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OBJECTIVE: Breathlessness is a common and disabling symptom of pulmonary disease. Measuring its severity is recommended as such measurements can be helpful in both clinical and research settings. The oxygen-cost diagram (OCD) and the Medical Research Council (MRC) dyspnea scale were developed in English to measure severity of dyspnea. These scales were previously translated to Spanish and adapted for use in a Hispanic population. The objective of this study is to assess the psychometric properties of these scales. We propose the scales correlate well with measures of physiological impairment. METHODS: Subjects having pulmonary disease rated their perceptions of dyspnea using the scales, performed a spirometry test, and did a 6-min walk. Spearman correlation coefficients (p) were used to correlate dyspnea scores with spirometric parameters and distance walked (6MWD). RESULTS: Sixty-six patients having stable asthma (n = 36), chronic obstructive pulmonary disease (n = 19), or interstitial lung disease (n = 11) participated in the study. OCD scores showed a significant correlation with FEV1 (p = 0.41; p < 0.01), FEV1% (p = 0.36; p < 0.01), FVC (p = 0.44; p < 0.01), and FVC% (p = 0.37; p < 0.01) in the study population. The OCD scores were highly correlated with 6MWD (p = 0.59, p < 0.01). The MRC dyspnea scale showed significant inverse correlation with FEV1 (p = -0.34; p < 0.01) and 6MWD (p = -0.33; p < 0.05), but the correlations were weaker compared to the correlations with the OCD scale. CONCLUSION: The severity of breathlessness as measured by the adapted Spanish OCD showed a moderate to high correlation with spirometric parameters and 6MWD; therefore, the adapted OCD should prove to be useful in Puerto Rico.
Subject(s)
Asthma/diagnosis , Dyspnea/diagnosis , Lung Diseases, Interstitial/diagnosis , Pulmonary Disease, Chronic Obstructive/diagnosis , Adult , Aged , Aged, 80 and over , Asthma/physiopathology , Cross-Sectional Studies , Dyspnea/etiology , Female , Forced Expiratory Volume , Humans , Language , Lung Diseases, Interstitial/physiopathology , Male , Middle Aged , Oxygen/metabolism , Psychometrics , Puerto Rico , Pulmonary Disease, Chronic Obstructive/physiopathology , Severity of Illness Index , Spirometry/methods , Statistics, Nonparametric , Walking/physiology , Young AdultABSTRACT
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by diverse clinical manifestations affecting multiple organs and systems. The understanding of genetic factors underlying the various manifestations of SLE has evolved considerably in recent years. This review provides an overview of the genetic implications in some of the most prevalent manifestations of SLE, including renal involvement, neuropsychiatric, cutaneous, constitutional, musculoskeletal, and cardiovascular manifestations. We discuss the current state of knowledge regarding the genetic basis of these manifestations, highlighting key genetic variants and pathways implicated in their pathogenesis. Additionally, we explore the clinical implications of genetic findings, including their potential role in risk stratification, prognosis, and personalized treatment approaches for patients with SLE. Through a comprehensive examination of the genetic landscape of SLE manifestations, this review aims to provide insights into the underlying mechanisms driving disease heterogeneity and inform future research directions in this field.
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Background: To improve the implementation of clinical trial interventions, there is a need to facilitate communication between key stakeholders and research teams. Community Advisory Boards (CAB) bring together a range of stakeholders not historically included in the research process to inform and work collaboratively with research teams. Objective: To describe our procedures and processes for (1) integration of a CAB into a pragmatic clinical trial of a telehealth-delivered group mindfulness program for persons with chronic low back pain (cLBP) within primary care, and (2) for the rapid uptake and implementation of CAB recommendations. Methods: The CAB we convened includes persons with cLBP who have undergone the mindfulness intervention, health care system leadership, advocacy groups, and mindfulness experts. The CAB members underwent a two hour initial training that introduced the research process and the CAB's role as research partners. The CAB met monthly for 1 hour. We used the Lighting Report method to summarize meetings and share feedback with the research team. Results: The recommendations of the CAB during the first year they met were divided into recruitment, informed consent, and survey recommendations. The study website also was overhauled based on recommendations, including a more engaging first page with rotating images of nature and testimonials. The language on the website was edited to be more concise and participant-friendly. The CAB recommended talking points to discuss with participants during screening or informed consent about the benefits of participating in research. Conclusion: We established a CAB that represented diverse perspectives, organizations, and experience with cLBP and mindfulness. The differing perspectives of the CAB resulted in recommendations that the research team itself would not have decided on their own. The Lightning Reports were also an effective way to efficiently communicate the CAB recommendations to the research team.
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The comparability assessment of a biological product after implementing a manufacturing process change should involve a risk-based approach. Process changes may occur at any stage of the product lifecycle: early development, clinical manufacture for pivotal trials, or post-approval. The risk of the change to impact product quality varies. The design of the comparability assessment should be adapted accordingly. A working group reviewed and consolidated industry approaches to assess comparability of traditional protein-based biological products during clinical development and post-approval. The insights compiled in this review article encompass topics such as a risk-evaluation strategy, the design of comparability studies, definition of assessment criteria for comparability, holistic evaluation of data, and the regulatory submission strategy. These practices can be leveraged across the industry to help companies in design and execution of comparability assessments, and to inform discussions with global regulators.
Subject(s)
Biological Products , Humans , Risk Assessment/methods , Drug Approval/methods , Drug Development/methodsABSTRACT
Background: Mindfulness research and clinical programs are widespread, and it is important that mindfulness-based interventions are delivered with fidelity, or as intended, across settings. The MBI:TAC is a comprehensive system for assessing teacher competence, yet it can be complex to implement. A standardized, simple fidelity/engagement tool to address treatment delivery is needed. Objective: We describe the development, evaluation, and outcomes of a brief, practical tool for assessing fidelity and engagement in online mindfulness-based programs. The tool contains questions about session elements such as meditation guidance and group discussion, and questions about participant engagement and technology-based barriers to engagement. Methods: The fidelity rating tool was developed and tested in OPTIMUM, Optimizing Pain Treatment in Medical settings Using Mindfulness. The OPTIMUM study is a 3-site pragmatic randomized trial of group medical visits and adapted mindfulness-based stress reduction for primary care patients with chronic low back pain, delivered online. Two trained study personnel independently rated 26 recorded OPTIMUM sessions to determine inter-rater reliability of the Concise Fidelity for Mindfulness-Based Interventions (CoFi-MBI) tool. Trained raters also completed the CoFi-MBI for 105 sessions. Raters provided qualitative data via optional open text fields within the tool. Results: Inter-rater agreement was 77-100% for presence of key session components, and 69-88% for Likert ratings of participant engagement and challenges related to technology, with discrepancies only occurring within 2 categories: 'very much' and 'quite a bit'. Key session components occurred as intended in 94-100% of the 105 sessions, and participant engagement was rated as 'very much' or 'quite a bit' in 95% of the sessions. Qualitative analysis of rater comments revealed themes related to engagement challenges and technology failures. Conclusion: The CoFi-MBI provides a practical way to assess basic adherence to online delivery of mindfulness session elements, participant engagement, and extent of technology obstacles. Optional text can guide strategies to improve engagement and reduce technology barriers.
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Pulmonary delivery is the main route of administration for treatment of local lung diseases. Recently, the interest in delivery of proteins through the pulmonary route for treatment of lung diseases has significantly increased, especially after Covid-19 pandemic. The development of an inhalable protein combines the challenges of inhaled as well as biologic products since protein stability may be compromised during manufacture or delivery. For instance, spray drying is the most common technology for manufacture of inhalable biological particles, however, it imposes shear and thermal stresses which may cause protein unfolding and aggregation post drying. Therefore, protein aggregation should be evaluated for inhaled biologics as it could impact the safety and/or efficacy of the product. While there is extensive knowledge and regulatory guidance on acceptable limits of particles, which inherently include insoluble protein aggregates, in injectable proteins, there is no comparable knowledge for inhaled ones. Moreover, the poor correlation between in vitro setup for analytical testing and the in vivo lung environment limits the predictability of protein aggregation post inhalation. Thus, the purpose of this article is to highlight the major challenges facing the development of inhaled proteins compared to parenteral ones, and to share future thoughts to resolve them.
Subject(s)
Biological Products , COVID-19 , Humans , Protein Aggregates , Pandemics , Administration, Inhalation , Powders , Particle Size , Dry Powder Inhalers , Respiratory Aerosols and DropletsABSTRACT
In the indigenous communities of central Veracruz, herds of creole sheep have been established and managed through traditional practices of crossing, but their genetic characteristics have never been examined in order to evaluate their state of endogamy, and to help the management programs to protect this genetic resource. The objective of the present study was to characterize the genetic diversity of three populations of creole sheep managed by indigenous communities in the central region of Veracruz, Mexico. Indigenous family producers of creole sheep were located and blood samples taken from 90 individual sheep from the municipalities of Tehuipango, Astacinga and Tlaquilpa, Veracruz. In the laboratory, the genomic DNA was extracted and genetic diversity characterized using four microsatellites (ILSTS11, ILSTS5, SRCRSP9 and OarFCB128) amplified by PCR and visualized on polyacrylamide gels. The four microsatellites were highly informative (PIC = 85%) and presented values of 0.6 to 0.81 of heterozygosity, with an average number of 16 alleles. According to the Hardy-Weinberg equilibrium model, three of the loci were not significant (p < 0.05), presumably this means that they do not deviate significantly from H-W predictions and there was slight genetic differentiation (FST = 0.025), along with a slight decrease in homozygotes (FIS = -0.021). According to the analysis of variance, 99% of the total variation was hosted at the individual level. It is concluded that the three creole sheep populations still present genetic diversity at the four loci and non-random pairings have occurred.
ABSTRACT
Between March 2020 and February 2021, the state of Baja California, Mexico, which borders the United States, registered 46,118 confirmed cases of COVID-19 with a mortality rate of 238.2 deaths per 100,000 residents. Given limited access to testing, the population prevalence of SARS-CoV-2 infection is unknown. The objective of this study is to estimate the seroprevalence and real time polymerase chain reaction (RT-PCR) prevalence of SARS-CoV-2 infection in the three most populous cities of Baja California prior to scale-up of a national COVID-19 vaccination campaign. Probabilistic three-stage clustered sampling was used to conduct a population-based household survey of residents five years and older in the three cities. RT-PCR testing was performed on nasopharyngeal swabs and SARS-CoV-2 seropositivity was determined by IgG antibody testing using fingerstick blood samples. An interviewer-administered questionnaire assessed participants' knowledge, attitudes, and preventive practices regarding COVID-19. In total, 1,126 individuals (unweighted sample) were surveyed across the three cities. Overall prevalence of SARS-CoV-2 infection by RT-PCR was 7.8% (95% CI 5.5-11.0) and IgG seroprevalence was 21.1% (95% CI 17.4-25.2). There was no association between border crossing in the past 6 months and SARS-CoV-2 prevalence (unadjusted OR 0.40, 95%CI 0.12-1.30). While face mask use and frequent hand washing were common among participants, quarantine or social isolation at home to prevent infection was not. Regarding vaccination willingness, 30.4% (95% CI 24.4-3 7.1) of participants said they were very unlikely to get vaccinated. Given the high prevalence of active SARS-CoV-2 infection in Baja California at the end of the first year of the pandemic, combined with its low seroprevalence and the considerable proportion of vaccine hesitancy, this important area along the Mexico-United States border faces major challenges in terms of health literacy and vaccine uptake, which need to be further explored, along with its implications for border restrictions in future epidemics.
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PURPOSE: To identify the association between single-nucleotide polymorphisms (SNPs) in CFH, ARMS2, HTRA1, CFB, C2, and C3 genes and exudative age-related macular degeneration (AMD) in a Spanish population. METHODS: In 187 exudative AMD patients and 196 healthy controls (61% women, mean age 75 years), 12 SNPs as risk factors for AMD in CFH (rs1410996, rs1061170, r380390), ARMS2 (rs10490924, rs10490923), HTRA1 (rs11200638), CFB (rs641153), C2 (rs547154, rs9332739), and C3 (rs147859257, rs2230199, rs1047286) genes were analyzed. RESULTS: The G allele was the most frequent in CFH gene (rs1410996) with a 7-fold increased risk of AMD (OR 7.69, 95% CI 3.17-18.69), whereas carriers of C allele in CFH (rs1061170) showed a 3-fold increased risk for AMD (OR 3.22, 95% CI 1.93-5.40). In CFH (rs380390), the presence of G allele increased the risk for AMD by 2-fold (OR 2.52, 95% CI 1.47-4.30). In ARMS2 (rs10490924), the T-allele was associated with an almost 5-fold increased risk (OR 5.49, 95% CI 3.23-9.31). The A allele in HTRA1 (rs11200638) was more prevalent in AMD versus controls (OR 6.44, 95% CI 3.62-11.47). In C2 gene (rs9332739) the presence of C increased risk for AMD by 3-fold (OR 3.10, 95% CI 1.06-9.06). CONCLUSION: SNPs in CFH, ARMS2, HTRA1, and C2 genes were associated in our study with an increased risk for exudative AMD in Spanish patients.
Subject(s)
Complement Factor H , Macular Degeneration , Aged , Complement C2/genetics , Complement Factor H/genetics , Female , Genotype , High-Temperature Requirement A Serine Peptidase 1/genetics , Humans , Macular Degeneration/genetics , Male , Polymorphism, Single Nucleotide , Proteins/genetics , SpainABSTRACT
The Rio Grande, which forms the United States-Mexico border for much of its course, receives diverse pollutants from both urban and agricultural areas, most notably in the sister cities of El Paso (TX, USA)-Ciudad Juárez (CHI, Mexico). This study aimed to describe regional trends in water quality in waters near the El Paso-Ciudad Juárez metroplex and to examine the potential for water quality improvement through the use of a created wetland. Very few differences in nutrient chemistry were found among drains, canals and the Rio Grande, with the exception of elevated chloride and lower phosphorus levels found in the drains. Overall, chloride concentrations increased with distance downstream, likely due to concentration of salts via evaporation from irrigated agriculture. A wastewater treatment plant (WWTP) contributed substantially to total phosphorus and nitrate levels, which, together with ammonia, tended to exceed state criteria for water quality downstream of the WWTP outflow. The created Rio Bosque wetlands reduced nitrate concentrations in the water, possibly via denitrification enhanced by algae; algae increased in biomass as water flowed through the wetlands. However, the diversion of water for irrigated agriculture, resulting in the absence of water, and thus aquatic plants, in the wetland in the summer has limited the ability of this wetland to improve regional water quality.
Subject(s)
Rivers/chemistry , Water Purification/methods , Wetlands , Conservation of Natural Resources/methods , Mexico , United StatesABSTRACT
Parkinson's disease (PD) is characterized by profound microglial driven inflammatory processes and the loss of dopamine neurons of the substantia nigra (SNc). Both microglia and dopamine neurons that are affected in the SNc are particularly vulnerable to environmental toxicants and finding more selective ways of targeting these cell types is of importance. Quantum dots (QDs) might be a useful vehicle for selectively delivering toxicants to microglia and owing to their fluorescent capability, they can be microscopically tracked within the cell. Accordingly, we assessed the impact of QDs alone and QDs conjugated to the ribosomal toxin, saporin, upon SNc microglia and dopamine neurons. We found that intra-SNc infused QDs selectively entered microglia and induced morphological changes consistent with an activated state. QDs conjugated to saporin also caused a significant loss of dopamine neurons and motor coordination (on a rotarod test) deficits, along with an increase in the inflammatory microglial actin regulatory factors, WAVE2. These data suggest that QDs might be a viable route for toxicant delivery and also has an added advantage of being fluorescently visible. Ultimately, we found SNc neurons to be exceptionally vulnerable to QD-saporin and suggest that this could be a novel targeted approach to model PD-like inflammatory pathology.
Subject(s)
Dopaminergic Neurons/drug effects , Microglia/drug effects , Pars Compacta/drug effects , Quantum Dots/toxicity , Saporins/toxicity , Animals , Dopaminergic Neurons/pathology , Drug Carriers/toxicity , Encephalitis/chemically induced , Encephalitis/metabolism , Mice, Inbred C57BL , Microglia/pathology , Pars Compacta/pathology , Toxicology/methodsABSTRACT
PURPOSE: To describe the Food and Drug Administration review and marketing approval considerations for panitumumab (Vectibix) for the third-line treatment of patients with epidermal growth factor receptor-expressing metastatic colorectal carcinoma. EXPERIMENTAL DESIGN: Food and Drug Administration reviewed a single, open-label, multicenter trial in which 463 patients with epidermal growth factor receptor-expressing metastatic colorectal cancer who had progressed on or following treatment with a regimen containing a fluoropyrimidine, oxaliplatin, and irinotecan were randomized (1:1) to receive best supportive care (BSC) with or without panitumumab (6 mg/kg every other week) administered until disease progression or intolerable toxicity. Progression and response were confirmed by an independent review committee masked to treatment assignment. At progression, patients in the BSC-alone arm were eligible to receive panitumumab. RESULTS: Although median progression-free survival (PFS) was similar in both treatment arms ( approximately 8 weeks), the mean PFS was approximately 50% longer among patients receiving panitumumab than among those receiving BSC alone (96 versus 60 days, respectively) and the objective response rate in patients receiving panitumumab was 8%. However, no difference in overall survival was shown between the two study arms. CONCLUSIONS: Panitumumab received accelerated approval based on improvement in PFS and an independently confirmed response rate of 8%, similar to that observed with other active agents at this advanced stage of disease. Confirmation of clinical benefit will be required for full approval.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Drug Approval , ErbB Receptors/metabolism , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Chemotherapy, Adjuvant , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Disease Progression , Disease-Free Survival , Fluorouracil/administration & dosage , Humans , Irinotecan , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Lymphatic Metastasis , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Panitumumab , Survival Rate , United States , United States Food and Drug AdministrationABSTRACT
The objective of this study was to determine the perspectives of drug users' relatives and acquaintances about protective factors for illicit drug use at a health center in Guayaquil. This is a descriptive, cross-sectional study. Data collection was performed through interviews using a questionnaire. Interviews were performed with 100 people who knew a drug user (relative or friend). The results showed that the following personal and family factors could be protective: 97% having solid moral principles, 96% express their feelings, 98% dedicate time for the family, and 95 % have a supportive relationship with one of the parents. Regarding the community, all participants (100%) agree there is a need for a government that understands this issue, 99% refer there should be honest policemen, and 99% state the need for programs that protect people from drug use and institutions that work with prevention. Family, community and personal decisions have effects on becoming involved, hence the need to reinforce protective factors and thus reduce the number of addicted individuals.
Subject(s)
Family , Friends , Illicit Drugs , Substance-Related Disorders , Adolescent , Adult , Cross-Sectional Studies , Ecuador , Female , Humans , Male , Substance-Related Disorders/epidemiology , Substance-Related Disorders/prevention & control , Surveys and Questionnaires , Urban Health , Young AdultABSTRACT
This cross-sectional multi-centre study explored how family members and friends of illicit drug users perceived protective and risk factors, treatment facilities and policies and laws regarding illicit drug use. Family members and friends of illicit drug users were recruited in 10 urban health care outpatient units in 7 Latin American countries (Brazil, Colombia, Costa Rica, Ecuador, Guatemala, Honduras and Mexico) to complete a questionnaire. The majority of the respondents chose psycho-social factors over genetic or biological explanations as causes of drug problems. Respondents felt that families and governments were responsible for preventing drug problems. Church/religious institutions were most often mentioned in the context of accessible treatment. When asked about access to treatment facilities, the majority said that there were not enough. Shame about drug use, cost, and limited treatment options were most often cited as barriers to treatment.
Subject(s)
Family , Friends , Illicit Drugs , Substance-Related Disorders , Cross-Sectional Studies , Humans , Latin America , Risk Factors , Substance-Related Disorders/epidemiology , Substance-Related Disorders/prevention & control , Surveys and QuestionnairesABSTRACT
A simple and economic high-performance liquid chromatography (HPLC-UV-Vis) analytical method was validated for the quantitation of specific Bisphenol-A migration from baby feeding bottles. Overall and specific migration assays were done with different food simulating matrices using the filling method. Good linearity was obtained over the concentration range of 0.01-0.6 mg/kg. The limit of detection (LOD) and limit of quantification (LOQ) were 0.004 and 0.010 mg/kg, respectively. The repeatability of the method (%RSD, n=10) was between 89.5 and 99.0%, while recovery ranged from 83.2 to 98.4%. The method was applied to specific migration assays from baby feeding bottles purchased from different plastic producers in Colombia. The results show that, in a first migration assay, Bisphenol-A was not detectable in all samples. In a second migration test, Bisphenol-A concentrations were higher than the most restricted limit (0.05 mg/kg) with ethanol 95% and isooctane as food simulants.
ABSTRACT
A dolichoectatic intracranial vessel with multiple fusiform aneurysms on the same vessel segment is rare, and usually managed with a bypass with aneurysm trapping. This video demonstrates trapping and a double-barrel superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass to treat two fusiform aneurysms in a left dolichoectatic superior MCA trunk. A 46-year-old man with AIDS presented with aphasia and hemiparesis. IRB approval and patient consent were obtained. Both STA branches (frontal and parietal) were harvested. After widely splitting the sylvian fissure from its proximal portion to the angular gyrus, the two fusiform aneurysms on the superior MCA trunk were identified in the insular recess and the circular sulcus. The outflow artery from each aneurysm was identified and prepared for the bypass. The STA was transected, and both limbs were brought down into the fissure. After trapping the distal aneurysm, an end-to-end anastomosis of the parietal STA branch to the M2 MCA was performed. Thereafter, a second bypass was performed in an end-to-side fashion to an M2 branch from the base of the first aneurysm. The second aneurysm was then trapped. Indocyanine green angiography confirmed the patency of both bypasses. Complete aneurysm occlusion and bypass patency were also confirmed with postoperative angiography. The patient recovered from his pre-operative neurological deficits. This case demonstrates the efficacy of double-barrel STA-MCA bypass in combination with aneurysm trapping in a patient with a complex dolichoectatic superior MCA trunk aneurysm. It also highlights the advantage of using end-to-end anastomosis for deep recipients with limited access.
ABSTRACT
BACKGROUND: Polycystic ovary syndrome is a complex and heterogeneous disease involving both reproductive and metabolic problems. It has been suggested a genetic predisposition in the etiology of this syndrome. The identification of calpain-10 gene (CAPN10) as the first candidate gene for type 2 diabetes mellitus, has focused the interest in investigating their possible relation with the polycystic ovary syndrome, because this syndrome is associated with hyperinsulinemia and insulin resistance, two metabolic abnormalities associated with type 2 diabetes mellitus. OBJECTIVE: To investigate if there is association between the SNP-63 and the variant indel-19 of the CAPN10 gene and polycystic ovary syndrome in women of reproductive age. MATERIAL AND METHODS: This study included 101 women (55 with polycystic ovary syndrome and 46 without polycystic ovary syndrome). The genetic variant indel-19 was identified by electrophoresis of the amplified fragments by PCR, and the SNP-63 by PCR-RFLP. RESULTS: The allele and genotype frequencies of the two variants do not differ significatly between women with polycystic ovary syndrome and control women group. The haplotype 21 (defined by the insertion allele of indel-19 variant and C allele of SNP-63) was found with higher frequency in both study groups, being more frequent in the polycystic ovary syndrome patients group, however, this difference was not statistically significant (p = 0.8353). CONCLUSIONS: The results suggest that SNP-63 and indel-19 variant of the CAPN10 gene do not represent a risk factor for polycystic ovary syndrome in our patients group.
Subject(s)
Calpain/genetics , INDEL Mutation , Polycystic Ovary Syndrome/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Alleles , DNA Mutational Analysis , Deoxyribonucleases, Type II Site-Specific , Electrophoresis, Polyacrylamide Gel , Female , Gene Frequency , Genotype , Haplotypes , Humans , Mexico/epidemiology , Polycystic Ovary Syndrome/epidemiology , Polymorphism, Restriction Fragment Length , Young AdultABSTRACT
The recent discoveries of the two interleukin (IL)-12-related cytokines, IL-23 and IL-27, reveal that the regulation of cellular immunity is more complex than originally thought. Until these discoveries, the role of IL-12 in modulating cellular immune responses had been overestimated due to the belief that the IL-12 p40 subunit was unique to IL-12. However, because p40 is shared between IL-12 and IL-23, it would be expected that p40(-/-) mice are doubly deficient in IL-12 and IL-23. Indeed, the essential role previously attributed to IL-12 in experimental autoimmune encephalitis during studies of p40(-/-) mice has been shown to be due to IL-23 instead. The newest addition to the IL-12 cytokine family, IL-27, has unique features as well. Its specific action on naive CD4+ T cells in both mice and humans appears to distinguish it from the other IL-12 family members. Although related, the IL-12 family of cytokines and their receptors have distinct patterns of expression and unique effects on developing immune responses. This review summarises much of the pertinent literature on the IL-12 cytokine family and provides predictions regarding their potential therapeutic roles based on what has been learned about their functions in vitro and in vivo in gene-deficient mice.
Subject(s)
Interleukin-12/physiology , Interleukins/physiology , Animals , Cell Differentiation/physiology , Humans , Interleukin-12/antagonists & inhibitors , Interleukin-12/therapeutic use , Interleukin-23 , Interleukin-23 Subunit p19 , Interleukins/antagonists & inhibitors , Interleukins/therapeutic use , Recombinant Proteins/therapeutic use , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/physiologyABSTRACT
Antimicrobial peptides have been proposed as new agents to distinguish between bacterial infections and sterile inflammatory processes. (99m)Tc-UBI labeled by a direct method has shown high in vitro and in vivo stability, specific uptake at the site of infection, rapid background clearance, minimal accumulation in non-target tissues and rapid detection of infection sites in mice. The aim of this study was to establish a (99m)Tc-UBI biokinetic model and evaluate its feasibility as an infection imaging agent in humans. Whole-body images from 6 children with suspected bone infection were acquired at 1, 30, 120, 240 min and 24 h after (99m)Tc-UBI administration. Regions of interest (ROIs) were drawn around source organs (heart, liver, kidneys and bladder) on each time frame. The same set of ROIs was used for all 6 scans and the cpm of each ROI were converted to activity using the conjugate view counting method. Counts were corrected by physical decay and by the background correction factor derived from preclinical phantom studies. The image sequence was used to extrapolate (99m)Tc-UBI time-activity curves in each organ and calculate the cumulated activity (A). Urine samples were used to obtain the cumulative percent of injected activity (% I.A.) versus time renal elimination. The absorbed dose in organs was evaluated according to the general equation described in the MIRD formalism. In addition, (67)Ga-citrate images were obtained from all the patients and used as a control. Biokinetic data showed a fast blood clearance with a mean residence time of 0.52 h. Approximately 85% of the injected activity was eliminated by renal clearance 24 h after (99m)Tc-UBI administration. Images showed minimal accumulation in non-target tissues with an average target/non-target ratio of 2.18 +/- 0.74 in positive lesions at 2 h. All infection positive(99m)Tc-UBI images were in agreement with those obtained with (67)Ga-citrate. The mean radiation absorbed dose calculated was 0.13 mGy/MBq for kidneys and the effective dose was 4.34 x 10(-3)mSv/MBq.