumor, is a useful tool for the diagnosis and early management of these tumors.

Analyses by GC-MS and GC-MS-MS of the Hantzsch synthesis products using hydroxy- and methoxy-aromatic aldehydes.

EI mass spectra of products of the dihydropyridine Hantzsch synthesis using hydroxy and methoxy aldehydes as starting materials are reported. The reaction products (C-4 hydroxy- and methoxyphenyl-1,4-dihydropyridines and chromeno[3,4,c]-pyridines) were derivatized with N-methyl-N-(trimethylsilyl)-trifluoracetamide to be analyzed by gas chromatographic techniques. Fragmentation pathways for 1,4-dihydropyridines and chromeno-pyridines are proposed. The study provides (mainly through MS-MS technique) useful data for the confirmation of the structure of the compounds and also is a valuable tool for further analytical purposes to follow both photostability and reactivity studies with free radicals for these types of compounds.

[Periodontal status and diabetes: evaluation of 80 patients with diabetes mellitus in Conakry Teaching Hospital]. / Evaluation de l'etat parodontal au cours au diabète : a propos de 80 patients au CHU Donka de Conakry.

INTRODUCTION: Dental and periodontal diseases are frequent in diabetics. Few studies were carried out on oral pathologies of the diabetics in Africa. The objective of this study was to assess periodontal conditions in a population of diabetics followed in a hospital environment by comparing them with non diabetics. PATIENTS AND METHOD: In a cross-sectional study realized from January to April 1999, 80 diabetic patients followed in the Service of Endocrinology were compared to 35 non-diabetic patients, chosen among the patients attending in the Service of Internal medicine of the Donka Teaching Hospital in Conakry in the same period. Both groups were compared according to the simplified oral hygiene index (OHIS) and community periodontal index of treatment needs (CPITN). RESULTS: There was no difference between diabetics and nondiabetics according to the OHIS. Diabetics CPITN index was higher compared to non-diabetics (p = 0.019). In diabetics, scores of CPITN increase significantly with duration of diabetes mellitus (p = 0.019). Also correlation was found between OHIS and the duration of diabetes. Glycemic control was significantly correlated with OHIS (p < 0.001) and CIPTN (p < 0.001). CONCLUSION: Diabetic patients have more periodontal treatment need than controls. Better collaboration between diabetologist and odontostomatologist is needed to preserve the oral health of diabetics.

Prevalence of late-onset pompe disease in Portuguese patients with diaphragmatic paralysis - DIPPER study.

Pompe disease is a rare autosomal recessive neuromuscular disorder caused by acid α-glucosidase enzyme (GAA) deficiency and divided into two distinct variants, infantile- and late-onset. The late-onset variant is characterized by a spectrum of phenotypic variation that may range from asymptomatic, to reduced muscle strength and/or diaphragmatic paralysis. Since muscle strength loss is characteristic of several different conditions, which may also cause diaphragmatic paralysis, a protocol was created to search for the diagnosis of Pompe disease and exclude other possible causes. METHODS: We collected a sample size of 18 patients (10 females, 8 males) with a median age of 60 years and diagnosis of diaphragmatic paralysis of unknown etiology, followed in the Pulmonology outpatient consultation of 9 centers in Portugal, over a 24-month study period. We evaluated data from patient's clinical and demographic characteristics as well as complementary diagnostic tests including blood tests, imaging, neurophysiologic and respiratory function evaluation. All patients were evaluated for GAA activity with DBS (dried blood test) or serum quantification and positive results confirmed by serum quantification and sequencing. RESULTS: Three patients were diagnosed with Pompe's disease and recommended for enzyme replacement therapy. The prevalence of Pompe, a rare disease, in our diaphragmatic paralysis patient sample was 16.8%. CONCLUSION: We conclude that DBS test for GAA activity should be recommended for all patients with diaphragmatic paralysis which, despite looking at all the most common causes, remains of unknown etiology; this would improve both the timing and accuracy of diagnosis for Pompe disease in this patient population. Accurate diagnosis will lead to improved care for this rare, progressively debilitating but treatable neuromuscular disease.

[Lymphoplasmacytic inflammatory pseudotumor of the liver]. / Pseudotumor inflamatorio hepático linfoplasmocítico.

We present the case of a middle-aged woman with antecedents of cholecystectomy and several episodes of resi-dual coledocolitiasis resolved endoscopically. She attended Emergency Services due to a new clinical picture of abdo-minal pain and alteration of hepatic enzymes. Image tests showed lesions that suggested hepatic abscesses without ruling out a malign origin. Given this doubt it was decided to carry out a thick needle biopsy obtaining a diagnosis of an inflammatory pseudotumour of the liver related to IgG4-related disease. This is an infrequent entity but must be taken into consideration because - unlike malign pathology, which is the main differential diagnosis - its behaviour is benign, with a good evolution with medical treatment. That is why a suitable diagnosis is vital to avoid aggressive, diagnostic-therapeutic procedures.

COVID 19 and the new challenges in health management: The pilot experience of the Internal Medicine Department of a Regional hospital / COVID 19 y los nuevos retos en gestión sanitaria: la experiencia piloto del Servicio de Medicina Interna de un hospital de primer nivel

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Tuberculosis in Anti-Tumour Necrosis Factor-treated Inflammatory Bowel Disease Patients After the Implementation of Preventive Measures: Compliance With Recommendations and Safety of Retreatment.

BACKGROUND AND AIMS: Despite having adopted preventive measures, tuberculosis (TB) may still occur in patients with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor (anti-TNF). Data on the causes and characteristics of TB cases in this scenario are lacking. Our aim was to describe the characteristics of TB in anti-TNF-treated IBD patients after the publication of the Spanish TB prevention guidelines in IBD patients and to evaluate the safety of restarting anti-TNF after a TB diagnosis. METHODS: In this multicentre, retrospective, descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary. RESULTS: We collected 50 TB cases in anti-TNF-treated IBD patients, 60% male, median age 37.3 years (interquartile range [IQR] 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated and 26% extrapulmonary. In 30 patients (60%), TB cases developed despite compliance with recommended preventive measures; *not performing 2-step TST (tuberculin skin test) was the main failure in compliance with recommendations. In 17 patients (34%) anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation. CONCLUSIONS: Tuberculosis could still occur in anti-TNF-treated IBD patients despite compliance with recommended preventive measures. A significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.

A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation.

The TrkA NGF receptor extracellular region contains three leucine repeats flanked by cysteine clusters and two immunoglobulin-like domains that are required for specific ligand binding. Deletion of the immunoglobulin-like domains abolishes NGF binding and causes ligand independent activation of the receptor. Here we report a specific mutation that increases the binding affinity of the TrkA receptor for NGF. A change of proline 203 to alanine (P203A) in the linker region between the leucine repeats and the first Ig-like domain increased NGF binding by decreasing the ligand rate of dissociation. This mutated receptor was appropriately expressed on the cell surface and promoted ligand-independent neurite outgrowth in PC12nnr5 cells. The mutant receptor was capable of spontaneous dimerization and was constitutively phosphorylated in the absence of ligand. Moreover, expression of TrkA-P203A receptor in fibroblasts induced DNA synthesis and transformation and generated tumours in nude mice. These data suggest that domains outside of the immunoglobulin-like structure contribute to ligand binding and constitutive activation of Trk receptors.