Fasting hypochlorhydria with gram positive gastric flora is highly prevalent in healthy old people.

Fifteen healthy old people mean age 84 years (range 80-91 years), were examined to assess the effect of advanced age on the microecology of the upper gastrointestinal tract. Twelve of 15 (80%) were hypochlorhydric with pH 6.6 (0.3) (mean (SEM) and a mean bacterial count of 10(8) colony forming units (CFU) per ml (range 10(5)-10(10)) in fasting gastric aspirate. Normochlorhydric subjects had low counts (< or = 10(1) CFU/ml). The microbial flora was dominated by viridans streptococci, coagulase negative staphylococci, and Haemophilus sp. Only one subject harboured significant concentrations of Gram negative bacilli with Escherichia coli (10(4-5) CFU/ml) and Klebsiella (10(4-5)). Strict anaerobes were not found. The total concentration of short chain fatty acids in gastric aspirate was 10.6 (2.9) mmol/l (mean (SEM). Absence of significant, intraluminal fermentation of xylose to CO2 was shown by the 14C-d Xylose breath test, and ambulatory manometry showed preserved fasting motility pattern of the small intestine. Serum immunoglobulins were normal. Advanced age is accompanied by fasting hypochlorhydria and colonisation with mainly Gram positive flora in the upper gut. Other factors than old age and fasting hypochlorhydria are required for colonisation with Gram negative bacilli.     

Old patients and uremia: rates of acceptance to and withdrawal from dialysis

We studied the entry of elderly uremic patients to chronic dialysis in the U.S. in 1979. We also reviewed long-term survival, causes of death, and risk factors for death in old patients on dialysis at one center for the period 1966 to 1983. A comparison of the number of patients at risk with the number entering dialysis in the United States in 1979 indicates that 80% of the patients aged 25-45 years, 30% of patients over the age of 65 years, and 6% of those over the age of 75 years entered dialysis during that period. Of 239 patients over the age of 70 years followed at the Regional Kidney Disease Program at Hennepin County Medical Center in Minneapolis, the seven-year cumulative survival was 17%. In this program withdrawal from dialysis was the commonest cause of death, accounting for 40% of all deaths. Age groups over 75 years, sex, time period, duration of dialysis, eight pre-existing degenerative diseases, living situation, family support, and site and type of dialysis were not risk factors for termination of dialysis, but living in a nursing home was. When compared to the young, total deaths and deaths from discontinuation were much higher, and this decision was made earlier. Half of the patients who died because dialysis was discontinued were competent and decided for themselves; the other half were incompetent and families and physicians made the decision.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2- nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane- induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.      

A model of corrective gene transfer in X-linked ichthyosis

Single gene recessive genetic skin disorders offer attractive prototypes for the development of therapeutic cutaneous gene delivery. We have utilized X-linked ichthyosis (XLI), characterized by loss of function of the steroid sulfatase arylsulfatase C (STS), to develop a model of corrective gene delivery to human skin in vivo. A new retroviral expression vector was produced and utilized to effect STS gene transfer to primary keratinocytes from XLI patients. Transduction was associated with restoration of full-length STS protein expression as well as steroid sulfatase enzymatic activity in proportion to the number of proviral integrations in XLI cells. Transduced and uncorrected XLI keratinocytes, along with normal controls, were then grafted onto immunodeficient mice to regenerate full thickness human epidermis. Unmodified XLI keratinocytes regenerated a hyperkeratotic epidermis lacking STS expression with defective skin barrier function, effectively recapitulating the human disease in vivo. Transduced XLI keratinocytes from the same patients, however, regenerated epidermis histologically indistinguishable from that formed by keratinocytes from patients with normal skin. Transduced XLI epidermis demonstrated STS expression in vivo by immunostaining as well as a normalization of histologic appearance at 5 weeks post-grafting. In addition, transduced XLI epidermis demonstrated a return of barrier function parameters to normal. These findings demonstrate corrective gene delivery in human XLI patient skin tissue at both molecular and functional levels and provide a model of human cutaneous gene therapy.      

Clearance and Glomerular Localization of Preformed DNP Anti-DNP Immune Complexes

The in vivo behaviour of well-defined immune complexes in rats was studied using complexes derived from DNP-conjugated bovine thyroglobulin (DNP-BTG) and purified specific goat anti-DNP IgG. Both clearance and glomerular localization were mainly dependent on the nature of the antigen. Soluble immune complexes formed with DNP17-BTG were cleared faster and showed a more marked localization in the glomerular mesangium than complexes formed with DNP3.4-BTG. A slight increase in the antibody to antigen ratio seemed to facilitate mesangial localization of soluble immune complexes. Insoluble immune complexes showed temporary localization as microemboli in the lumina of glomerular and peritubular capillaries. This study thus shows that not only the size and composition of the complexes but also the nature of the antigen within the complex can influence the clearance and organ localization of circulating immune complexes.