The Effect of 3'-Deoxyadenosine N1-Oxide on Growth in Vitro and in vivo on Ehrlich Ascites Tumor and on a Human Squamous Lung Cell Carcinoma Xenograft in Nude Mice

The effect of 3'-deoxyadenosine N¹-oxide (3'-dANO) on Ehrlich ascites tumor and a human squamous lung cell carcinoma was investigated. The 3'-dANO concentration that inhibited the cell growth 50% (IC₅₀) in Ehrlich ascites tumor cells in vitro was 0.15 mM, and the killing efficiency concentration (concentration of the drug that kills all cells) was 1 mM. By simultaneous administration of 3'-dANO and the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), the IC₅₀ of 3'-dANO was unchanged, but the killing efficiency concentration of 3'-dANO was reduced to 0.3 mM. When mice bearing Ehrlich ascites tumor were treated i.p. with 3'-dANO doses of 200 mg/kg daily for 4 days, the mean increased life span (ILS) was 200%. 3'-dANO in combination with EHNA did not further increase the life span of the tumor-bearing mice. The specific growth delay (SGD) of the Ehrlich tumor and of a human squamous lung cell carcinoma growing subcutaneously in 3'-dANO-treated mice were calculatedfrom Gomperts tumor growth curves. The Ehrlich tumor-bearing mice received 3'-dANO i.p. at doses of 250 mg/kg daily for 4 days, and the nude mice bearing human carcinoma received 3'-dANO i.p. at doses of 225 mg/kg daily for 5 days. The SGD for the investigated tumors were calculated to be 1.0 and 1.1, respectively.     

Intestinal transmission of macromolecules (BSA and FITC-labelled dextrans) in the neonatal pig. Influence of age of piglet and molecular weight of markers

The intestinal transmission of two macromolecular markers, of similar molecular weight but different susceptibility to proteolytic digestion, was investigated in the neonatal pig. Piglets of varying age (0 h-7 days old) were given a mixture of bovine serum albumin (BSA) and fluorescein-isothiocyanate labelled dextran 70,000 (FITC-D 70) by stomach tube, and the serum concentrations were determined 2 h after feeding. A high correlation between the patterns of transmission were obtained for the two marker substances (r=0.91, n=39). Furthermore, a rapid decrease in the transmission of the markers was observed during the first day of life in suckled piglets, and intestinal macromolecular closure was well developed in the piglets after 18-36 h of life. These findings indicate that 'closure' is unrelated to changes in intestinal proteolytic activity. After closure, only small amounts of the markers were transmitted to the serum. During the first day of life, great individual differences in the transmission were found between piglets. As shown by feeding different-sized FITC-D (MW = 3,000-70,000 dalton) and unconjugated FITC (MW = 389 dalton), molecules having a molecular weight greater than 3,000 daltons were excluded upon macromolecular closure. On the other hand, smaller molecules like FITC were transmitted across the intestinal barriers independent of closure.     

Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P <.05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass.     

Regional specification of rodent and human neurospheres

Neural precursor cells were isolated from various regions of the developing rat and human brain and grown in culture as aggregates termed neurospheres. We asked whether cells within human and rodent neurospheres are identical, or whether they have species specific characteristics or differences based on their region of origin. Under our culture conditions, rodent neurospheres isolated from the cortex (ctxNS) and striatum (strNS) grew faster than those from the mesencephalon (mesNS), but stopped growing after only eight to ten population doublings. In contrast, human neurospheres under identical culture conditions, continued to grow for over 40 population doublings. Following migration and differentiation of both rodent and human cultures, ctxNS and strNS generated high numbers of small neurons whereas mesNS generated small numbers of large neurons with many long fibres. Only very rare neurons from mesNS expressed dopaminergic markers, and thus may require further signals to fully mature. While the rat neurospheres generated high numbers of oligodendrocytes, very few were found to develop from human neurospheres from any region after a few weeks of passaging. FACS analysis revealed a unique population of smaller cells within human strNS and ctxNS, which appeared to be neuronal progenitors. However, large cells within neurospheres were capable of generating these small neuronal progenitors following further proliferation. Together, our data show that rat and human neurospheres have unique characteristics with regard to growth and differentiation, and that the majority of precursor cells within neurospheres are regionally specified to generate set numbers of neurons. These findings have important implications for understanding the nature of proliferating neural precursors isolated from the developing CNS, and their potential for brain repair.     

Treatment of Hypertension with Alternative Therapies (THAT) Study: a randomized clinical trial

OBJECTIVES: To examine the effect of spinal manipulation on blood pressure. DESIGN: This randomized clinical trial compared the effects of chiropractic spinal manipulation and diet with diet alone for lowering blood pressure in participants with high-normal blood pressure or stage I hypertension. Blood pressure observers were blinded to treatment group. SETTING: The study was conducted at the Berman Center for Clinical and Outcomes Research in Minnesota. Chiropractic treatments were administered by chiropractic physicians within private practice settings.PARTICIPANTS One hundred and forty men and women, aged 25-60 years, with high-normal blood pressure or stage I hypertension, were enrolled. One hundred and twenty-eight participants completed the study. INTERVENTIONS: (i) A dietary intervention program administered by a dietitian or (ii) a dietary intervention program administered by a doctor of chiropractic in conjunction with chiropractic spinal manipulation. The frequency of treatment for both groups was three times per week for 4 weeks, for a total of 12 visits. MAIN OUTCOME MEASURES: The primary outcomes for this study were change from baseline in diastolic and systolic blood pressure. RESULTS: Study groups were comparable at baseline. Changes in potentially confounding covariates did not differ between groups. Average decreases in systolic/diastolic blood pressure were -4.9/5.6 mmHg for diet group and -3.5/4.0 mmHg for the chiropractic group. Between group changes were not statistically significant. CONCLUSIONS: For patients with high normal blood pressure or stage I hypertension, chiropractic spinal manipulation in conjunction with a dietary modification program offered no advantage in lowering either diastolic or systolic blood pressure compared to diet alone.     

Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT)

Context  The sixth Joint National Committee (JNC-VI) classification system of blood pressure emphasizes both systolic blood pressure (SBP) and diastolic blood pressure (DBP) for cardiovascular disease risk assessment. Pulse pressure may also be a valuable risk assessment tool. Objective  To compare relationships of SBP, DBP, and pulse pressure, separately and jointly, with cardiovascular disease-related mortality in men. Design and Setting  Data from the Multiple Risk Factor Intervention Trial (MRFIT), which screened men aged 35 to 57 years from 1973 through 1975 at 22 US centers, was used to assess cardiovascular disease-related mortality through 1996. Participants  A total of 342 815 men without diabetes or a history of myocardial infarction were divided into 2 groups based on their age at MRFIT screening (35- to 44-year-olds and 45- to 57-year olds). Participant blood pressure levels were classified into a JNC-VI blood pressure category based on SBP and DBP (optimal, normal but not optimal, high normal, stage 1 hypertension, stage 2-3 hypertension), and pulse pressure was calculated. Main Outcome Measure  Cardiovascular disease-related mortality. Results  There were 25 721 cardiovascular disease-related deaths. Levels of SBP and DBP were more strongly related to cardiovascular disease than pulse pressure. Relationships of SBP, DBP, and pulse pressure to cardiovascular disease-related mortality varied within JNC-VI category. Concordant elevations of SBP and DBP were associated with a greater risk of cardiovascular disease-related mortality for both age groups of men. Among men aged 45 to 57 years, higher SBP and lower DBP (discordant elevations) also yielded a greater risk of cardiovascular disease-related mortality. Conclusion  In both age groups, cardiovascular disease risk assessment was improved by considering both SBP and DBP, not just SBP, DBP, or pulse pressure separately.      

Neural stem cells: from cell biology to cell replacement

A large number of crippling neurological conditions result from the loss of certain cell populations from the nervous system through disease or injury, and these cells are not intrinsically replaced. Mounting evidence now suggests that replacement of depleted cell populations by transplantation may be of functional benefit in many such diseases. A diverse range of cell populations is vulnerable, and the loss of specific populations results in circumscribed deficits in different conditions. This diversity presents a considerable challenge if cell replacement therapy is to become widely applicable in the clinical domain, because each condition has specific requirements for the phenotype, developmental stage, and number of cells required. An ideal cell for universal application in cell replacement therapy would possess several key properties: it would be highly proliferative, allowing the ex vivo production of large numbers of cells from minimal donor material; it would also remain immature and phenotypically plastic such that it could differentiate into appropriate neural and glial cell types on, or prior to, transplantation. Critically, both proliferation and differentiation would be controllable. This review considers some of the evidence that stem cells exist in the central nervous system and that they may possess characteristics that make them ideal for broad application in cell replacement therapy.     

Accelerated pubertal development in patients with shunted hydrocephalus

OBJECTIVE: To evaluate pubertal development and peripheral concentrations of gonadotrophins and sex hormones in children with shunted hydrocephalus compared with healthy controls. STUDY DESIGN: 114 patients (52 females, 62 males) and 73 healthy controls (35 females, 38 males) aged 5 to 20 years were analysed for stage of puberty, age at menarche, testicular volume, basal serum follicle stimulating hormone (FSH), luteinising hormone (LH), sex hormone binding globulin (SHBG), testosterone and oestradiol concentrations, and free androgen index. RESULTS: Male gonadal and male and female pubic hair development occurred significantly earlier in the patients than in the controls. The mean age at menarche was significantly lower in the female patients than in their controls (11.7 v 13.2 years; p < 0.001), and lower than it had been for their mothers (v 13.1 years; p < 0.001). Relative testicular volume was higher in the male patients than in their controls (1.2 standard deviation score (SDS) v 0.2 SDS; p < 0.001). The prepubertal patients had higher basal LH (0.13 U/l v 0.08 U/l; p < 0.001) and SHBG (132.3 nmol/l v 109.1 nmol/l; p < 0.01) than the controls. Both the prepubertal and pubertal females had significantly higher basal FSH than their controls (1.57 U/l v 1.03 U/l; p < 0.05, and 4.0 U/l v 2.9 U/l; p < 0.01, respectively). CONCLUSIONS: Hydrocephalic children experience accelerated pubertal maturation, reflected in a younger age at menarche in females and an increased testicular volume in males. This may be because of enhanced gonadotrophin secretion, possibly resulting from unphysiological variations in intracranial pressure.