Over-the-Counter Alkali Agents to Raise Urine pH and Citrate Excretion: A Prospective Crossover Study in Healthy Adults.

OBJECTIVE: To assess the effect of 2 over-the-counter alkalizing agents on 24 hour urinary parameters. MATERIALS AND METHODS: Ten healthy volunteers without a history of kidney stones were recruited to complete a baseline 24 hour urinalysis with a 4 day diet inventory. Participants then maintained the same diet on either LithoLyte (20 mEq 2 times per day) or KSPtabs (1 tablet 2 times per day) and submitted another 24 hour urinalysis. The process was repeated with the other supplement. Urinary alkali parameters were compared to baseline, and side effects were elicited with a questionnaire. RESULTS: LithoLyte intake resulted in a non-significant increase in citrate (597-758 mg/day, P =.058, an increase in urine pH (6.46-6.66, P =.028), and a decrease in urine ammonium (41-36 mmol/day, P =.005) compared to baseline. KSPtabs resulted in an increase in citrate (597-797 mg/day, P =.037) and urine pH (6.46-6.86, P =.037), with a non-significant decrease in ammonium (41-34 mmol/day, P =.059). No significant differences were seen comparing urinary analytes between LithoLyte and KSPtabs. With Litholyte, no side effects, mild, moderate, and severe side effects were seen in 50%, 40%, 10%, and 0%, respectively. With KSPtabs, rates were 60%, 20%, 10%, and 10%, respectively. CONCLUSION: In healthy participants without a history of kidney stones, LithoLyte and KSPtabs are effective over-the-counter alkali supplements, with a similar side effect profile to prescription potassium citrate.

Frequency and spectrum of mutations across 94 cancer predisposition genes in African American women with invasive breast cancer.

African American women are at increased risk of being diagnosed at a young age and/or with triple negative breast cancer, both factors which are included in current guidelines for identifying women who may benefit from genetic testing. Commercial breast cancer predisposition genetic panels, based largely on data derived from women of European ancestry, may not capture the full spectrum of cancer predisposition genes associated with breast cancer in African American women. Between 2001 and 2018, 488 unselected African American women with invasive breast cancer enrolled in the Clinical Breast Care Project. National Comprehensive Cancer Network (NCCN) Hereditary Cancer testing criteria version 1.2020 were applied to determine genetic risk. Targeted sequencing was performed using the TruSight Cancer panel and variants classified using the ClinVar database. Using NCCN criteria, 64.1% of African American women would be eligible for genetic testing. Fifty pathogenic or likely pathogenic mutations were detected in 19 genes with the highest frequencies in BRCA2 (29.4%) and BRCA1 (15.7%). Mutation frequencies in test-eligible and test-ineligible women were 13.1% and 3.5%, respectively. One-third of women harbored variants that could not be classified. While these data do not suggest a need to expand current commercial gene panels, NCCN criteria would fail to identify 12.5% of African American women with mutations in hereditary cancer predisposing genes.

In Vitro Antioxidant Potential and Effect of a Glutathione-Enhancer Dietary Supplement on Selected Rat Liver Cytochrome P450 Enzyme Activity.

BACKGROUND: There is considerable evidence that many people take dietary supplements including those of herbal origin as an alternative therapy to improve their health. One such supplement, with an amalgam of constituents, is CellGevity®. However, the effect of this dietary supplement on drug-metabolizing enzymes is poorly understood, as it has not been studied extensively. Therefore, we investigated the effect of CellGevity dietary supplement on selected rat liver microsomal cytochrome P450 (CYP) enzymes, the most common drug-metabolizing enzymes. We also determined the total antioxidant potential of this dietary supplement in vitro. METHODS: To determine the antioxidant potential of CellGevity dietary supplement, 2,2-diphenyl-2-picryl-hydrazyl (DPPH), total phenolic, and flavonoid assays were used after initial preparation of a solution form of the supplement (low dose, LD; 4 mg/kg and high dose, HD; 8 mg/kg). Rats received oral administration of these doses of the supplement for 7 days, after which the effect of the supplement on selected liver CYP enzymes was assessed using probe substrates and spectroscopic and high-performance liquid chromatographic methods. Rats which received daily administration of 80 mg/kg of phenobarbitone and distilled water served as positive and negative controls, respectively. RESULTS: The IC50 value of the supplement 0.34 ± 0.07 mg/ml compared to 0.076 ± 0.03 mg/ml of the BHT (positive control). The total phenolic content of the supplement at a concentration of 2.5 mg/ml was 34.97 g gallic acid equivalent (GAE)/100 g while its total flavonoid content at a concentration of 2.5 mg/ml was 6 g quercetin equivalent (QE)/100 g. The supplement significantly inhibited rat CYP2B1/2B2 (LDT 92.4%; HDT 100%), CYP3A4 (LDT 81.2%; HDT 71.7%), and CYP2C9 (LDT 21.7%; HDT 28.5%) while it had no significant inhibitory effect on CYPs 1A1/1A2, CYP1A2, and CYP2D6. CONCLUSION: CellGevity dietary supplement possesses moderate antioxidant activity in vitro and has an inhibitory effect on selected rat liver CYP enzymes, suggesting its potential interaction with drugs metabolized by CYP enzymes.

Voiding Dysfunction in Multiple Sclerosis.

Voiding dysfunction is a common and debilitating consequence of multiple sclerosis (MS). The prevalence and severity of voiding dysfunction increases with the increasing severity of MS, but even the mildest forms of the disease are associated with urinary symptoms in 30% of patients. Every component of the central nervous system is involved in regulating voiding; as a result, MS can lead to a wide variety of urinary symptoms and urologic complications. The effect of MS on voiding can be classified according to the resulting function of the bladder and the urethral sphincter during storage and emptying of urine. Therapy is targeted to the specific bladder and sphincter abnormalities that occur. The primary goals of therapy are prevention of injury to the upper urinary tract (kidneys), reduction in urinary tract infections, and maintenance of urinary continence. These goals can be achieved by interventions ranging from behavioral modification to major reconstructive surgery.

Personalized medicine for the management of benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia affects more than 50% of men by age 60 years, and is the cause of millions of dollars in health care expenditure for the treatment of lower urinary tract symptoms and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic benign prostatic hyperplasia. At least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5α-reductase type 2, and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of benign prostatic hyperplasia progression as well as the key genes and signaling pathways implicated in the process such as 5α-reductase. We also explore the potential of biomarker screening and gene specific therapies as tools to risk stratify patients with benign prostatic hyperplasia and identify those with symptomatic or medically resistant forms. MATERIALS AND METHODS: A PubMed® literature search of current and past peer reviewed literature on prostate development, lower urinary tract symptoms, benign prostatic hyperplasia pathogenesis, targeted therapy, biomarkers, epigenetics, 5α-reductase type 2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined, as were their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications. RESULTS: Benign prostatic hyperplasia is associated with a state of hyperplasia of the stromal and epithelial compartments, with 5α-reductase type 2 and androgen signaling having key roles in the development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities have complex roles in prostate tissue homeostasis as well as its evolution into the clinical state of benign prostatic hyperplasia. Resistance to medical therapy with finasteride may occur through silencing of the 5α-reductase type 2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5α-reductase type 2. Novel biomarkers such as single nucleotide polymorphisms may be used to risk stratify patients with symptomatic benign prostatic hyperplasia and identify those at risk for progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate benign prostatic hyperplasia progression and may offer alternative targets for medical therapy. CONCLUSIONS: Progressive worsening of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia is the result of multiple pathways including androgen receptor signaling, proinflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene specific targets. As personalized medicine continues to develop, the ability to risk stratify patients with symptomatic benign prostatic hyperplasia, identify those at higher risk for progression, and seek alternative therapies for those in whom conventional options are likely to fail will become the standard of targeted therapy.

In vitro activity of extract and fractions of natural cocoa powder on Plasmodium falciparum.

Several flavonoids isolated from certain plants have demonstrated antiplasmodial activity, after their initial indigenous use in malaria treatment. Cocoa has been found to be a rich food source of flavonoids in comparison with many common foods and beverages. The aim of this work was to investigate the in vitro activity of natural cocoa powder on the growth of Plasmodium falciparum. Prepared crude methanol extract was partitioned successively with petroleum ether, ethyl acetate, chloroform, and butanol. Total flavonoid concentration in the crude methanol extract and fractions was measured by the AlCl(3) colorimetric assay. Direct inhibitory activity of the natural cocoa powder was assessed by culturing extract and fractions with P. falciparum in vitro. Greater antiplasmodial activity was observed in nonpolar solvent fractions (chloroform, ethyl acetate, and petroleum ether) compared with polar solvents. The chloroform fraction was most active, with mean±SEM 50% and 90% inhibition concentrations of 48.3±0.9 and 417±7.8 µg/mL, respectively. The study showed a weak association between total flavonoid concentration and antiplasmodial activity. Early trophozoite (ring-stage) synchronized cultures treated with the chloroform fraction of natural cocoa powder showed a decline in growth. Further reduction in parasitemia was also observed for other erythrocytic stages. These results suggest that natural cocoa powder has measurable direct in vitro inhibitory effect on P. falciparum and support the anecdotal reports of its ability to prevent malaria as a result of regular intake as a beverage.

Long-term functional restoration by neural progenitor cell transplantation in rat model of cognitive dysfunction: co-transplantation with olfactory ensheathing cells for neurotrophic factor support.

Neural progenitor cell transplantation has emerged as a promising approach for cell replacement therapy in the brain of neurodegenerative diseases. These are multipotent stem cells with self-renewal capabilities and can give rise to cells of all the three lineages of nervous system and can be maintained and differentiated to desirable neuronal subtypes in vitro with known trophic factors. However, like fetal cells, neural progenitor cells after differentiating to specific neuronal type also require continuous neurotrophic factor support for their long-term survival following transplantation. Recent reports suggest that olfactory ensheathing cells are capable of providing continuous neurotrophic factor to the transplanted neural progenitor cells for their long-term survival. In the present investigation, an attempt has been made to validate functional restoration in kainic acid lesioned rat model of cognitive dysfunction following co-transplantation of neural progenitor cells with olfactory ensheathing cells. Animals lesioned with kainic acid in CA3 subfield of hippocampal region were transplanted with neural progenitor cells, olfactory ensheathing cells or neural progenitor cells+olfactory ensheathing cells together. Twelve weeks post-transplantation functional restoration was assessed using neurobehavioral, neurochemical, and immunohistochemical approaches. Significant recovery in learning and memory (89%) was observed in co-transplanted group when compared to lesioned group. This was accompanied by significantly higher expression of choline acetyltransferase and restoration in cholinergic receptor binding in co-transplanted group (61%) over the animals transplanted either olfactory ensheathing cells or neural progenitor cells alone. Role of olfactory ensheathing cells in supplementing neurotrophic factors was further substantiated in vitro by pronounced differentiation of neural progenitor cells to choline acetyltransferase/acetylcholine esterase immunoreactive cells when co-cultured with olfactory ensheathing cells as compared to neural progenitor cells alone. The results strengthened the hypothesis that co-transplantation of olfactory ensheathing cells and neural progenitor cells may be a better approach for functional restoration in kainic acid induced rat model of cognitive dysfunction.

Neuroprotective and neurorescue effect of black tea extract in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

In the present study, an attempt has been made to explore the neuroprotective and neuroreparative (neurorescue) effect of black tea extract (BTE) in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In the neuroprotective (BTE + 6-OHDA) and neurorescue (6-OHDA + BTE) experiments, the rats were given 1.5% BTE orally prior to and after intrastriatal 6-OHDA lesion respectively. A significant recovery in d-amphetamine induced circling behavior (stereotypy), spontaneous locomotor activity, dopamine (DA)-D2 receptor binding, striatal DA and 3-4 dihydroxy phenyl acetic acid (DOPAC) level, nigral glutathione level, lipid peroxidation, striatal superoxide dismutase and catalase activity, antiapoptotic and proapoptotic protein level was evident in BTE + 6-OHDA and 6-OHDA + BTE groups, as compared to lesioned animals. BTE treatment, either before or after 6-OHDA administration protected the dopaminergic neurons, as evident by significantly higher number of surviving tyrosine hydroxylase immunoreactive (TH-ir) neurons, increased TH protein level and TH mRNA expression in substantia nigra. However, the degree of improvement in motor and neurochemical deficits was more prominent in rats receiving BTE before 6-OHDA. Results suggest that BTE exerts both neuroprotective and neurorescue effects against 6-OHDA-induced degeneration of the nigrostriatal dopaminergic system, suggesting that possibly daily intake of BTE may slow down the PD progression as well as delay the onset of neurodegenerative processes in PD.

Alkaloids of Fumaria indica: Further Studies on Narceimine and Narlumidine.

The structures of the FUMARIA INDICA alkaloids narceimine and narlumidine, earlier proposed by us, have been substantiated by further chemical reactions and characterisation of chemical transformation products. Isolation and characterisation of two naturally occurring alkaloid salts, protopine nitrate and tetrahydrocoptisine hydrochloride, along with (+)-adlumidine, norsanguinarine and an uncharacterised alkaloid, C (20)H (17)NO (6) (M (+) 367), mp 250-251 degrees C, from the same plant are also reported.

Flavonoids from the flowers of Clerodendron infortunatum.

Apigenin, acacetin and a new flavone glycoside, characterised as the methyl ester of acacetin-7-0-glucuronide have been isolated from the flowers of Clerodendron infortunatum.