Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs.

Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

A novel electroanalytical approach to the measurement of B vitamins in food supplements based on screen-printed carbon sensors.

This paper describes the development of a novel electrochemical assay for the measurement of water-soluble vitamins in food and pharmaceutical products. The optimum conditions for the determination of vitamin B1 (thiamine), B2 (riboflavin) and B6 (pyridoxine) in phosphate buffer were established using cyclic voltammetry in conjunction with screen printed carbon electrodes (SPCEs). The optimum current response for all three vitamins was achieved in 0.1M phosphate buffer pH 11 using an initial potential of -1.0V. Using square wave voltammetry, the linear ranges for thiamine, riboflavin, and pyridoxine were found to be: 15-110µg/ml, 0.1-20µg/ml, and 2-80µg/ml respectively. The application of the method to a commercial food product yielded a recovery of 95.78% for riboflavin, with a coefficient of variation (CV) of 3.38% (n = 5). The method was also applied to a multi-vitamin supplement for the simultaneous determination of thiamine, riboflavin and pyridoxine. In both cases only simple dilution with buffer followed by centrifugation was required prior to analysis. The resulting square wave voltammetric signals were completely resolved with Ep values of -0.7V, +0.2V, and +0.6V respectively. The recoveries determined for the vitamin B complex in a commercial supplement product were found to be 110%, 114%, and 112% respectively (CV = 7.14%, 6.28%. 5.66% respectively, n = 5).

Talk of the town in 1921: chiropractic and "talking sickness".

In 1921 Waukegan, Illinois, there was an eight-year-old girl who had what was called "talking sickness." She reportedly talked constantly for eight straight days and nights. After medical care failed to help, a local chiropractor was called to adjust the young girl, and she apparently experienced marked improvement thereafter. News of the seemingly spectacular recovery reached a fever pitch across the United States in the spring of 1921, in both lay and professional publications. The slightly different versions of this case, from slightly biased sources on each side of the fence (such as Fountain Head News on the one side and The Journal of the American Medical Association on the other), as well as coverage from newspaper reports are explored.

Victor Coxon, member, B.J.'s Black Tie Club at Palmer, 1936-1941.

The 1930's era was a turbulent time for B.J. Palmer who was proposing radical changes in chiropractic methodologies, i.e., the Hole-in-one upper cervical approach, neurocalometer examinations and heavy reliance on x-ray for vertebral listings. Palmer needed and found an inner circle of loyal supporters at the Fountain Head who were named the "Black Tie Club," identified at important Palmer functions wearing the flowing black tie--the Windsor. One such Black Tie Club member was Victor Coxon--a 1930 Palmer School graduate who passed away recently. The present article explores Coxon's assistant directorship of the B.J. Palmer Chiropractic Clinic, some of his many writings, as well as correspondence Dr. Coxon had with the author.

Ultrastructure of human colostral cells.

The ultrastructural architecture of colostral cells of mothers of pre- and full-term infants is described. The polymorphonuclears were engaged in vivid phagocytosis of fat droplets. Similar findings were observed on the macrophages. The lymphocytes appeared normal in size and ultrastructure. A small number of eosinophils and basophils were also detected. The number of colostral cells was higher in the colostrum of mothers of preterm newborns. The number of the cells in the colostrum in mothers of both groups decreased with advancement of lactation.

Did D.D. Palmer visit A.T. Still in Kirksville?

It has been claimed that prior to the discovery of chiropractic in 1895, D.D. Palmer, the discoverer of chiropractic, visted A.T. Still, the founder of osteopathy, in Kirksville, Missouri, where Still started the first school of osteopathy. Palmer's signature supposedly can be found in A.T. Still's guestbook. Palmer denied ever being in Kirksville, as did his son B.J. This article explores the evidence on both sides of the question.

Remembering Dr. Lyle Wheeler Sherman.

Lyle Wheeler Sherman was a chiropractor with a passion for chiropractic. He brought dignity to the chiropractor; but most profoundly, he brought dignity to the chiropractic profession. He rendered a quality professional service and helped his fellow chiropractor do the same. He was a published author and co-developer of various chiropractic instruments. A renowned teacher, former assistant director and chief of staff of the B.J. Palmer Chiropractic Research Clinic in Davenport, Iowa, he was a sought-after speaker at both state and national chiropractic conventions. Dr. Sherman was a man of knowledge and wisdom. Local chiropractors sought his technical advice and assistance which he provided at no charge. Both laymen and chiropractors recognized him as a chiropractic authority. He regularly received letters from patients who had traveled both the medical route and the chiropractic route and were seeking the more specific care offered by Dr. Sherman. He always attempted to accommodate them. His gentle personality and sense of humor, coupled with his exactness in chiropractic analysis and adjustment procedures, won the respect of students, colleagues and patients. His expertise was recognized by his appointment to many state and national offices and by the many awards he received. His greatest and most lasting award was the chiropractic college that bears his name: Sherman College of Straight Chiropractic in Spartanburg, South Carolina--the first chiropractic college in the southeast.

Estimation of vitamin needs--riboflavin, vitamin B6 and ascorbic acid-according to blood parameters and functional-cognitive and emotional indices in a selected well-established group of elderly in a home for the aged in Israel.

OBJECTIVE: To evaluate the vitamin status and the effects of micronutrient supplementation as determined by biochemical assays and functional, cognitive and emotional tests in a selected well-established group of elderly people, average age above 80 years. METHODS: Dietary consumption was evaluated by in-person interview using a food frequency questionnaire. Medical, biochemical, nutritional, functional, cognitive and behavioral parameters were assessed in elderly subjects (n = 12) living in a home for the aged, at baseline and after 42 days of micronutrient supplementation. The same parameters were assessed in additional subjects (n = 9), at baseline only. RESULTS: In all subjects, most of the micronutrients were not supplied at an adequate level. Supplementation of micronutrients at a level of 100% RDA improved parameters related to vitamin status, the activation coefficients (AC) of GR (glutathione reductase) and AST, blood ascorbic acid concentrations, functional-cognitive evaluation values, blood pressure, pulse rate, and serum cholesterol and triglycerides levels. At baseline, the following parameters significantly correlated with vitamin intake and were used for the estimation of vitamin needs: AC of GR, Tinetti Balance Evaluation, FIM and recorded morbidity. CONCLUSIONS: On the basis of limited available data, calculation of vitamin needs based on regression lines resulted in estimates (mg/day) of: > 150 for ascorbic acid, > 3 for riboflavin, > 3 for vitamin B6. Expanding the current practice of supplementing micronutrients at a level of 100% RDA (in tablet form) that already exists in some elderly societies should be considered after a comprehensive study in a large group of elderly people.

Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period.

Surgical stress and general anesthesia suppress immune functions, including natural killer cell cytotoxicity (NKCC). This suppression could be attributable, at least in part, to opiates. We have previously shown that large-dose fentanyl administration suppressed NKCC in rats. The present study sought to compare the effects of two anesthetic protocols, based on large- (LDFA) versus small (SDFA)-dose fentanyl anesthesia on NKCC in the perioperative period. Forty patients were included in this study; half were assigned to each protocol of anesthesia. In each anesthetic group, half the patients were undergoing surgery for malignant diseases, and half for benign conditions. Blood samples were collected during the perioperative period. NKCC was assessed using the chromium release assay. Initially, both types of anesthesia similarly suppressed NKCC, with a peak effect 24 h after surgery. The two types of anesthesia, however, differed in the rate of recovery of NKCC suppression. By the second postoperative day, NKCC returned to control values in the SDFA patients, whereas NKCC was still significantly suppressed after LDFA. These results indicate that LDFA causes prolonged suppression of NK cell function. Whether this suppression might have a long-term impact on the overall outcome, especially in cancer patients, remains to be determined.

Human colostrum stimulates cytokine production.

The effect of human colostrum on the production of IL-1, IL-3 and IL-6 by peripheral blood mononuclear cells (PBMCs) has been investigated. The aqueous phase of human colostrum significantly stimulated the production of these three cytokines. These findings show the importance of breast feeding not only as a well-balanced nutrient supply but also as a source for growth-promoting factors. It is suggested that the enhanced secretion of IL-1, IL-3 and IL-6 induced by human colostrum may compensate for the lower capacity of neonatal PBMCs to produce these cytokines. It is also possible that, by stimulating the secretion of these cytokines, breast feeding may provide an additional mechanism for the regulation of the neonatal immune system and hematopoiesis.

Resolution of Helicobacter pylori-associated gastric lymphoproliferative disease in a child.

A possible causative association between Helicobacter pylori infection and gastric lymphoproliferative disorders has recently been recognized. The case of a 14-year-old girl who was diagnosed with H. pylori gastritis and associated gastric lymphoproliferative disease of the low-grade mucosa-associated lymphoid tissue type is reported. The patient was treated only for the H. pylori infection (amoxicillin, bismuth, and metronidazole) without any adjuvant chemotherapy or surgery for her lymphoproliferative disorder. This treatment not only resulted in the eradication of the microorganism but also complete resolution of her lymphoproliferative disease. The patient was subsequently followed up for a period of 7 years. There has been no histological recurrence of H. pylori gastritis or gastric lymphoproliferative disease. It is believed that this is the first report to describe a long-term follow-up of an H. pylori-associated gastric lymphoproliferative disorder in a pediatric patient who was exclusively treated for H. pylori infection. The observations in this report suggest that H. pylori-associated low-grade gastric lymphoproliferative disease can be completely cured by eradicating the organism. Therefore, this therapeutic approach, combined with close follow-up, should be the treatment of choice in children with this associated condition before attempting more aggressive treatments, thus potentially avoiding chemotherapy and/or (partial) gastrectomy.

1 alpha,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol, a noncalcemic analogue of 1 alpha,25-dihydroxyvitamin D3, inhibits azoxymethane-induced colonic tumorigenesis.

Vitamin D3 and its metabolites, particularly 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25(OH)2D3), have received increasing attention as potential anticarcinogens in the prevention of cancers in a number of organs, including the colon. These agents, however, have the potential to induce hypercalcemia, thus limiting their practical use for these purposes. In the present studies it was, therefore, of interest to determine whether dietary supplementation with 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (RO24-5531), a recently synthesized apparently noncalcemic analogue of 1 alpha,25(OH)2D3, inhibited colon cancer induced by azoxymethane (AOM). Rats were placed on a standard diet or fed this diet with supplemental RO24-5531 (2.5 nmol/kg feed) before and during (initiation arm), or after AOM or vehicle administration (postinitiation arm). After 34 weeks of study, animals in each group were sacrificed, and their colons were removed and examined macroscopically and microscopically for the presence of tumors. At the time of sacrifice, the animals' serum calcium, phosphorus, 25-hydroxyvitamin D3 and 1 alpha,25(OH)2D3 levels were also analyzed. The results of these studies demonstrated that dietary RO24-5531 supplementation during the initiation arm of these experiments significantly reduced (by 70%) the incidence of AOM-induced colonic tumors compared to rats on the standard diet without RO24-5531. Moreover, this dietary regimen abolished the development of adenocarcinomas in this model. Although there was also a trend for dietary RO24-5531 supplementation during the postinitiation arm of this study to reduce the incidence of colon tumors, this did not reach statistical significance (P > 0.05). In addition, neither dietary RO24-5531 supplementation regimen significantly influenced the animals' rates of growth or their serum levels of calcium, phosphorus, or 25-hydroxyvitamin D3. These studies, therefore, demonstrate for the first time that supplemental dietary RO24-5531 is a chemopreventive agent in the AOM model of experimental colonic carcinogenesis. They also suggest that this agent may ultimately prove useful in clinical colon cancer chemopreventive trials.

Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications.

Unconventional medical practices, including the use of herbal remedies, are prevalent in the United States. Chaparral is an herbal preparation made from a desert shrub and used for its antioxidant properties. We report the case of a 60-year-old woman who took chaparral for 10 months and developed severe hepatitis for which no other cause could be found. Despite aggressive supportive therapy, the patient deteriorated and required orthotopic liver transplantation. She is now well, more than 1 year after her transplant. This case suggests that chaparral can cause serious liver injury and fulminant hepatic failure. Herbal medications should be considered as potential causes of liver toxicity.

Phagocytosis-promoting factor in human colostrum.

The effect of colostrum of mothers of preterm and full-term newborns on the phagocytic activity for latex particles by normal peripheral blood polymorphonuclear cells was examined. The results showed that human colostrum contains a phagocytosis-promoting factor(s), which not only increases the number of phagocytic cells, but also stimulates the phagocytic activity of the individual cell. This factor(s) was more active in preterm colostrum. Thus, while term colostrum increased the number of phagocytic cells by 95% in comparison with the control, preterm colostrum enhanced the number of phagocytic cells by 300%. Similarly, term colostrum increased the phagocytic capacity of the individual cell by 51%, whereas preterm colostrum by 137%. The difference between the results in all experimental points was statistically highly significant.