Long-term outcome after marrow transplantation for severe aplastic anemia

We reviewed the records and reevaluated 212 patients with aplastic anemia transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1970 and 1993 who survived >/=2 years and who have been followed for up to 26 years. Parameters analyzed included hematopoietic function, chronic graft-versus-host disease (GVHD), skin disease, cataracts, lung disease, skeletal problems, posttransplant malignancy, depression, pregnancy/fatherhood, and the return to work or school, as well as patient self-assessment of physical and psychosocial health, social interactions, memory and concentration, and overall severity of symptoms. Survival probabilities at 20 years were 89% for patients without (n = 125) and 69% for patients with chronic GVHD (n = 86) (the status was uncertain in 1 surviving patient). All patients had normal hematopoietic parameters. Skin problems occurred in 14%, cataracts in 12%, lung disease in 24%, and bone and joint problems in 18% of patients. Eleven patients (12%) developed a solid tumor malignancy and 19% of patients experienced depression. Chronic GVHD was the dominant risk factor for late complications. Seventeen patients died at 2.5 to 20.4 years posttransplant; 13 of these had chronic GVHD and related complications. At 2 years, 83% of patients had returned to school or work; the proportion increased to 90% by 20 years. At least half of the patients preserved or regained the ability to become pregnant or father children. Patients rated their quality of life as excellent and symptoms as minimal or mild. In conclusion, marrow transplantation in patients with aplastic anemia established long-term normal hematopoiesis. No new hematologic disorders occurred. The major cause of morbidity and mortality was chronic GVHD. However, the majority of patients who survived beyond 2 years returned to a fully functional life.     

A point mutation in the bulge of the iron-responsive element of the L ferritin gene in two families with the hereditary hyperferritinemia-cataract syndrome

The molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome is the presence of a mutation in the iron-responsive element (IRE) of the L ferritin gene, located on chromosome 19q13.3-13.4. Two mutations have been reported so far, altering adjacent nucleotides in the IRE loop, in a region that has been extensively studied in vitro and shown to mediate high affinity interaction with the iron-responsive protein. In this report, we describe two families with a new mutation in the bulge of the IRE stem, and we show that this mutation alters the protein-binding affinity of the IRE in vitro to the same extent as the loop mutation. In addition, we present evidence that some variability in the age of onset of cataract can be associated with this genetic syndrome, probably because of additional genetic or environmental factors that modulate the penetrance of the L ferritin defect in the lens. We confirm that the patients do not have increased iron stores despite the persistence of elevated serum ferritin levels and that, accordingly, they do not tolerate well venesection therapy. Further studies will be necessary to elucidate the mechanism responsible for the onset of cataract.     

L-ascorbyl-2-polyphosphate as a vitamin C source for segregated and conventionally weaned pigs

We conducted two experiments to evaluate the efficacy of a stable source of vitamin C for improving performance and iron status in early-weaned pigs. A preparation of L-ascorbyl-2-polyphosphate (Rovimix Stay-C 25, Roche Vitamins, Ames, IA and Bramus, NJ), which supplies 25% ascorbic acid activity in a stable form, served as the vitamin C source and was incorporated at dietary vitamin C levels of 0, 75, or 150 ppm. In Exp. 1, 72 pigs (14 +/- 2 d of age and 4.98 kg BW) were blocked based on initial BW and penned in groups of three (eight pens per treatment) in an off-site nursery for 42 d. Phase 1 lasted from d 0 to 14, Phase 2 from d 14 to 28, and Phase 3 from d 28 to 42 after weaning. Daily gain and gain:feed ratio (G/F) increased during Phase 1 (quadratic, P < .1 and P < .05, respectively), Phase 3 (linear, P < .1 and P < .01, respectively), and for the overall 42-d experiment (linear, P < .05 and P < .1, respectively) in response to increasing dietary vitamin C. At 14 d after weaning, plasma vitamin C increased (linear, P < .05) with increasing dietary vitamin C, but plasma iron, hemoglobin, and hematocrit were not influenced by dietary vitamin C. In Exp. 2, 120 pigs (20 +/- 3 d of age and 7.2 kg BW) were blocked based on initial BW and penned in groups of five (eight pens per treatment) in a conventional nursery system for 31 d. Phase 1 consisted of d 0 to 7, Phase 2 from d 7 to 17, and Phase 3 from d 17 to 31 after weaning. During the period from d 0 to 17 after weaning, ADG and G/F were improved (linear, P < .1) with increasing dietary vitamin C. At d 17 after weaning, plasma vitamin C and serum iron increased (linear, P < .05), but unbound iron-binding capacity and total iron-binding capacity decreased (linear, P < .05 and P < .1, respectively) with increasing dietary vitamin C. These results suggest that dietary vitamin C is needed during the first 42 d after weaning when pigs are weaned as early as 12 d of age and reared in an off-site nursery and during the first 17 d after weaning when pigs are weaned as early as 17 d of age and reared in a conventional nursery system. L-Ascorbyl-2-polyphosphate at a supplemental level of 75 ppm was adequate to meet the dietary vitamin C requirement of early-weaned pigs. Vitamin C supplementation with a stable product will improve performance in young pigs during the high-stress postweaning period and may be particularly beneficial to pigs weaned at a very early age.     

A blue encrustation found on skeletal remains of Americans missing in action in Vietnam

We review and present current evidence supporting independent regulation of nuclear Ca2+ ([Ca2+]n). The nucleus and nuclear envelope contain proteins to both regulate and respond to changes in [Ca2+]n. However, this does not prove that [Ca2+]n is independently regulated from cytosolic Ca2+ ([Ca2+]c). Studies using fluorescent dyes suggested that changes in [Ca2+]n differed in magnitude from changes in [Ca2+]c. These studies have been criticised as the nuclear environment alters the fluorescent characteristics of these dyes. We have evaluated this question with aequorin targeted to the nucleus and cytoplasm and shown that the characteristics of the indicators are not altered in their respective environments. We have demonstrated that different stimuli induce changes in [Ca2+]n and [Ca2+]c that vary both temporally and in magnitude. The nucleus appeared to be shielded from increases in [Ca2+]c, either through a mechanism involving the nuclear envelope or by cytosolic buffering of localised increases in Ca2+. In addition, agonist stimulation resulted in an increase in [Ca2+]n, consistent with release from the perinuclear Ca2+ store. There was a stimulus dependence of the relation between [Ca2+]n and [Ca2+]c suggesting differential regulation of [Ca2+]n. These results have important implications for the role of Ca2+ as a specific regulator of nuclear events through Ca2+ binding proteins. In addition, they highlight the advantages of using targeted aequorin in intact cells to monitor changes in organelle [Ca2+].     

Transconjunctival application of mitomycin C in combination with laser sclerostomy ab interno: a long-term morphological study of the postoperative healing process

The precise mechanism whereby mitomycin C enhances IOP reduction in glaucoma filtering surgery still eludes us. Ten rabbits received full-thickness Nd:YAG laser sclerostomy ab interno and adjunctive intraoperative treatment with mitomycin C (MMC) applied topically over the intact conjunctiva (0.5 mg ml-1 for 5 min). A systematic ultrastructural analysis of the fistulas and surrounding tissue was then conducted in conjunction with clinical observations, over the ensuing 10 weeks. In order to investigate also the extent to which MMC impedes fistula occlusion in the absence of percolating aqueous humour, we created non-perforating ('half-thickness') sclerostomies ab interno in three additional rabbits, one with and two without MMC therapy. Transconjunctival MMC application resulted in no serious complications. Eight of the ten full-thickness fistulas remained patent throughout the study, maintaining significant IOP reduction; the other two sclerostomies were compromised by iris incarceration. The MMC-treated, half-thickness canal remained as a tissue-free cul de sac; the two non-treated ones became completely occluded within one week without having recourse to extraocular cell populations. MMC suppressed the migration and proliferation of fibroblasts, macrophages and clump cells from the episclera, sclera, ciliary body and iris root. Repolymerization of heat-damaged collagen was abortive; neosynthesis was not observed. Myofibroblasts were encountered in the vicinity of the sclerostomy canals, and, after the fifth week, these cells were also found to be deployed as a canal-lining layer, delimiting the lumen from the surrounding stroma along most of the fistula length. Towards the external ostium, this layer of myofibroblasts was incomplete or absent. Near the internal ostium, lining cells were derived from the corneal endothelium. The transconjunctival mode of applying MMC appears to be efficient. This antifibrotic drug exerts its inhibitory influence by suppressing not only cell migration and proliferation, but also phagocytic and synthetic activities. However, exposed tissues are not acellular, and amongst the populations present, myofibroblasts are found to dominate the scene. The canal-delimiting cellular lining may play a role in maintaining fistula patency in MMC-treated eyes.     

Endopeptidase 24.11 inhibition does not modify uterotonic effects of endothelins in rat uterus

We investigated effects of the endopeptidase 24.11 inhibitor, SCH 39370, on uterotonic effects of endothelins (ETs) and sarafotoxin S6b. Responses of uteri from non-pregnant rats were inhibited by the ETA receptor antagonist, BQ123 (1 microM) but not the ETB receptor antagonist, BQ 788 (1 microM). ET-1, sarafotoxin S6b and ET-2 were more potent than ET-3 in tissues from non-pregnant and pregnant rats. SCH 39370 (10 microM) did not affect uterotonic responses to these peptides in either group, but inhibited those of big ET-1 in non-pregnant rat tissues, indicating inhibition of conversion of big ET-1 to ET-1. These data indicate that endopeptidase 24.11 does not inactivate the endothelin peptides in the rat uterus.     

Quality of life in relation to overweight and body fat distribution

OBJECTIVES: This study quantified the impairment of quality of life attributable to body fatness by using the standardized SF-36 Health Survey. METHODS: Tertiles of waist circumference and body mass index (BMI) in 1885 men and 2156 women aged 20 to 59 years in the Netherlands in 1995 were compared. RESULTS: The odds ratios and 95% confidence intervals of subjects with the largest waist circumferences, compared with those in the lowest tertile, were 1.8 (1.3, 2.4) in men and 2.2 (1.7, 2.9) in women with difficulties in bending, kneeling, or stooping; 2.2 (1.4, 3.7) in men and 1.7 (1.2, 2.6) in women with difficulties in walking 500 m; and 1.3 (1.0, 1.9) in men and 1.5 (1.1, 1.9) in women with difficulties in lifting or carrying groceries. Anthropometric measures were less strongly associated with social functioning, role limitations due to physical or emotional problems, mental health, vitality, pain, or health change in 1 year. The relationship between quality of life measures and BMI were similar to those between quality of life measures and waist circumference. CONCLUSIONS: Large waist circumferences and high BMIs are more likely to be associated with impaired quality of life and disability affecting basic activities of daily living.