Colocalization of ß-Sheets and Carotenoids in Aß Plaques Revealed with Multimodal Spatially Resolved Vibrational Spectroscopy.

The aggregation of amyloid ß(Aß) peptides is at the heart of Alzheimer's disease development and progression. As a result, amyloid aggregates have been studied extensively in vitro, and detailed structural information on fibrillar amyloid aggregates is available. However, forwarding these structural models to amyloid plaques in the human brain is still a major challenge. The chemistry of amyloid plaques, particularly in terms of the protein secondary structure and associated chemical moieties, remains poorly understood. In this report, we use Raman microspectroscopy to identify the presence of carotenoids in amyloid plaques and demonstrate that the abundance of carotenoids is correlated with the overall protein secondary structure of plaques, specifically to the population of ß-sheets. While the association of carotenoids with plaques has been previously identified, their correlation with the ß structure has never been identified. To further validate these findings, we have used optical photothermal infrared (O-PTIR) spectroscopy, which is a spatially resolved technique that yields complementary infrared contrast to Raman. O-PTIR unequivocally demonstrates the presence of elevated ß-sheets in carotenoid-containing plaques and the lack of ß structure in noncarotenoid plaques. Our findings underscore the potential link between anti-inflammatory species as carotenoids to specific secondary structural motifs within Aß plaques and highlight the possible role of chemically distinct plaques in neuroinflammation, which can uncover new mechanistic insights and lead to new therapeutic strategies for AD.

Dedifferentiated endometrial carcinoma metastasis to axillary lymph node: a case report.

BACKGROUND: We present an unusual case of a left axillary lymph node metastasis from a primary dedifferentiated endometrial carcinoma. This pattern of metastasis is likely the result of circulating tumor cells reaching the node through its arterial blood supply. CASE PRESENTATION: In this report, a 68-year-old white woman with a dedifferentiated endometrial carcinoma underwent a hysterectomy. She later developed an enlarged axillary lymph node due to metastatic dedifferentiated endometrial carcinoma, treated with chemotherapy and anti-programmed cell death protein 1 immunotherapy resulting in a complete clinical and radiological response. CONCLUSION: A review of the literature reveals the rarity of blood-borne lymph node metastasis, especially with uterine carcinoma. Immunotherapy has shown promising results in the treatment of some subtypes of metastatic uterine carcinoma.

Pulmonary restriction predicts long-term pulmonary impairment in people with HIV and tuberculosis.

BACKGROUND: While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment. METHODS: In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment and constructed logistic regression models to identify characteristics associated with pulmonary impairment. RESULTS: Among 134 participants with a median CD4 count of 110 cells/µl, 112 (83%) completed baseline spirometry at which time 32 (29%) had restriction, 13 (12%) had obstruction, and 9 (7%) had a mixed pattern. Lung function was dynamic over time and 30 (33%) participants had impaired lung function at 12 months. Baseline restriction was associated with greater symptoms and with long-term pulmonary impairment (adjusted odds ratio 5.44, 95% confidence interval 1.16-25.45), while baseline obstruction was not (adjusted odds ratio 1.95, 95% confidence interval 0.28-13.78). CONCLUSIONS: In this cohort of people with HIV and tuberculosis, restriction was the most common, symptomatic, and persistent pattern of pulmonary impairment. These data can help to raise awareness among clinicians about the heterogeneity of post-tuberculosis pulmonary impairment, and highlight the need for further research into mediators of lung injury in this vulnerable population.

Global cellulose biomass, horizontal gene transfers and domain fusions drive microbial expansin evolution.

Plants must rearrange the network of complex carbohydrates in their cell walls during normal growth and development. To accomplish this, all plants depend on proteins called expansins that nonenzymatically loosen noncovalent bonding between cellulose microfibrils. Surprisingly, expansin genes have more recently been found in some bacteria and microbial eukaryotes, where their biological functions are largely unknown. Here, we reconstruct a comprehensive phylogeny of microbial expansin genes. We find these genes in all eukaryotic microorganisms that have structural cell wall cellulose, suggesting expansins evolved in ancient marine microorganisms long before the evolution of land plants. We also find expansins in an unexpectedly high diversity of bacteria and fungi that do not have cellulosic cell walls. These bacteria and fungi inhabit varied ecological contexts, mirroring the diversity of terrestrial and aquatic niches where plant and/or algal cellulosic cell walls are present. The microbial expansin phylogeny shows evidence of multiple horizontal gene transfer events within and between bacterial and eukaryotic microbial lineages, which may in part underlie their unusually broad phylogenetic distribution. Overall, expansins are unexpectedly widespread in bacteria and eukaryotes, and the contribution of these genes to microbial ecological interactions with plants and algae has probbaly been underappreciated.

A Common NLRC4 Gene Variant Associates With Inflammation and Pulmonary Function in Human Immunodeficiency Virus and Tuberculosis.

BACKGROUND: Inflammasomes mediate inflammation in adults living with both human immunodeficiency virus (HIV) and tuberculosis (TB), but the relevance of inflammasome gene polymorphisms in TB-associated pulmonary damage is unknown. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in inflammasome pathway genes modify systemic and pulmonary inflammation, contributing to respiratory impairment in adults living with HIV/pulmonary TB. METHODS: This was a prospective cohort study set in South Africa following individuals living with HIV/TB up to 48 weeks post-antiretroviral therapy (ART) initiation. Ten functional SNPs in 5 inflammasome pathway genes were related to circulating inflammatory biomarkers and lung function assessed by spirometry pre- and post-ART initiation. Analyses used 2-sided t tests, Wilcoxon rank sum tests, Spearman correlation coefficients, linear regression, and generalized estimating equation models. RESULTS: Among 102 patients with baseline samples, the minor allele (T) in NLRC4 rs385076 was independently associated with lower levels of interleukin (IL)-18 and IL-6 before and up to 12 weeks post-ART initiation (Benjamini-Hochberg corrected P values < .02). Patients with the CT/TT genotypes also had improved lung function vs CC patients up to 48 weeks post-ART initiation (forced vital capacity, 206 mL higher; 95% confidence interval [CI], 67-345 mL; P = .004 and forced expiratory volume in 1 second, 143 mL higher; 95% CI, 11-274 mL; P = .034). CONCLUSIONS: A common SNP in the NLRC4 inflammasome may modify TB-associated inflammation in clinically relevant ways. This SNP may identify high-risk groups for lung damage in TB. Inhibition of NLRC4 activity may be an important approach for TB host-directed therapy.

Declines in Lung Function After Antiretroviral Therapy Initiation in Adults With Human Immunodeficiency Virus and Tuberculosis: A Potential Manifestation of Respiratory Immune Reconstitution Inflammatory Syndrome.

End-organ impairment has received relatively little research attention as a possible manifestation of tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS). In this prospective cohort study, one-half of adults with human immunodeficiency virus and pulmonary tuberculosis experienced meaningful declines in lung function on antiretroviral therapy, suggesting a role for lung function in TB-IRIS definitions.

Altered hypothalamic-pituitary-adrenocortical function in rhesus monkeys (Macaca mulatta) with self-injurious behavior.

Individually housed rhesus monkeys sometimes spontaneously develop self-injurious behavior (SIB) in the form of self-directed biting that, on occasion, results in severe tissue damage and mutilation. We previously demonstrated lower levels of plasma cortisol in rhesus monkeys with a history of self-wounding (SW) when compared to non-wounders (NW). Furthermore, cortisol levels were negatively correlated with rates of self-directed biting. The present study was designed to further characterize the relationships between hypothalamic-pituitary-adrenocortical (HPA) activity, self-wounding, and self-directed biting. Basal 24-h urinary free cortisol excretion, the urinary free cortisol response to a low dose of dexamethasone, and the plasma cortisol response to ACTH were examined in 24 individually housed rhesus monkeys, based on wounding history, i.e. the presence/absence of a veterinary record of self-wounding, and current rates of self-directed biting, i.e. the median split of self-directed biting frequency (independent of wounding status). There were no reliable group differences on any of the physiological measures when analyzed by wounding history. However, the plasma cortisol response 30 min post-ACTH stimulation was significantly correlated with wounding recency, such that lower responsivity was associated with more recent wounding episodes. When the results were analyzed on the basis of biting frequency, high frequency biters (HFB) compared to low frequency biters (LFB) showed decreased HPA negative feedback sensitivity to dexamethasone and a trend towards an attenuated plasma cortisol response to ACTH stimulation. These findings suggest that SIB in socially reared monkeys is associated with complex changes in HPA axis function that are related to the expression of the pathology, i.e. self-directed biting, and to the recency of a wounding episode. It remains to be determined whether humans who exhibit SIB show similar alterations in HPA function.

Self-injurious behavior in male rhesus macaques does not reflect externally directed aggression.

Self-injurious behaviors (SIB), such as self-biting and self-wounding, have been observed in a small percentage of captive nonhuman primates. Because rhesus monkeys that exhibit SIB also tend to be more aggressive, it was hypothesized that SIB is related to externally directed aggression and is associated with contexts in which physical contact between participants is prevented. The purpose of this study was to test the hypothesized relationship between SIB and outward aggression. Subjects were first presented with videotapes of conspecifics, scenery and a blank screen, and their behavior was recorded. Levels of salivary cortisol, an indicator of stress, were also measured before and after presentation of the videos. Although aggression increased when subjects viewed tapes containing conspecifics, neither cortisol levels nor self-biting behavior varied as a function of tape content. The subjects were then placed in two additional test situations: an empty room and the same room containing an unfamiliar conspecific. Aggression was significantly higher in the stranger condition compared to the empty room condition. The two situations yielded parallel increases in cortisol, suggesting that being alone was just as stressful as being paired with an unfamiliar conspecific. Self-biting rates were also similar in these two conditions. Thus, contrary to our prediction, increases in aggression did not correlate with increases in SIB. These results suggest that under similarly stressful conditions, SIB and externally directed aggression are unrelated.

Unintended and unwanted pregnancy in St. Lucia

Among 200 mothers interviewed in St. Lucia, 82//described their pregnancy as unintended and 44//as unwanted; 80//of women having an intended pregnancy and 94.6//having an unintended pregnancy were unmarried and 18.5//were teenagers. Mothers of unintended pregnancies were significantly younger, were significantly higher parity and had begun sexual relations at a significantly earlier age than mothers of intended pregnancies; and unlike mothers of plannerd pregnancies, their desired interpregnancy interval was significantly longer than the actual interval. These results and the sporadic and ineffective use of contraception in St. Lucia emphasize the need for improvements in fertility regulation in that country

Unintended and unwanted pregnancy in St. Lucia

Among 200 mothers interviewed in St. Lucia, 82 percent described their pregnancy as unintended and 44 percent as unwanted; 80 percent of women having an intended pregnancy and 94.6 percent having an unintended pregnancy were unmarried and 18.5 percent were teenagers. Mothers of unintended pregnancies were significantly younger, were significantly higher parity and had begun sexual relations at a significantly earlier age than mothers of intended pregnancies; and unlike mothers of plannerd pregnancies, their desired interpregnancy interval was significantly longer than the actual interval. These results and the sporadic and ineffective use of contraception in St. Lucia emphasize the need for improvements in fertility regulation in that country (AU)

Vitamin E, lipid fractions, and fatty acid composition of colostrum, transitional milk, and mature milk: an international comparative study

Triglycerides, cholesterol, fatty acid composition, and tocopherols were determined in colustrum, transitional milk, and mature milk in St. Lucia. With progress of lactation, triglycerides and percentage medium-chain fatty acids increased whereas tocopherols, cholesterol and percentage long-chain polyunsaturated fatty acids decreased. These changes reflect augmented de novo synthesis of fatty acids (8:0, 10:0, 12:0, and 14:0) in the mammary gland and a tendency of increasing fat-globule size as milk matures. Transitional and mature milks, but particularly colustrum, contained higher concentrations of components considered to be derived from the fat-globule membrane (cholesterol, tocopherols, percentage long-chain polyunsaturated fatty acids) compared with those reported for Western countries. Percentage medium-chain fatty acids in mature milk was two to three times higher than in developed countries. Differences from data from studies in Western countries are discussed in relation to analytical methods and possible consequences for lipid digestion, lipid absorption, growth, and brain development.(AU)