Medical Aid in Dying.

As the nation's 75 million baby boomers enter into a new phase of their life, care for their aging parents, and contemplate their own mortality, many have come to realize that our end-of-life care system is hamstrung by outdated modes of dying. This chapter discusses the current status of medical aid in dying in the United States as a legal and medically recognized medical option for supporting patients at life's end.

Delayed spironolactone administration prevents the transition from acute kidney injury to chronic kidney disease through improving renal inflammation.

BACKGROUND: Acute kidney injury (AKI) is not as harmless as previously thought since it may lead to chronic kidney disease (CKD). Because most of the time ischemic AKI occurs unexpectedly, it is difficult to prevent its occurrence and there are no specific therapeutic approaches to prevent the AKI to CKD transition. We aimed to determine whether mineralocorticoid receptor blockade (MRB) in the first days after ischemia/reperfusion (IR) can prevent progression to CKD. METHODS: Four groups of male Wistar rats were included: sham and three groups of bilateral renal ischemia for 45 min, one without treatment and the other two receiving spironolactone for 5 or 10 days, starting 24 h after IR. The rats were studied at 10 days or 5 months after ischemia induction. RESULTS: After 5 months of follow-up, the untreated group exhibited clear evidence of AKI to CKD progression, such as proteinuria, reduced renal blood flow, tubulointerstitial fibrosis, glomerulosclerosis and glomerular hypertrophy. All these alterations were prevented by both spironolactone treatments initiated 24 h after IR, the 10-day treatment being more effective. Within the early mechanisms of the MRB protective effect are the reduction of inflammation and increased endothelin-B-receptor expression and endothelial nitric oxide synthase activation in the first 10 days after IR. CONCLUSIONS: We propose that MRB, administered 24 h after the ischemic injury that leads to AKI, reduces inflammation and promotes efficient tissue repair that avoids the AKI to CKD transition. These data highlight a therapeutic window to preclude CKD development after AKI.

Geraniin is a diuretic by inhibiting the Na+-K+-2Cl- cotransporter NKCC2.

Geranium seemannii Peyr is a perennial plant endemic to central Mexico that has been widely used for its diuretic effect, but the responsible compound of this effect is unknown as well as the mechanism by which the diuretic effect is achieved. Geraniin is one of the compounds isolated from this kind of geranium. This study was designed to determinate whether geraniin possesses diuretic activity and to elucidate the mechanism of action. Geraniin was extracted and purified from Geranium seemannii Peyr. Male Wistar rats were divided into four groups: 1) Control, 2) 75 mg/kg of geraniin, 3) 20 mg/kg of furosemide, and 4) 10 mg/kg of hydrochlorothiazide. Each treatment was administered by gavage every 24 h for 7 days. The urinary excretion of electrolytes and the fractional excretion of sodium (FENa) were determined. To uncover the molecular target of geraniin, Xenopus laevis oocytes were microinjected with cRNAs encoding the Na+-Cl- cotransporter (NCC) and the Na+-K+-2Cl- cotransporter NKCC2 to functionally express these cotransporters. Geraniin significantly increased diuresis, natriuresis, and calciuresis to a similar extent as was observed in the furosemide-treated rats. Consistent with the furosemide-like effect, in X. laevis oocytes, geraniin significantly reduced the activity of NKCC2, with no effect on NCC activity. In contrast to furosemide, the effect of geraniin on NKCC2 was irreversible, apparently due to its inhibitory effect on heat shock protein 90. Our observations suggest that geraniin could have a potential role in the treatment of hypertension or edematous states.

HSP72 is an early biomarker to detect cisplatin and acetaminophen nephrotoxicity.

OBJECTIVE: To evaluate whether the urinary HSP72 levels (uHSP72) are a useful biomarker for early diagnosis of acute kidney injury (AKI) induced by two widely used drugs: cisplatin and acetaminophen. MATERIALS AND METHODS: To analyze the time-course of nephrotoxic injury and uHSP72 levels, male Wistar rats were administered a single high dose of cisplatin (7 mg/kg) or acetaminophen (750 mg/kg) and were assessed at 6, 12, 24, 48, 72, 96 and 120 h. RESULTS: AKI induced by cisplatin was characterized by tubular injury that started at 6 h and was enhanced after 48 h. Plasma creatinine was increased only after 72 h. In contrast, uHSP72 levels were augmented after 6 h and were enhanced after 48 h of cisplatin administration, which was consistent with the tubular injury. In acetaminophen-induced AKI, the tubular lesions were less severe and predominantly characterized by tubular cell detachment. Interestingly, uHSP72 levels were increased after 6 h of acetaminophen injection and remained elevated at the following time points, reflecting the tubular injury, even in the absence of major functional changes. CONCLUSIONS: In two models of renal injury induced by nephrotoxic drugs, we showed that uHSP72 could be used as an early biomarker to detect subtle to severe tubular injury.

Insulin and SGK1 reduce the function of Na+/monocarboxylate transporter 1 (SMCT1/SLC5A8).

SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced α-keto-isocaproate (KIC)-dependent 22Na+ uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent 22Na+ uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent 22Na+ uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na+ uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-14C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent 22Na+ uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas.

Ovarian hormones and prolactin increase renal NaCl cotransporter phosphorylation.

Unique situations in female physiology require volume retention. Accordingly, a dimorphic regulation of the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) has been reported, with a higher activity in females than in males. However, little is known about the hormones and mechanisms involved. Here, we present evidence that estrogens, progesterone, and prolactin stimulate NCC expression and phosphorylation. The sex difference in NCC abundance, however, is species dependent. In rats, NCC phosphorylation is higher in females than in males, while in mice both NCC expression and phosphorylation is higher in females, and this is associated with increased expression and phosphorylation of full-length STE-20 proline-alanine-rich kinase (SPAK). Higher expression/phosphorylation of NCC was corroborated in humans by urinary exosome analysis. Ovariectomy in rats resulted in decreased expression and phosphorylation of the cotransporter and promoted the shift of SPAK isoforms toward the short inhibitory variant SPAK2. Conversely, estradiol or progesterone administration to ovariectomized rats restored NCC phosphorylation levels and shifted SPAK expression and phosphorylation towards the full-length isoform. Estradiol administration to male rats induced a significant increase in NCC phosphorylation. NCC is also modulated by prolactin. Administration of this peptide hormone to male rats induced increased phosphorylation of NCC, an effect that was observed even using the ex vivo kidney perfusion strategy. Our results indicate that estradiol, progesterone, and prolactin, the hormones that are involved in sexual cycle, pregnancy and lactation, upregulate the activity of NCC.

Polyphenols and Health Benefits: Volume I.

Natural polyphenols are functional and bioactive substances widely present in plant-based sources such as fruits, vegetables, and other food items [...].

Sexual Intimacy in Persons with Amyotrophic Lateral Sclerosis and their Partners: A Pilot Study.

OBJECTIVE: The objective of this study was to describe concerns experienced among persons with amyotrophic lateral sclerosis (PALS) and their partners regarding sexual intimacy, as well as preferences regarding discussion of the topic with healthcare providers. METHODS: A total of 27 survey responses including 13 PALS and 14 partners were received. Surveys included both quantitative and qualitative data addressing the importance of sexual intimacy to quality of life, assistance required to participate in sexual intimacy, concerns for safety, and preferred timing and method of discussing/receiving information from healthcare professionals. RESULTS: 100% of respondents stated they had never been asked about sexual intimacy by any healthcare provider. 92% of participants agreed ALS had affected their ability to express sexual intimacy. Participants discussed loss of intimacy as due to muscle weakness, respiratory concerns, and role change among other contributors to the overall experienced change in expression of sexual intimacy. With regards to their preferred method of receiving/discussing information on the effect of ALS on sexual intimacy, 48% of participants preferred use of an online video series, 44% chose a pamphlet, 24% chose a one-on-one discussion with a healthcare provider, and 12% chose a private conversation with their partner and healthcare provider. CONCLUSIONS: The findings greatly illustrate the difficulties and concerns experienced with sexual intimacy among PALS and their partners as well as the preferred methods for receiving information on the topic.

Mechanism of cadmium-induced nephrotoxicity.

Heavy metals are found naturally in our environment and have many uses and applications in daily life. However, high concentrations of metals may be a result of pollution due to industrialization. In particular, cadmium (Cd), a white metal abundantly distributed in the terrestrial crust, is found in mines together with zinc, which accumulates after volcanic eruption or is found naturally in the sea and earth. High levels of Cd have been associated with disease. In the human body, Cd accumulates in two ways: via inhalation or consumption, mainly of plants or fish contaminated with high concentrations. Several international organizations have been working to establish the limit values of heavy metals in food, water, and the environment to avoid their toxic effects. Increased Cd levels may induce kidney, liver, or neurological diseases. Cd mainly accumulates in the kidney, causing renal disease in people exposed to moderate to high levels, which leads to the development of end-stage chronic kidney disease or death. The aim of this review is to provide an overview of Cd-induced nephrotoxicity, the mechanisms of Cd damage, and the current treatments used to reduce the toxic effects of Cd exposure.

Vasorelaxant Effect and Blood Pressure Reduction Potential of Pitaya Juice Concentrate (Stenocereus huastecorum) Associated with Calcium Channel Blockade.

Arterial hypertension is a highly prevalent chronic disease worldwide, with several etiologies and treatments that may eventually have side effects or result in patients developing tolerance. There is growing interest in traditional medicine and functional foods to isolate biomolecules that could be useful as coadjuvants for treating several aliments. Pitaya, a desert fruit endemic in Mexico, is a rich source of bioactive molecules (betalains and phenolic compounds). In this work, the vasorelaxation properties of pitaya juice concentrate and fraction one were investigated using aortic and mesenteric rings from rats. The incubation of rings with pitaya juice concentrate or fraction one induced significant vasorelaxation, independent of the endothelium, and showed resistance to potassium channel blockers. This vasorelaxation was associated with the transmembrane influx of extracellular calcium through the vascular smooth muscle cells, with an inhibitory effect on the voltage-dependent calcium channel currents. Also, 400 mg/mL of pitaya juice concentrate in spontaneous hypertensive rats reduced their blood pressure for 48 h. Phytochemical analyses showed that the primary compounds in F1 were glycosidic in nature, and could be a complex mixture of disaccharides, dimeric disaccharides, or even tetrasaccharides. The glycosidic compounds found in F1 primarily contributed to vasodilatation, establishing a voltage-dependent calcium channel inhibition as a possible molecular target.

Fibrinogen ß-derived Bß(15-42) peptide protects against kidney ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgß, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgß chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgß-derived Bß(15-42) peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

Developmental Programming in Animal Models: Critical Evidence of Current Environmental Negative Changes.

The Developmental Origins of Health and Disease (DOHaD) approach answers questions surrounding the early events suffered by the mother during reproductive stages that can either partially or permanently influence the developmental programming of children, predisposing them to be either healthy or exhibit negative health outcomes in adulthood. Globally, vulnerable populations tend to present high obesity rates, including among school-age children and women of reproductive age. In addition, adults suffer from high rates of diabetes, hypertension, cardiovascular, and other metabolic diseases. The increase in metabolic outcomes has been associated with the combination of maternal womb conditions and adult lifestyle-related factors such as malnutrition and obesity, smoking habits, and alcoholism. However, to date, "new environmental changes" have recently been considered negative factors of development, such as maternal sedentary lifestyle, lack of maternal attachment during lactation, overcrowding, smog, overurbanization, industrialization, noise pollution, and psychosocial stress experienced during the current SARS-CoV-2 pandemic. Therefore, it is important to recognize how all these factors impact offspring development during pregnancy and lactation, a period in which the subject cannot protect itself from these mechanisms. This review aims to introduce the importance of studying DOHaD, discuss classical programming studies, and address the importance of studying new emerging programming mechanisms, known as actual lifestyle factors, during pregnancy and lactation.

The Development of Dyslipidemia in Chronic Kidney Disease and Associated Cardiovascular Damage, and the Protective Effects of Curcuminoids.

Chronic kidney disease (CKD) is a health problem that is constantly growing. This disease presents a diverse symptomatology that implies complex therapeutic management. One of its characteristic symptoms is dyslipidemia, which becomes a risk factor for developing cardiovascular diseases and increases the mortality of CKD patients. Various drugs, particularly those used for dyslipidemia, consumed in the course of CKD lead to side effects that delay the patient's recovery. Therefore, it is necessary to implement new therapies with natural compounds, such as curcuminoids (derived from the Curcuma longa plant), which can cushion the damage caused by the excessive use of medications. This manuscript aims to review the current evidence on the use of curcuminoids on dyslipidemia in CKD and CKD-induced cardiovascular disease (CVD). We first described oxidative stress, inflammation, fibrosis, and metabolic reprogramming as factors that induce dyslipidemia in CKD and their association with CVD development. We proposed the potential use of curcuminoids in CKD and their utilization in clinics to treat CKD-dyslipidemia.

Effectiveness of scapular mobilization in patients with primary adhesive capsulitis: A systematic review and meta-analysis.

BACKGROUND: The aim of this study was to determine the effectiveness of scapular mobilization on range of motion, shoulder disability, and pain intensity in patients with primary adhesive capsulitis (AC). METHODS: An electronic search was performed in the MEDLINE, EMBASE, SCOPUS, CENTRAL, LILACS, CINAHL, SPORTDiscus, and Web of Science databases up to March 2023. The eligibility criteria for selected studies included randomized clinical trials that included scapular mobilization with or without other therapeutic interventions for range of motion, shoulder disability, and pain intensity in patients older than 18 years with primary AC. Two authors independently performed the search, study selection, and data extraction, and assessed the risk of bias using the Cochrane Risk of Bias 2 tool. RESULTS: Six randomized clinical trials met the eligibility criteria. For scapular mobilization versus other therapeutic interventions, there was no significant difference in the effect sizes between groups: the standard mean difference was -0.16 (95% confidence interval [CI] = -0.87 to 0.56; P = .66) for external rotation, -1.01 (95% CI = -2.33 to 0.31; P = .13) for flexion, -0.29 (95% CI = -1.17 to 0.60; P = .52) for shoulder disability, and 0.65 (95% CI = -0.42 to 1.72; P = .23) for pain intensity. CONCLUSIONS: Scapular mobilization with or without other therapeutic interventions does not provide a significant clinical benefit regarding active shoulder range of motion, disability, or pain intensity in patients with primary AC, compared with other manual therapy techniques or other treatments; the quality of evidence was very low to moderate according to the grading of recommendation, assessment, development and evaluation approach.

Radical mechanism in the elimination of 2-arylsulfinyl esters.

The mechanism of the dehydrosulfenylation of 2-arylsulfinyl esters was investigated. The reaction was found to follow a homolytic cleavage mechanism as verified by electrospray ionization tandem mass spectrometry and experimental work. Rearranged sulfoxides are obtained as byproduct during the elimination reaction.

Exploration of Shoulder Abscess Association With Prompt Aggregatibacter aphrophilus Growth in Infective Endocarditis.

Aggregatibacter aphrophilus, formerly known as Haemophilus aphrophilus, is one member of a group of bacteria referred to as HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella) organisms. Infections from any of the HACEK organisms typically lead to very poor outcomes and can be difficult to manage, especially when complicated by intracranial hemorrhage (ICH). HACEK organisms can also be difficult to grow on blood cultures, and A. aphrophilus is rarely seen, if at all. Traditionally, most laboratories follow an extended incubation protocol of 14 to 21 days to aid the growth of HACEK bacteria. Herein we report a case of infective endocarditis where A. aphrophilus resulted on blood culture in three days, in a patient with a right shoulder abscess, complicated by septic embolization leading to ICH. We explore a potential link between the prompt growth of A. aphrophilus on blood culture and the presence of the right shoulder abscess.

Effectiveness of manual therapy in patients with distal radius fracture: a systematic review and meta-analysis.

OBJECTIVE: To determine the effectiveness of manual therapy (MT) for functional outcomes in patients with distal radius fracture (DRF). METHODS: An electronic search was performed in the Medline, Central, Embase, PEDro, Lilacs, CINAHL, SPORTDiscus, and Web of Science databases. The eligibility criteria for selecting studies included randomized clinical trials that included MT techniques with or without other therapeutic interventions in functional outcomes, such as wrist or upper limb function, pain, grip strength, and wrist range of motion in patients older than 18 years with DRF. RESULTS: Eight clinical trials met the eligibility criteria; for the quantitative synthesis, six studies were included. For supervised physiotherapy plus joint mobilization versus home exercise program at 6 weeks follow-up, the mean difference (MD) for wrist flexion was 7.1 degrees (p = 0.20), and extension was 11.99 degrees (p = 0.16). For exercise program plus mobilization with movement versus exercise program at 12 weeks follow-up, the PRWE was -10.2 points (p = 0.02), the DASH was -9.86 points (p = 0.0001), and grip strength was 3.9 percent (p = 0.25). For conventional treatment plus manual lymph drainage versus conventional treatment, for edema the MD at 3-7 days was -14.58 ml (p = 0.03), at 17-21 days -17.96 ml (p = 0.009), at 33-42 days -15.34 ml (p = 0.003), and at 63-68 days -13.97 ml (p = 0.002). CONCLUSION: There was very low to high evidence according to the GRADE rating. Adding mobilization with movement and manual lymphatic drainage showed statistically significant differences in wrist, upper limb function, and hand edema in patients with DRF.

Different Protein Sources in the Maternal Diet of the Rat during Gestation and Lactation Affect Milk Composition and Male Offspring Development during Adulthood.

Protein sources in maternal diet are important for mammary gland differentiation and milk protein; however, few studies have examined the metabolic and cellular adaptations of mothers based on protein source diets during pregnancy and lactation, and leptin concentration in offspring. We evaluated metabolic parameters and maternal key organs and milk components in mothers at the end of lactation, who were fed different sources of proteins. In postnatal day 110 and 250, we studied development parameters and leptin in male offspring. Female rats received a Vegetal (V) or Animal (A) diet during pregnancy and lactation. After weaning, male offspring ate V diet until postnatal day 250, which yielded two groups: Vv and Av. Milk dry, protein and fat were analyzed. Maternal metabolic parameters, leptin, and liver, adipose tissue and mammary gland histological analyses were studied. Body weight, food intake and leptin were analyzed in offspring at two ages. Adipose tissue weight and cells size and liver fat, mammary gland apoptosis, weight, milk protein and leptin were higher in A vs V. Maternal liver and milk dry were lower in A vs V. All offspring parameters were higher in Av vs Vv at postnatal day 110; however, at postnatal day 250, leptin was higher in Av vs Vv. Maternal serum and milk leptin had a positive correlation with offspring serum leptin at both ages. Consumption of animal protein-based diets by mothers during developmental periods affects specific maternal organs and changes milk composition during lactation, leading to a hyperleptinemic phenotype in male offsprings.

Lactation Plays a Fundamental Role in Developmental Programming.

Breast milk has been considered the best source of nutrition for newborns. Several epidemiological and basic experimental studies have been conducted to understand the nutritional advantages of breast milk. Previous findings have emphasized the importance of good maternal nutrition. Maternal milk provides macromolecules, minerals, immune cells, antibodies, hormones, and regular flora to strengthen their offspring preventing various diseases. Maternal milk helps to facilitate physiological, and molecular maturation of several systems, which are important for the final maturation of organs and newborn body development. Currently, breastfeeding is being abandoned for various reasons, such as lower milk production, lack of time, abandonment of the family, social or emotional problems and adverse environmental conditions. These permanent alterations during a critical developmental window have negative consequences in regard to the development of the offspring and organ maturation leading to metabolic, reproductive, hormonal and physiological problems from early life to adulthood. This review describes the advantages of breast milk and the importance for the mother to maintain an adequate diet during pregnancy and lactation, in addition to maintaining a healthy lifestyle and harmonious family relationships. Such an environment will contribute to the complete maturation and development of the offspring.

The Role of the Unfolded Protein Response on Renal Lipogenesis in C57BL/6 Mice.

Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal lipogenesis due to endoplasmic reticulum (ER) stress contributes to kidney injury. The aim of the present study was to elucidate the role of pharmacological ER stress in renal structure and function and its effect on renal lipid metabolism of C57BL/6 mice. ER stress increased serum creatinine and induced kidney structural abnormalities. Tunicamycin-administered mice developed hyperinsulinemia, augmented lipolysis and increased circulating leptin and adiponectin. Renal unfolded protein response (UPR) gene expression markers, the lipogenic transcription factor SREBP1 and the phosphorylation of eIF2α increased 8 h after tunicamycin administration. At 24 h, an increase in BiP protein content was accompanied by a reduction in p-eIF2α and increased SREBP-1 and FASn protein content, in addition to a significant increase in triglyceride content and a reduction in AMPK. Thus, ER stress induces in situ lipid synthesis, leading to renal lipid accumulation and functional alterations. Future pharmacological and/or dietary strategies must target renal ER stress to prevent kidney damage and the progression of metabolic diseases.