Chronodisruption and Gut Microbiota: Triggering Glycemic Imbalance in People with Type 2 Diabetes.

The desynchronization of physiological and behavioral mechanisms influences the gut microbiota and eating behavior in mammals, as shown in both rodents and humans, leading to the development of pathologies such as Type 2 diabetes (T2D), obesity, and metabolic syndrome. Recent studies propose resynchronization as a key input controlling metabolic cycles and contributing to reducing the risk of suffering some chronic diseases such as diabetes, obesity, or metabolic syndrome. In this analytical review, we present an overview of how desynchronization and its implications for the gut microbiome make people vulnerable to intestinal dysbiosis and consequent chronic diseases. In particular, we explore the eubiosis-dysbiosis phenomenon and, finally, propose some topics aimed at addressing chronotherapy as a key strategy in the prevention of chronic diseases.

Clinicoepidemiological characteristics of viral hepatitis in migrants and travellers of the +Redivi network.

BACKGROUND: Continuous growth of mobile populations has influenced the global epidemiology of infectious diseases, including chronic and acute viral hepatitis. METHOD: A prospective observational multicentre study was performed in a Spanish network of imported infections. Viral hepatitis cases from January 2009 to September 2017 were included. RESULTS: Of 14,546 records, 723 (4.97%) had imported viral hepatitis, including 48 (6.64%) acute cases and 675 (93.36%) chronic cases. Of the 48 acute cases, 31 were travellers and immigrants returning from visiting friends or relatives (VFR), while 19 (61%) were acute Hepatitis A or Hepatitis B. Only 18.2% of VFR immigrants and 35% of travellers received pre-travel advice. Acute hepatitis was more frequent in VFR immigrants (AOR 2.59, CI95% 1.20-5.60) and travellers (AOR 2.83, CI95% 1.46-5.50) than immigrants. Of the 675 Chronic cases, 570 were immigrants, and 439 (77%) had chronic Hepatitis B. Chronic hepatitis was more frequent in immigrants (AOR 20.22, CI95% 11.64-35.13) and VFR immigrants (AOR 11.12, CI95% 6.20-19.94) than travellers. CONCLUSIONS: Chronic viral hepatitis was typical of immigrants, acute viral hepatitis was common among travellers, and VFR immigrants had mixed risk. Improving pre-travel consultation and screening of immigrants may contribute to preventing new cases of viral hepatitis and avoiding community transmission.

National Registry of Cardiac Rehabilitation Programs in Mexico II (RENAPREC II) / Registro Nacional de Programas de Rehabilitación Cardiaca en México II (RENAPREC II)

Abstract: Objective: The aim of this paper is to compare the state of Cardiac Rehabilitation Programs (CRP) in 2009 with 2015. Focus is directed on health care, training of health-providers, research, and the barriers to their implementation. Methods: All authors of RENAPREC-2009, and other cardiac rehabilitation leaders in Mexico were requested to participate. These centres were distributed into two groups: RENAPREC-2009 centres that participated in 2015, and the new CRP units. Results: In 2009 there were 14 centres, two of which disappeared and another two did not respond. CRP-units increased by 71% (n = 24), and their geographic distribution shows a centripetal pattern. The coverage of CRP-units was 0.02 centres per 100,000 inhabitants. Only 4.4% of eligible patients were referred to CRP, with a rate of 10.4 patients/100,000 inhabitants in 2015. The ratio of Clinical Cardiologists to Cardiac Rehabilitation Specialists was 94:1, and the ratio of Intervention Specialists to cardiac rehabilitation experts was 16:1. Cardiac rehabilitation activities and costs varied widely. Patient dropout rate in phase II was 12%. Several barriers were identified: financial crisis (83%), lack of skilled personnel (67%), deficient equipment (46%), inadequate areas (42%), and a reduced number of operating centres (38%). Conclusions: CRPs in Mexico are still in the process of maturing. Mexican CRP-centres have several strengths, like the quality of the education of the professionals and the multidisciplinary programs. However, the lack of referral of patients and the heterogeneity of procedures are still their main weaknesses.

Resumen: Objetivo: El propósito de este trabajo es comparar el estado actual de los programas de rehabilitación cardiaca (PRC) en México con el RENAPREC-2009, dirigido a la asistencia, docencia, investigación y barreras. Métodos: Se convocó a participar a todos los autores de RENAPREC-2009 y a otros líderes en rehabilitación cardiaca de México. Los centros fueron distribuidos en 2 grupos: los que participaron en el 2015 y las nuevas unidades de PRC. Resultados: En 2009 había 14 centros operativos, de los cuales 2 cerraron y 2 no respondieron. En 2015 se registraron 24 centros en total, representando un aumento neto del 71%. La distribución geográfica fue centrípeta. La cobertura fue de 0.02 centros/100,000 habitantes y de solamente un 4.4% de los pacientes elegibles (10.4 pacientes/100,000 habitantes). La relación cardiólogo clínico-rehabilitador cardiaco es de 94:1 y la de intervencionista-rehabilitador cardiaco es de 16:1. Las actividades realizadas y los costos de los PRC varían de forma importante de centro a centro. En promedio, el 12% de los pacientes en fase ii abandonaron el programa. Las principales barreras para el desarrollo de PRC fueron: económicas (83%), falta de personal capacitado (67%), falta de equipo (46%), áreas inadecuadas (42%) y un insuficiente número de centros operativos (38%). Conclusiones: Los PRC en nuestro país continúan en crecimiento. Se observan fortalezas como el nivel de docencia y el enfoque multidisciplinario, así como deficiencias en la homogeneidad de las actividades y la falta de referencia de la población elegible.

Imported malaria in Spain (2009-2016): results from the +REDIVI Collaborative Network.

BACKGROUND: Imported malaria is a frequent diagnosis in travellers and migrants. The objective of this study was to describe the epidemiological and clinical characteristics of patients diagnosed with imported malaria within a Spanish collaborative network registering imported diseases (+REDIVI). In addition, the possible association between malaria and type of case, gender, age or area of exposure was explored. METHODS: Cases of imported malaria were identified among all cases registered in the +REDIVI database during the period October 2009-October 2016. Demographic, epidemiological and clinical characteristics were analysed. RESULTS: In total, 11,816 cases of imported infectious diseases were registered in +REDIVI's database between October 2009 and October 2016. Immigrants seen for the first time after migration accounted for 60.2% of cases, 21.0% of patients were travellers, and 18.8% were travellers/immigrants visiting friends and relatives (VFRs). There were 850 cases of malaria (850/11,816, 7.2%). Malaria was significantly more frequent in men than in women (56.8% vs 43.2%) and in VFR-immigrants (52.6%) as compared to travellers (21.3%), immigrants (20.7%) and VFR-travellers (5.4%) (p < 0.001). Although this data was not available for most patients with malaria, only a minority (29/217, 13.4%) mentioned correct anti-malarial prophylaxis. Sub-Saharan Africa was found to be the most common region of acquisition of malaria. Most common reason for consultation after travel was a febrile syndrome although an important proportion of immigrants were asymptomatic and presented only for health screening (27.3%). Around 5% of travellers presented with severe malaria. The most prevalent species of Plasmodium diagnosed was Plasmodium falciparum (81.5%). Malaria due to Plasmodium ovale/Plasmodium vivax was frequent among travellers (17%) and nearly 5% of all malaria cases in immigrants were caused by Plasmodium malariae. CONCLUSIONS: Malaria was among the five most frequent diagnoses registered in +REDIVI's database. Some significant differences were found in the distribution of malaria according to gender, type of case, species. Among all malaria cases, the most frequent diagnosis was P. falciparum infection in VFR-immigrant men.

National Registry of Cardiac Rehabilitation Programs in Mexico II (RENAPREC II).

OBJECTIVE: The aim of this paper is to compare the state of Cardiac Rehabilitation Programs (CRP) in 2009 with 2015. Focus is directed on health care, training of health-providers, research, and the barriers to their implementation. METHODS: All authors of RENAPREC-2009, and other cardiac rehabilitation leaders in Mexico were requested to participate. These centres were distributed into two groups: RENAPREC-2009 centres that participated in 2015, and the new CRP units. RESULTS: In 2009 there were 14 centres, two of which disappeared and another two did not respond. CRP-units increased by 71% (n=24), and their geographic distribution shows a centripetal pattern. The coverage of CRP-units was 0.02 centres per 100,000 inhabitants. Only 4.4% of eligible patients were referred to CRP, with a rate of 10.4 patients/100,000 inhabitants in 2015. The ratio of Clinical Cardiologists to Cardiac Rehabilitation Specialists was 94:1, and the ratio of Intervention Specialists to cardiac rehabilitation experts was 16:1. Cardiac rehabilitation activities and costs varied widely. Patient dropout rate in phase II was 12%. Several barriers were identified: financial crisis (83%), lack of skilled personnel (67%), deficient equipment (46%), inadequate areas (42%), and a reduced number of operating centres (38%). CONCLUSIONS: CRPs in Mexico are still in the process of maturing. Mexican CRP-centres have several strengths, like the quality of the education of the professionals and the multidisciplinary programs. However, the lack of referral of patients and the heterogeneity of procedures are still their main weaknesses.

Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.

BACKGROUND: The objective of this study is to analyze the factors that are associated with the adequacy of empirical antibiotic therapy and its impact in mortality in a large cohort of patients with extended-spectrum ß-lactamase (ESBL)--producing Escherichia coli and Klebsiella spp. bacteremia. METHODS: Cases of ESBL producing Enterobacteriaceae (ESBL-E) bacteremia collected from 2003 through 2008 in 19 hospitals in Spain. Statistical analysis was performed using multivariate logistic regression. RESULTS: We analyzed 387 cases ESBL-E bloodstream infections. The main sources of bacteremia were urinary tract (55.3%), biliary tract (12.7%), intra-abdominal (8.8%) and unknown origin (9.6%). Among all the 387 episodes, E. coli was isolated from blood cultures in 343 and in 45.71% the ESBL-E was multidrug resistant. Empirical antibiotic treatment was adequate in 48.8% of the cases and the in hospital mortality was 20.9%. In a multivariate analysis adequacy was a risk factor for death [adjusted OR (95% CI): 0.39 (0.31-0.97); P = 0.04], but not in patients without severe sepsis or shock. The class of antibiotic used empirically was not associated with prognosis in adequately treated patients. CONCLUSION: ESBL-E bacteremia has a relatively high mortality that is partly related with a low adequacy of empirical antibiotic treatment. In selected subgroups the relevance of the adequacy of empirical therapy is limited.

Seeing double: a comparison of microstructure, biomechanical function, and adjacent disc health between double- and single-layer vertebral endplates.

STUDY DESIGN: Experimental and computational assessment of thickness, porosity, biomechanical behavior, and adjacent disc glycosaminoglycan content in double- and single-layer bony endplate samples harvested from human cadaver spines. OBJECTIVE: To determine if the second layer of bone in double-layer vertebral endplates allows the superficial layer to achieve a more optimal balance between its biomechanical and nutritional functions. SUMMARY OF BACKGROUND DATA: Proper disc health requires the endplate to balance opposing biomechanical and nutritional functions. Previous studies investigating endplate function report seeing double: some endplates have a second layer of bone. However, it remains unclear whether the second layer of bone has any functional advantage. Such information could shed light on the factors that protect against disc degeneration. METHODS: Six lumbar spines were obtained from human cadavers (32-84 yr) and scanned with magnetic resonance imaging. Cylindrical cores that included the endplate and underlying trabecular bone were harvested from the center of the superior vertebral endplates (6 double- and 12 single-layer endplates) and imaged using micro-computed tomography. The thickness and porosity of the bony endplate layers were measured for each core. High-resolution finite element analysis was performed to assess biomechanical behavior. Glycosaminoglycan content within the adjacent nucleus tissue was quantified using the dimethylmethylene blue technique. RESULTS: The superficial layer of the double-layer endplates was 50% thinner (P = 0.009) and tended also to be more porous than single-layer endplates. Strains were higher in thinner endplates; however, the second layer of bone in the double-layer endplates had a stiffening effect so that despite being thinner than single-layer endplates, the superficial layer of the double-layer endplates had a similar risk of damage. After adjusting for age, glycosaminoglycan content was significantly higher in the nucleus tissue adjacent to the double-layer endplates (P = 0.01). CONCLUSION: Compared with single-layer endplates, double-layer endplates seem to permit a more optimal balance between endplate biomechanical and nutritional functions, and may therefore offer a significant protective factor against disc degeneration.

Morphology of the human vertebral endplate.

It is presumed that poor intervertebral disc cell nutrition is a contributing factor in degeneration, and is exacerbated by vertebral endplate sclerosis. Yet, quantitative relationships between endplate morphology and degeneration are unavailable. We investigated how endplate bone microstructure relates to indices of disc degeneration, such as morphologic grade, proteoglycan content, and cell density. Intervertebral core samples [n = 96, 14 subjects, L1-L5 level, ages 35-85 (64 ± 16 years), degeneration grade 1 (n = 4), grade 2 (n = 32), grade 3 (n = 44), grade 4 (n = 10), grade 5 (n = 6)] that included subchondral bone, cartilage endplate, and adjacent nucleus were harvested from human cadaveric lumbar spines. The morphology of the vertebral endplate was analyzed using µCT and the adjacent nucleus tissue was collected for biochemical and cellular analyses. Relationships between vertebral endplate morphology and adjacent disc degeneration were analyzed. Contrary to the prevailing notion, vertebral endplate porosity increased between 50% and 130% and trabecular thickness decreased by between 20% and 50% with advancing disc degeneration (p < 0.05). We also observed that nucleus cell density increased (R(2) = 0.33, p < 0.05) and proteoglycan content decreased (R(2) = 0.47, p < 0.05) as the endplate became more porous. Our data suggest that endplate sclerosis is not a fundamental factor contributing to disc degeneration. Rather, the opposite was observed in our samples, as the endplate became progressively more porous with age and degeneration. Since ischemic disc cell behavior is commonly associated with degenerative change, this may be related to other factors such as the quality of vertebral capillaries, as opposed to decreased permeability of intervening tissues.

Human disc nucleus properties and vertebral endplate permeability.

STUDY DESIGN: Experimental quantification of relationships between vertebral endplate morphology, permeability, disc cell density, glycosaminoglycan (GAG) content, and degeneration in samples harvested from human cadaveric spines. OBJECTIVE: To test the hypothesis that variation in endplate permeability and porosity contributes to changes in intervertebral disc cell density and overall degeneration. SUMMARY OF BACKGROUND DATA: Cells within the intervertebral disc are dependent on diffusive exchange with capillaries in the adjacent vertebral bone. Previous findings suggest that blocked routes of transport negatively affect disc quality, yet there are no quantitative relationships between human vertebral endplate permeability, porosity, cell density, and disc degeneration. Such relationships would be valuable for clarifying degeneration risk factors and patient features that may impede efforts at disc tissue engineering. METHODS: Fifty-one motion segments were harvested from 13 frozen cadaveric human lumbar spines (32-85 years) and classified for degeneration using the magnetic resonance imaging-based Pfirrmann scale. A cylindrical core was harvested from the center of each motion segment that included vertebral bony and cartilage endplates along with adjacent nucleus tissue. The endplate mobility, a type of permeability, was measured directly using a custom-made permeameter before and after the cartilage endplate was removed. Cell density within the nucleus tissue was estimated using the picogreen method, while the nuclear GAG content was quantified using the dimethylmethylene blue technique. Specimens were imaged at 8 µm resolution using microCT; bony porosity was calculated. Analysis of variance, linear regression, and multiple comparison tests were used to analyze the data. RESULTS.: Nucleus cell density increased as the disc height decreased (R² = 0.13; P = 0.01) but was not related to subchondral bone porosity (P > 0.5), total mobility (P > 0.4), or age (P > 0.2). When controlling for disc height, however, a significant, negative effect of age on cell density was observed (P = 0.03). In addition to this, GAG content decreased with age nonlinearly (R² = 0.83, P < 0.0001) and a cell function measurement, GAGs/cell, decreased with degeneration (R² = 0.24; P < 0.0001). Total mobility (R² = 0.14; P < 0.01) and porosity (R² = 0.1, P < 0.01) had a positive correlation with age. CONCLUSION: Although cell density increased with degeneration, cell function indicated that GAGs/cell decreased. Because permeability and porosity increase with age and degeneration, this implies that cell dysfunction, rather than physical barriers to transport, accelerates disc disease.

The tissue diagnostic instrument.

Tissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument (TDI), a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection.

Mechanical profiling of intervertebral discs.

Despite recent advances in imaging diagnostic technology and additional treatment options our ability to prevent or inhibit discogenic back pain has not drastically improved. The challenge of linking early degenerative patterns to dysfunction and pain remains. Using a novel material testing device designated the tissue diagnostic instrument (TDI) we measured the local stiffness and strain energy absorption in the radial direction of 13 intact intervertebral discs; effectively generating a mechanical profile of each disc. Prior to measuring mechanical properties, an MR image was taken of each spine segment and the discs were radiologically scored according to the Pfirrmann scale. After testing, a sagittal portion of each L1-L2 disc was excised from each of four spines for histology. No significant correlations were found between Pfirrmann grade and mechanical data. However, polarized light microscopy images of disc sections indicated correlations between local tissue modulus measured with the TDI and the clarity and density of lamellar striations.

Stab incision for inducing intervertebral disc degeneration in the rat.

STUDY DESIGN: The degenerative response of rat tail and lumbar intervertebral discs to a stab incision was evaluated. OBJECTIVE: To examine and compare the postinjury degenerative response of lumbar and tail discs. SUMMARY OF BACKGROUND DATA: Although successful in larger animals, a stab incision for inducing disc degeneration in rats has not been evaluated. Rodents are desirable models for disc repair studies due to their low cost, ease of care, and fast healing times. METHODS: Lumbar and tail discs were exposed surgically and stabbed with a number 11 blade. Disc architecture, levels of IL-1beta, IL-6, and TNF-alpha, and biomechanical properties were analyzed. A functional disability secondary to multilevel lumbar disc injury was quantified and compared with that of rats undergoing sham surgery. RESULTS: Histologic evaluation of stabbed tail discs demonstrated a nucleus pulposus size decrease, anular collagen layer disorganization, and cellular metaplasia of anular fibroblasts to chondrocyte-appearing cells. Besides the continued presence of the stab injury tract, few changes were observed in the lumbar disc histology. Cytokine measurements indicated a transient peak in IL-1beta in tail discs 4 days following injury. No significant changes in IL-1beta, IL-6, or TNF-alpha were measured. No significant differences in biomechanical properties were observed between stab injury and sham surgery discs. Yet, despite insignificant differences in histologic, cytochemical, or biomechanical properties in the lumbar discs, the rats with lumbar stab injury had a significant decrease in walking ability 28 days after surgery. CONCLUSIONS: Tail disc stab injury was successful in creating morphologic signs of degeneration and transient high concentrations of IL-1beta. However, the degenerative response in the lumbar discs was much slower, suggesting that site-specific factors, such as increased stability due to posterior elements and torso musculature, helped facilitate healing. Yet, functional assessment indicated that the rats were partially disabled by multiple lumbar injuries.

Indications, usage, and dosage of the transfer factor.

The transfer factor (TF) was described in 1955 by S. Lawrence. In 1992 Kirkpatrick characterized the specific TF at molecular level. The TF is constituted by a group of numerous molecules, of low molecular weight, from 1.0 to 6.0 kDa. The 5 kDa fraction corresponds to the TF specific to antigens. There are a number of publications about the clinical indications of the TF for diverse diseases, in particular those where the cellular immune response is compromised or in those where there is a deficient regulation of the immune response. In this article we present our clinical and basic experiences, especially regarding the indications, usage and dosage of the TF. Our group demonstrated that the TF increases the expression of IFN-gamma and RANTES, while decreases the expression of osteopontine. Using animal models we have worked with M. tuberculosis, and with a model of glioma with good therapeutic results. In the clinical setting we have worked with herpes zoster, herpes simplex type I, herpetic keratitis, atopic dermatitis, osteosarcoma, tuberculosis, asthma, post-herpetic neuritis, anergic coccidioidomycosis, leishmaniasis, toxoplasmosis, mucocutaneous candidiasis, pediatric infections produced by diverse pathogen germs, sinusitis, pharyngitis, and otits media. All of these diseases were studied through protocols which main goals were to study the therapeutic effects of the TF, and to establish in a systematic way diverse dosage schema and time for treatment to guide the prescription of the TF.

[Transfer factor as specific immunomodulator in the treatment of moderate-severe atopic dermatitis]. / Factor de transferencia como inmunomodulador específico en el tratamiento de la dermatitis atópica moderada a severa.

BACKGROUND: Atopic dermatitis is a skin inflammatory disease which has been associated to high levels of IgE, eosinophiles and change of T lymphocytes. The transfer factor is an immunomodulator active substance and decreases the number of inflammatory cells and the severity of the symptoms of atopic dermatitis. OBJECTIVE: To determine the efficacy of the transfer factor as treatment of moderate and severe atopic dermatitis. MATERIAL AND METHODS: Articles related to treatment with transfer factor in the atopic dermatitis were looked up in Medline and EMBASE, and the ones referring to controlled studies in patients with moderate and severe atopic dermatitis in accord to SCORAD. RESULTS: We found seven articles with 121 patients and 88 controls demonstrating significant decrease in the symptoms of the SCORAD index, decreased IgE, and eosinophils in patients treated with transfer factor. CONCLUSIONS: The transfer factor is a choice treatment for moderate and severe atopic dermatitis.