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Background The HIV pandemic continues to cause a high burden of morbidity and mortality due to delayed diagnosis. Histoplasmosis is prevalent in Latin America and Colombia, is difficult to diagnose and has a high mortality. Here we determined the clinical characteristics and risk factors of histoplasmosis in people living with HIV (PLWH) in Pereira, Colombia. Materials and methods This was a retrospective cross-sectional study (2014–2019) involving two tertiary medical centers in Pereira, Colombia. People hospitalized with HIV were included. Histoplasma antigen detection was performed in urine samples. Probable histoplasmosis was defined according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group/National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria. Results 172 HIV-infected patients were analyzed. Histoplasmosis was confirmed in 29% (n = 50/172) of patients. The logistic regression analysis showed that the risk factors for histoplasmosis were pancytopenia (OR 4.1, 95% CI 1.6–10.3, P = 0.002), 46 IU/L (OR 3.2, 95% CI 1.3–8, P = 0.010). Conclusions Histoplasmosis is highly prevalent in hospitalized patients with HIV in Pereira, Colombia. The clinical findings are nonspecific, but there are some clinical abnormalities that can lead to suspicion of the disease, early diagnosis and prompt treatment. Urine antigen detection is useful for diagnosis, but is not widely available. An algorithmic approach is proposed for low-resource clinical settings.

Geriatricians and others must embrace the emerging field of geroscience. Until recently geroscience research was pursued in laboratory animals, but now this field requires specialized expertise in the care of vulnerable older patients with multiple chronic diseases and geriatric syndromes, the population likely to benefit the most from emerging therapies. While chronological aging measures the inevitable passage of clock time that occurs equally for everyone, biological aging varies among individuals, and importantly, it is modifiable. Advances in our understanding of biological aging, the discovery of strategies for modifying its rate, and an appreciation of aging as a shared risk factor for chronic diseases have jointly led to the Geroscience Hypothesis. This hypothesis states that interventions modifying aging biology can slow its progression-resulting in the delay or prevention of the onset of multiple diseases and disorders. Here we wish to report on the Third Geroscience Summit held at National Institutes of Health on November 4-5, 2019, which highlighted the importance of engaging other disciplines including clinicians. Involvement by scientists with expertise in clinical trials, health outcomes research, behavioral and social sciences, health policy, and economics is urgently needed to translate geroscience discoveries from the bench to clinical care and health policy. Adding to the urgency of broadening this geroscience coalition is the emergence of biological aging as one the most important modifiable factors of COVID-19, combined with the inability of our society to once again recognize and confront aging as a priority and opportunity when facing these types of public health emergencies.

Introduction: Histoplasmosis is an opportu­nistic granulomatous fungal infection. Peritoneal histoplasmosis (PH) is a rare form of dissem­inated histoplasmosis (DH).Case description: A 44-year-old male pa­tient with history of HIV infection, systemic lupus erythematosus with lupus nephritis, and chronic kidney disease on peritoneal dialysis, presented with recurrent ascites without clear etiology in the serial study of ascitic fluid. Con­trast computed tomography of the abdomen showed a nonspecific peritoneal nodule, for which laparoscopy and biopsy were performed, identifying Histoplasma capsulatum infection. The subject received 15 days of in-hospital treatment with amphotericin B deoxycholate with good evolution, no recurrence of ascites, and indefinite outpatient management with itraconazole.Discussion: The first case of PH was described in 1970 but this is the first case reported in Co­lombia. Most cases of PH have been associated with peritoneal dialysis. Its diagnosis is based on the study of ascitic fluid and its treatment follows the guidelines of other forms DH.Conclusions: PH is a rare entity that requires high clinical suspicion, especially in immuno­compromised patients.

Introduction: Congenital fibrinogen disorders are rare conditions in which there are quantitative and qualitative alterations of factor I; the vast majority of patients are asymptomatic.Case presentation: A 19-year-old female patient with a history of congenital hypofibrinogenemia presented with spontaneous vulvar hematoma along with hypotension, tachycardia, stupor and hematoma of 20cm in the right labium majus. On admission, the young woman had hemoglobin 6.6 g/dL, fibrinogen 74 mg/dL and prolonged clotting times. She received red blood cells transfusion and cryoprecipitates, followed by surgical drainage and intravenous fibrinogen replacement, adjusting the dose according to fibrinogen levels in plasma. The patient presented progressive improvement without hemorrhagic recurrence and fibrinogen levels within the target values until hospital discharge.Discussion: Afibrinogenemia and hypofibrin­ogenemia are part of the quantitative factor I disorders; in the first case, there is total absence of circulating fibrinogen, and in the second case the levels are below 150 mg/dL. Sponta­neous vulvar hematoma as a severe hemorrhagic manifestation is not frequent in symptomatic patients; its treatment is based on fibrinogen replacement in an individualized manner and surgical management when required.Conclusion: Hypofibrinogenemia is a rare dis­ease, and fibrinogen replacement is one of the mainstays of treatment.

The data on COVID-19 is clear on at least one point: Older adults are most vulnerable to hospitalization, disability and death following infection with the novel coronavirus. Therefore, therapeutically addressing degenerative aging processes as the main risk factors appears promising for tackling the present crisis and is expected to be relevant when tackling future infections, epidemics and pandemics. Therefore, utilizing a geroscience approach, targeting aging processes to prevent multimorbidity, via initiating broad clinical trials of potential geroprotective therapies, is recommended.

Introducción: se define neumomediastino espontáneo (NE) a la presencia de aire en el intersticio mediastinal. Es una entidad rara, considerada benigna y autolimitada que afecta, en la mayoría de los casos, a adultos jóvenes. Su diagnóstico es clínico y radiológico.Descripción del caso: hombre de 21 años de edad con tos y expectoración verdosa de cuatro días, síntomas asociados a disnea, dolor torácico, fiebre y enfisema subcutáneo supraclavicular bilateral. La radiografía tórax sugirió neumomediastino, el cual fue confirmado por tomografía. El paciente fue hospitalizado para observación y tratamiento. Luego de una evolución positiva, fue dado de alta al sexto día.Discusión: el NE es un diagnóstico diferencial en pacientes que consultan por dolor torácico y disnea. Su prevalencia es inferior a 0.01% y su mortalidad es baja. Debe sospecharse en pacientes con dolor torácico y enfisema subcutáneo al examen físico. Entre 70 y 90% de los casos pueden identificarse mediante radiografía de tórax, mientras que su confirmación puede obtenerse a través de tomografía de tórax. En la mayoría de casos no requiere estudios adicionales.Conclusión: el NE es una causa poco conocida de dolor torácico agudo, rara vez se tiene en cuenta como diagnóstico diferencial; es auto limitado y tiene buen pronóstico.

Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as increased vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, HIV care, nephrology, and in the behavioral and social sciences. Incorporation of frailty assessment and frailty research into the specialties is hindered by a lack of a consensus definition, by the proliferation of measurement tools, inadequate understanding of the biology of frailty, and lack of validated clinical algorithms for patients who have frailty. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA) and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA sponsored ‘Grants for Early Medical/Surgical Specialists Transition into Aging Research (GEMSSTAR)’1 program to review the current state of the knowledge regarding frailty in the sub-specialties, as well as to highlight key examples of integrating frailty research into the medical specialties. Key research questions to advance frailty research into specialty medicine are proposed.

Aging is the major risk factor for both the development of chronic diseases and loss of functional capacity. Geroscience provides links among the biology of aging, the biology of disease, and the physiology of frailty, three fields where enormous progress has been made in the last few decades. While, previously, the focus was on the role of aging in susceptibility to disease and disability, the other side of this relationship, which is the contribution of disease to aging, has been less explored at the molecular/cellular level. Indeed, the role of childhood or early adulthood exposure to chronic disease and/or treatment on accelerating aging phenotypes is well known in epidemiology, but the biological basis is poorly understood. A recent summit co-organized by the National Institutes of Health GeroScience Interest Group and the New York Academy of Sciences explored these relationships, using three chronic diseases as examples: cancer, HIV/AIDS, and diabetes. The epidemiological literature clearly indicates that early exposure to any of these diseases and/or their treatments results in an acceleration of the appearance of aging phenotypes, including loss of functional capacity and accelerated appearance of clinical symptoms of aging-related diseases not obviously related to the earlier event. The discussions at the summit focused on the molecular and cellular relationships between each of these diseases and the recently defined molecular and cellular pillars of aging. Two major conclusions from the meeting include the desire to refine an operational definition of aging and to concomitantly develop biomarkers of aging, in order to move from chronological to physiological age. The discussion also opened a dialogue on the possibility of improving late-life outcomes in patients affected by chronic disease by including age-delaying modalities along with the standard care for the disease in question.

Resumen Objetivo Describir la prevalencia de enfermedades reumaticas en una cohorte de pacientes con infeccion por VIH y sus caracteristicas demograficas y clinicas. Pacientes y metodos Estudio descriptivo de corte transversal de una cohorte de 1.712 pacientes con infeccion por VIH, en un hospital universitario, seguidos desde enero del 2005 hasta septiembre del 2013. Resultados Se encontro una prevalencia de enfermedades reumaticas del 5,2% (n = 89 casos), el 24% de sexo femenino y el 76% de sexo masculino. Edad promedio ± desviacion estandar 45 ± 11 anos. Las enfermedades encontradas fueron: artritis reactiva 15% (n = 14), artrosis 15% (n = 14), purpura trombocitopenica inmune 11% (n = 10), otras 59% (n = 53). El tiempo promedio entre el diagnostico de VIH y la condicion reumatica fue de 73 ± 66 meses. Dentro de las comorbilidades se encontraron: dislipidemia 39% (n = 43), hepatitis B 17% (n = 19), lipodistrofia 11% (n = 12), herpes zoster 10% (n = 11) e hipotiroidismo 9% (n = 10). Conclusiones Se presenta informacion respecto a las comorbilidades reumaticas en una cohorte de pacientes con infeccion por VIH. Como se ha documentado en otras series, la artritis reactiva fue la enfermedad reumatica mas frecuente junto con osteoartrosis. Nuestro estudio evidencia una tendencia hacia el envejecimiento de los pacientes con VIH gracias a un mejor control de la enfermedad, con el uso de terapia antirretroviral, lo cual aumenta la prevalencia de osteoartrosis.

Introducción: el infarto pulmonar ocurre entre un 29 y un 32% de pacientes con tromboembolismo pulmonar (TEP). Por su parte, la infección de un infarto pulmonar complica aproximadamente del 2 al 7% de los casos, lo que hace que el infarto pulmonar infectado sea una entidad poco frecuente.Descripción del caso: mujer de 49 años con dolor pleurítico en hemitórax izquierdo, irradiado a región dorsal, asociado a disnea y edema doloroso de miembro inferior izquierdo de dos días de evolución. Dos semanas antes de su ingreso la paciente sufrió trauma de rodilla izquierda, el cual que requirió intervención quirúrgica; sin embargo, por motivos desconocidos, no recibió profilaxis anti trombótica. En el examen físico se encontró taquicardia, taquipnea y edema doloroso con eritema en pierna izquierda. Al existir alta sospecha de tromboembolia pulmonar se inició anticoagulación y se solicitó angiotomografía de tórax, con la cual fue posible confirmar el diagnóstico. Durante su evolución, la paciente experimentó signos de respuesta inflamatoria sistémica, deterioro respiratorio. Se realizó tomografía de control sugestiva de infarto pulmonar infectado. Se inició antibiótico y la paciente mejoró de forma progresiva; después de esta mejora, fue dada de alta para continuar anticoagulación y seguimiento ambulatorios.Conclusiones: el infarto pulmonar es una complicación frecuente en pacientes con TEP. Por lo tanto, debe sospecharse infarto pulmonar infectado en pacientes con deterioro clínico y respuesta inflamatoria sistémica. La diferencia radiológica entre infarto pulmonar y neumonía no es fácil de identificar, su enfoque diagnóstico es clínico y el tratamiento anticoagulante y antimicrobiano debe iniciarse de manera oportuna.

Population aging is unprecedented, without parallel in human history, and the 21st century will witness even more rapid aging than did the century just past. Improvements in public health and medicine are having a profound effect on population demographics worldwide. By 2017, there will be more people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60 (http://unfpa.org/ageingreport/). Although we can reasonably expect to live longer today than past generations did, the age-related disease burden we will have to confront has not changed. With the proportion of older people among the global population being now higher than at any time in history and still expanding, maintaining health into old age (or healthspan) has become a new and urgent frontier for modern medicine. Geroscience is a cross-disciplinary field focused on understanding the relationships between the processes of aging and age-related chronic diseases. On October 30-31, 2013, the trans-National Institutes of Health GeroScience Interest Group hosted a Summit to promote collaborations between the aging and chronic disease research communities with the goal of developing innovative strategies to improve healthspan and reduce the burden of chronic disease.

There is considerable controversy about the molecular mechanisms responsible for the variations in innate immunity associated with age. While in vivo, aged animals and humans react to an inflammatory signal with an excessive production of pro-inflammatory cytokines, studies in vitro generally show that this response is attenuated in macrophages from old individuals. In an effort to examine possible extrinsic factors that might affect the response of macrophages to lipopolysaccharide (LPS), we have challenged peritoneal macrophages obtained from young rats with sera obtained from rats of different ages. Our results indicate that the serum from aged rats significantly impairs the capacity of young macrophages to induce tumor necrosis factor-alpha (TNF-alpha) production, while at the same time it increases the basal levels of interleukin-6 (IL-6). The effect of serum from aged donors on TNF-alpha secretion requires pre-incubation and is sensitive to heat inactivation. In contrast, the stimulating effect on IL-6 is resistant to heat, and thus should not be due to a protein factor. Therefore, our results indicate that the age-related changes in macrophage activity are not only the consequence of intrinsic changes, but there also appears to be a modulatory effect imparted by the external milieu.

Senescence has been proposed as an important safeguard against neoplasia. One of the hallmarks of cellular senescence in vitro as well as human aging in vivo is a reduced intracellular protein catabolism. The pathways affected and the mechanisms responsible for the decrease in overall protein turnover in aging cells are not well understood. Our aim was to determine whether or not expression of one of the major hepatic lysosomal cysteine peptidases, cathepsin B, changes during aging of Sprague-Dawley rats. Cathepsin B activity was assessed in whole rat liver homogenates, and was found to be increased fourfold (Por =0.001) in aged livers compared with younger counterparts. This was paralleled by an at least a twofold increase in mature cathepsin B protein. Nonetheless, Northern blot analysis of total liver RNA revealed no change in steady-state levels of cathepsin B mRNAs. These findings seem to contradict the present dogma according to which aging tissues have a reduced intracellular capacity to catabolise proteins. We propose that our earlier observation of the accumulation of T-kininogen, a potent but reversible cysteine peptidase inhibitor, in aging rat liver may provide a plausible explanation for this discrepancy.

The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation in Age-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified.

In the rat, kininogens are produced from two distinctly regulated gene families, T- and K-kininogens. We have previously established that T-kininogen (T-KG, thiostatin) gene expression is increased in the liver of old rats, as compared to their younger counterparts. In this report, we have used Northern blot analysis to show that the steady state mRNA levels for either the LMW (Low Molecular Weight) or HMW (High Molecular Weight) forms of K-KG do not change significantly between 15 and 25 months of age. On the other hand, probing of Western blots containing total serum proteins showed that, as for T-KG, old animals have consistently elevated levels of HMW-KG. These results indicate that old rats contain elevated serum levels of both T- and K-KG. Nuclear run on experiments have shown that the increase in T-KG gene expression is controlled primarily at the transcriptional level. Our present results with K-KG, on the other hand, indicate that its expression is controlled post-transcriptionally.

Aging is associated with a deterioration of the acute phase response to inflammatory challenges. However, the nature of these defects remains poorly defined. We analyzed the hepatic inflammatory response after intraperitoneal administration of lipopolysaccharide (LPS) given to Fisher 344 rats aged 6, 15, and 22-23 months. Induction of the acute phase proteins (APPs), haptoglobin, alpha-1-acid glycoprotein, and T-kininogen was reduced and/or retarded with aging. Initial induction of interleukin-6 in aged rats was normal, but the later response was increased relative to younger counterparts. An exacerbated hepatic injury was observed in aged rats receiving LPS, as evidenced by the presence of multiple microabscesses in portal tracts, confluent necrosis, higher neutrophil accumulation, and elevated serum levels of alanine aminotransferase, relative to younger animals. Our results suggest that aged rats displayed a reduced expression of APPs and increased hepatic injury in response to the inflammatory insult.

Aging results in a general decline in the response to external insults, including acute inflammatory challenges. In young animals, the inflammatory response requires activation of the sympathetic system, including neurotransmitters such as ATP, and catecholamines (epinephrine and norepinephrine). To test whether aging affects activation of this axis, and whether this in turn might affect cytokine release, we administered lipopolysaccharide (LPS) i.p. to adult, middle-aged and aged Fisher 344 rats (6-, 15- and 23-month old, respectively) and evaluated the early (0-12h) serum levels of Neuropeptide-Y (NP-Y), ATP and vanillyl mandelic acid (VMA, as an indirect measurement of catecholamine levels). In addition, we evaluated the association between these factors and serum levels of the cytokines tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL-10). Induction of both ATP and NP-Y was markedly reduced in the serum of aged animals, when compared to their younger counterparts, while induction of VMA was not affected by age. In spite of these changes, serum levels of TNFalpha and IL-10 were strongly hyper induced and delayed in aged rats. The results suggest that during aging there is a dysregulation in sympathetic neurotransmitter regulatory mechanisms, and this might play a role in the impairment of the inflammatory response.

T-kininogen (T-KG) is a reliable biomarker of aging in male Sprague-Dawley rats. Here we confirm, in a longitudinal study, a similar behavior in Fisher 344 rats of both sexes. In males, the increase in serum levels of T-KG follows an exponential curve, whereas in females the increase is best fitted by a linear curve. In both genders, dietary restriction delays the increase in T-KG. We have previously shown that T-KG inhibits T lymphocyte proliferation. Here we show that serum T-KG levels correlate negatively with the ability of splenocytes (most likely B cells) to proliferate in response to lipopolysaccharide. A similar correlation was not observed with other markers of inflammation, including alpha1-acid glycoprotein (AGP), haptoglobin, or interleukin-10. We conclude that the increase in serum T-KG represents a useful biomarker of aging in Fisher 344, and it correlates with decreased lymphocyte proliferation with age, although a cause-effect relationship has not been established.

Basal proliferation of endothelial cells increases with age, and this might play a role in the etiology of age-related vascular diseases, as well as angiogenesis. Serum kininogen levels increase during aging in rats and humans, and T-kininogen (T-KG) can affect proliferative homeostasis in several cell models. Both kinins and kininogens have been shown previously to be angiogenic through activation of endothelial cell proliferation, and here we show that exposure of endothelial cells to T-KG results in vigorous cell proliferation, accompanied by ERK/AKT activation. In our experiments, the proliferative response requires B1 and B2 kinin receptors, even though kinins are not released from the precursor. We hypothesize that the age-related increase in T-KG could play a significant role in the age-related dysregulation of vascular physiology and function.

Kinins are vasoactive peptides released from precursors called kininogens, and serum levels of both T- and K-kininogens increase dramatically as rats age. Kinin release is tightly regulated, and here we show that serum kinin levels also increase with age, from 63 +/- 16 nmol/L in young Fisher 344 rats to 398 +/- 102 nmol/L in old animals. Both K- and T-kininogens contribute sequentially to this increase, with the increase in middle-aged animals being driven primarily by K-kininogen, whereas the further augmentation in older rats occurs by increasing T-kininogen. By measuring ERK activation, we show that aorta endothelial cells from old animals are hyporesponsive to exogenous bradykinin. However, if serum kinin levels are experimentally decreased by lipopolysaccharide treatment, then the endothelial response to bradykinin is re-established. These results indicate that serum levels of kinins increase with age, whereas the responsiveness of target cells to kinins is reduced in these same animals.

During the past ten years considerable progress has been made in discovering genes that regulate longevity by identifying single gene mutations that lead to increased longevity. The initial success in nematodes was quickly followed by comparable success in fruit flies and mice. In contrast, mutations that cause a decrease in longevity have been largely discounted as unlikely to be informative about aging mechanisms. However, the recent creation of several mutant mouse models that develop a variety of aging-like phenotypes and die prematurely, suggests that such models may be useful in understanding aging mechanisms, particularly as they relate to progressive tissue and organ dysfunction. A possible common feature of these models may be an imbalance between loss of cells by apoptosis and subsequent cell replacement, leading gradually to a net loss of cells in multiple tissues.

Mitogen activated protein kinases (MAPK) are activated by a wide variety of signals leading to cell proliferation and differentiation in different cell types. With aging, there is a marked decrease in proliferation of T-lymphocytes in response to a variety of mitogens. Several age-related changes in the activation of MAPK pathways in T-lymphocytes activated via the T-cell receptor (TCR) have been described in different species. This way, some TCR proximal defects in tyrosine kinase activity have been delineated. In this study, we have used rat splenic lymphocytes to measure the effect of aging on the activation of two MAP kinase families: ERK and JNK. In order to bypass the receptor-proximal age-dependent defects previously described, we used phorbol ester (PMA) and Ca2+ ionophore (A23187) as co-mitogens. Our results demonstrate that splenic lymphocytes from old rats have a disturbance in the activation of the ERK and JNK MAPK signal transduction pathways, that are located downstream of the receptor-proximal events. At least part of the age-related defect leading to decreased ERK activity appears to be located upstream of ERK itself, since activation of MEK is also impaired. On the other hand, the observed defects in MAPK activation do result in decreased activation of downstream events, such as c-Jun phosphorylation. Thus, we conclude that aging of splenic lymphocytes results in a functional decline in signal transduction, and at least some of these defects are located downstream of the receptor-proximal events previously described by others. The impaired activity of these two MAP kinase pathways is likely to play a role in the diminished lymphoproliferation observed in old individuals.

We have previously reported on the identification of T-kininogen (T-KG) as a gene whose expression is increased during senescence in male Sprague–Dawley (S–D) rats. Serum T-KG levels increase 2.5–4 months before the time of death for any given animal, irrespective of the actual age of the animal at the time of this event. Furthermore, dietary restriction (DR) delays, but does not prevent, the increase in serum T-KG levels. In the present study, we have assessed whether or not the age-related increase in T-KG is a common feature of senescence in other strains of rat. We have analyzed hepatic T-KG mRNA levels in male Fischer 344 rats (F344), as well as in male and female (Fischer 344×Brown Norway)F1 rats (F1). In both of these strains, we observed a dramatic increase in hepatic T-KG mRNA levels when male rats approach senescence. The mRNA levels behave similarly in F1 and S–D rats, in that the increase occurs late in life, and it is either repressed or delayed by DR. In contrast, the increase in T-KG mRNA levels in F344 rats occurs earlier in life, and is not significantly affected by DR. Young female F1 rats fed ad libitum (AL) show a statistically significant ( P =0.0009) 2.6-fold higher level of T-KG mRNA, as compared to their male counterparts. Thus, while we still observe an age-related increase in this parameter in both AL and DR female F1 rats, the difference is statistically significant ( P =0.0001) only in DR animals. We conclude that the increase in T-KG gene expression is a common feature of senescence and that, at least in males of these commonly used rat strains, T-KG can be used as a reliable biomarker of aging. Since the increase in T-KG gene expression does not appear to correlate with inflammatory processes, and since different strains of animals succumb to different pathologies, these results further suggest that the increase in T-KG expression might be related to the process of aging per se, rather than to any given age-related pathology.