An elevated CA 19-9 is associated with invasive cancer and worse survival in IPMN.

BACKGROUND: Current guidelines for IPMN include an elevated serum carbohydrate antigen (CA) 19-9 among the worrisome features. However, the correlation of CA 19-9 with histological malignant features and survival is unclear. Serum CEA is also currently used for preoperative management of IPMN, although its measurement is not evidence-based. Accordingly, we aimed to assess the role of these tumor markers as predictors of malignancy in IPMN. METHODS: IPMN resected between 1998 and 2018 at Massachusetts General Hospital were analyzed. Clinical, pathological and survival data were collected and compared to preoperative levels of CA 19-9 and CEA. Receiver operating characteristic (ROC) and Cox regression analyses were performed considering cut-offs of 37 U/ml (CA 19-9) and 5 µg/l (CEA). RESULTS: Analysis of 594 patients showed that preoperative CA 19-9 levels > 37 U/ml (n = 128) were associated with an increased likelihood of invasive carcinoma when compared to normal levels (45.3% vs. 18.0%, P < 0.001), while there was no difference with respect to high-grade dysplasia (32.9% vs 31.9%, P = 0.88). The proportion of concurrent pancreatic cancer was higher in patients with CA 19-9 > 37 U/ml (17.2% vs 4.9%, P < 0.001). An elevated CA 19-9 was also associated with worse overall and disease-free survival (HR = 1.943, P = 0.007 and HR = 2.484, P < 0.001 respectively). CEA levels did not correlate with malignancy. CONCLUSION: In patients with IPMN, serum CA19-9 > 37 U/ml is associated with invasive IPMN and concurrent pancreatic cancer as well as worse survival, but not with high-grade dysplasia. Serum CEA appears to have minimal utility in the management of these patients.

Risk of malignancy in small pancreatic cysts decreases over time.

BACKGROUND: Pancreatic cysts <15 mm without worrisome features have practically no risk of malignancy at the time of diagnosis but this can change over time. Optimal duration of follow-up is a matter of debate. We evaluated predictors of malignancy and attempted to identify a time to safely discontinue surveillance. METHODS: Bi-centric study utilizing prospectively collected databases of patients with pancreatic cysts measuring <15 mm and without worrisome features who underwent surveillance at the Massachusetts General Hospital (1988-2017) and at the University of Verona Hospital Trust (2000-2016). The risk of malignant transformation was assessed using the Kaplan-Meier method and parametric survival models, and predictors of malignancy were evaluated using Cox regression. RESULTS: 806 patients were identified. Median follow-up was 58 months (6-347). Over time, 58 (7.2%) cysts were resected and of those, 11 had high grade dysplasia (HGD) or invasive cancer. Three additional patients had unresectable cancer for a total rate of malignancy of 1.7%. Predictors of development of malignancy included an increase in size ≥2.5 mm/year (HR = 29.54, 95% CI: 9.39-92.91, P < 0.001) and the development of worrisome features (HR = 9.17, 95% CI: 2.99-28.10, P = 0.001). Comparison of parametric survival models suggested that the risk of malignancy decreased after three years of surveillance and was lower than 0.2% after five years. CONCLUSIONS: Pancreatic cysts <15  mm at the time of diagnosis have a very low risk of malignant transformation. Our findings indicate the risk decreases over time. Size increase of ≥2.5 mm/year is the strongest predictor of malignancy.

Disposal of radioactive wastes.

Scientists appointed by the International Council of Scientific Unions have concluded that nuclear wastes may be safely disposed of using current technology. Interim storage for 50 to 100 years greatly reduces the problem of thermal loading at the final disposal sites, but more research devoted to such interim storage is needed.

Visual and nonvisual auditory systems in mammals. Anatomical evidence indicates two kinds of auditory pathways and suggests two kinds of hearing in mammals.

Examination of the structural organization of the auditory system of the brain stem shows that the system is composed of a number of separate ascending pathways. This suggests that there may be at least two auditory systems, analogous to the rod and cone pathways in vision. We examined this possibility by investigating the variation in relative size of the medial and lateral superior olivary nuclei in a number of different mammalian species. The lateral superior olive is present in the hedgehog (an insectivore), cat (acarnivore), and squirrel monkey a(primate), but the medial superior olive is absent in the hedgehog. In a group of animals of the same taxonomic order (rodents) the lateral superior olive was present in all species examined, but the medial superior olive was almost wholly absent in the mouse and very prominent in the chinchilla and guinea pig. The absence of the medial superior olive in some animals is surprising because recent anatomical and physiological work has implicated the nucleus in auditory localization. Because of this implication, the medial and lateral olivary nuclei were examined in three species of bat and one dolphin, all echolocating animals. The medial superior olive was absent in these animals, and the lateral superior olive was prominent. These observations support the idea that the medial and lateral superior olives are nuclei on two different ascending auditory systems. It was also noted that the medial superior olive was always well developed in animals with well-developed eyes, and this suggested that the nucleus is in some way related to the visual system. We examined this idea by studying the relation between the numbers of cells in the medial superior olive and in the nucleus of the 6th cranial nerve (one of the motor nuclei concerned with eye movement) in a number of mammalian species. An approximately linear function was found between the sizes of the 6th nucleus and of the medial superior olive in three primates with cone-cell retinas (squirrel monkey, man, and macaque) and four rodents with rod-cell retinas (mouse, rat, guinea pig, and chinchilla). The cell numbers for the ground squirrel (a rodent with cone-cell retina) fitted an extension of the primate curve, and the cell numbers for the cat (in whose retina rods predominate) fitted an extension of the rodent curve. Thus, it is clear that the medial superior olive is related to the visual system, and that it is present in animals with cone-cell fovea and retina (diurnalanimals) and animals with rod-cell retina (that is, nocturnal animals) having good vision. In nonvisual nocturnal animals the nucleus is small or absent. The medial superior olive is probably not concerned with auditory localization in the psychophysical sense but is probably concerned with the movement of head and eyes in the direction of a sound in space. Localization in the psychophysical sense and fine auditory discrimination probably depend upon the ascending pathway which includes the lateral superior olive.

A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS).

BACKGROUND: Dietary interventions including consumption of flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with MS (pwMS) have been performed. The hypothesis is that the consumption of a flavonoid-rich pure cocoa beverage will reduce fatigue in pwMS. The aim of this study is to determine the feasibility and potential outcome of running a trial to evaluate this hypothesis. METHODS: Using a randomised (1:1) double-blind placebo-controlled feasibility study, 40 men and women (20 in each trial arm) with a recent diagnosis (< 10 years) of relapsing and remitting MS (RRMS) and who are over 18 years of age will be recruited from neurology clinics and throughout the Thames Valley community. During a 6-week nutrition intervention period, participants will consume the cocoa beverage, high flavonoid or low flavonoid content, at breakfast daily. At baseline, demographic factors and disease-related factors will be assessed. Fatigue, activity and quality of life, in addition to other measures, will be taken at three visits (baseline, week 3 and week 6) in a university setting by a researcher blinded to group membership. Feasibility and fidelity will be assessed through recruitment and retention, adherence and a quantitative process evaluation at the end of the trial.We will describe demographic factors (age, gender, level of education) as well as disease-related factors (disease burden scores, length of time diagnosed with MS) and cognitive assessment, depression and quality of life and general physical activity in order to characterise participants and determine possible mediators to identify the processes by which the intervention may bring about change. Feasibility (recruitment, safety, feasibility of implementation of the intervention and evaluation, protocol adherence and data completion) and potential for benefit (estimates of effect size and variability) will be determined to inform future planned studies. Results will be presented using point estimates, 95% confidence intervals and p values. Primary statistical analysis will be on an intention-to-treat basis and will use the complete case data set. DISCUSSION: We propose that a flavonoid-enriched cocoa beverage for the management of fatigue will be well received by participants. Further, if it is implemented early in the disease course of people diagnosed with RRMS, it will improve mobility and functioning by modifying fatigue. TRIAL REGISTRATION: Registered with ISRCTN Registry. Trial registration No: ISRCTN69897291; Date April 2016.

Further studies of the frequency and significance of the Tgamma-chain of human fetal hemoglobin.

A further study of the Tgamma-chain in a variety of conditions has revealed its presence in the cord bloods of ethnic groups previously unstudied. Heterozygous newborn average 17-19% Tgamma-chain while the mean value in four presumed homozygotes was 31%. The Tgamma-chain is readily detectable in beta-thalassemia of various ethnic groups (although infrequent in Blacks) as well as in deltabeta-thalassemia. Studies of a few families have provided an opportunity to determine whether or not certain individuals are heterozygous or homozygous for the Tgamma-gene. The Tgamma-chain has not been detected in the human fetal hemoglobin that is synthesized in increased amounts in persons with the hereditary persistence of fetal hemoglobin. Although the Tgamma-chain is detectable in sickle cell anemia, its frequency appears to be lower than in normal individuals. By focusing upon the relationship of the percentage of Tgamma-chain to the sources of human fetal globulin from determinants in cis and in trans, the conclusion has been reached that the Tgamma-chain is the product of a mutant Agamma-locus which should be named the TAgamma-chain.

Flavonoid rich dark cocoa may improve fatigue in people with multiple sclerosis, yet has no effect on glycaemic response: An exploratory trial.

CONTEXT: Current research suggests that dark cocoa may reduce fatigue; however, the effect on fatigue in people with MS (pwMS) has never been established. The objective of this feasibility study was to explore the acute effect of high flavonoid cocoa on measures of fatigue and glycaemic response. METHODS: This was a randomised crossover participant blind exploratory study in 12 participants (2 male and 10 female) with MS-related fatigue (>4 on the Fatigue Severity Scale; FSS). After fasting overnight, participants consumed the high flavonoid cocoa drink (350 mg gallic acid equivalents {GAE}/g) or a low flavonoid cocoa control (120 mg GAE/g), consuming the alternative drink on the next visit. Fatigue was self-reported on a 100 mm visual analogue scale at 30-min time intervals for 2 h post cocoa consumption and every 2 h for the rest of the day. Fatigability was monitored using a 6 min walk test (6MWT) at the end of the visit (2 h), and activity monitors worn for 24 h commencing at 12 noon on the day of testing. The feasibility of performing the trial including outcome measures was documented. RESULTS: A moderate effect was found in self-reported fatigue throughout the day in favour of the high flavonoid group (Cohen's d 0.32, 95% non-central t CI -0.57 to 1.20). Fatigability measures did not change. Participants consumed and enjoyed the cocoa, all participants completed the study and outcome measures were accepted. CONCLUSION: The results of this study support further trials to investigate the feasibility and efficacy of pure cocoa as a dietary supplement for fatigue in pwMS.

Prophylactic agents for venous thrombosis in elective hip surgery. Meta-analysis of studies using venographic assessment.

BACKGROUND: We determined the relative efficacy of various agents or combinations of agents in the prophylaxis of deep venous thrombosis after elective hip arthroplasty. METHODS: Peer-reviewed, English-language, human studies articles from 1975 through 1991 were obtained through a MEDLINE database search. Additional references were obtained from bibliographies. Articles that compared the effect of two or more prophylactic agents or placebo in preventing deep venous thrombosis as assessed by venography were selected for further review. Only studies of elective hip surgery in which all patients had venographic screening for thrombosis were included. Twenty-three of 101 studies met these criteria. Data were abstracted by one of us. Methodologic criteria and outcome data from each study were recorded and analyzed. RESULTS: There was significant heterogeneity in the deep venous thrombosis rate among studies. Although the rates were lowest for low-molecular-weight heparin with or without the use of stockings, adjusted-dose heparin, and warfarin, many agents had similar low rates. There was less heterogeneity when the relative risk was used as a summary statistic for studies in which two agents were compared. With pairwise comparisons, low-molecular-weight heparin performed better than every agent with which it was compared. Other agents performed well but were not consistently better. CONCLUSIONS: Multiple agents or combinations are effective prophylaxis for deep venous thrombosis, but none decreases the rate to zero. There was overlap in the 95% confidence intervals for the probability of deep venous thrombosis for various agents and especially for the probabilities for proximal thrombi. Many agents have not been compared directly with each other, but low-molecular-weight heparin consistently performed well.

Screening for cognitive impairment in older individuals. Validation study of a computer-based test.

OBJECTIVE: This study examined the validity of a computer-based cognitive test that was recently designed to screen the elderly for cognitive impairment. DESIGN: Criterion-related validity was examined by comparing test scores of impaired patients and normal control subjects. Construct-related validity was computed through correlations between computer-based subtests and related conventional neuropsychological subtests. SETTING: University center for memory disorders. PARTICIPANTS: Fifty-two patients with mild cognitive impairment by strict clinical criteria and 50 unimpaired, age- and education-matched control subjects. Control subjects were rigorously screened by neurological, neuropsychological, imaging, and electrophysiological criteria to identify and exclude individuals with occult abnormalities. RESULTS: Using a cut-off total score of 126, this computer-based instrument had a sensitivity of 0.83 and a specificity of 0.96. Using a prevalence estimate of 10%, predictive values, positive and negative, were 0.70 and 0.96, respectively. Computer-based subtests correlated significantly with conventional neuropsychological tests measuring similar cognitive domains. Thirteen (17.8%) of 73 volunteers with normal medical histories were excluded from the control group, with unsuspected abnormalities on standard neuropsychological tests, electroencephalograms, or magnetic resonance imaging scans. CONCLUSIONS: Computer-based testing is a valid screening methodology for the detection of mild cognitive impairment in the elderly, although this particular test has important limitations. Broader applications of computer-based testing will require extensive population-based validation. Future studies should recognize that normal control subjects without a history of disease who are typically used in validation studies may have a high incidence of unsuspected abnormalities on neurodiagnostic studies.

Differences among humans in steady-state evoked potentials: evaluation of alpha activity, attentiveness and cognitive awareness of perceptual effectiveness.

We examined some of the variables that were possible sources of the wide variability among and within human subjects in their steady-state visual evoked potentials (VEP) in response to continuously counter-phased visual stimuli (vertical bars). We found that within a given subject the magnitude of VEP was reasonably consistent during replicate trials under comparable conditions. However, across subjects there were enormous differences (as much as 17-fold) in the VEP magnitude (i.e. in the spectral power developed at the stimulus reversal frequency). These differences could not be explained by differences among subjects in arousal (alpha activity before or during stimulation), attentiveness (as indicated by reaction times to random cueing), or by a person's subjective impression of his responsiveness to stimulation.

The surprisingly high acceptability of low-efficacy vaccines for otitis media: a survey of parents using hypothetical scenarios.

OBJECTIVE: To determine parental thresholds for accepting vaccines for otitis media prevention given tradeoffs of efficacy, adverse effects, and administration mode. METHOD: We interviewed 601 randomly selected parents with children 0 through 6 years of age presenting to our community pediatric clinic. For each of five hypothetical vaccines, which varied administration mode from nasal spray to two injections and adverse effects from mild to severe, parents indicated the lowest number of otitis media episodes that the vaccine had to prevent in the next 6 months for them to accept the vaccine. RESULTS: About half the parents would accept any one of the vaccines if it would prevent three or more infections in the next 6 months. When the vaccine would prevent one episode of otitis media over the next 6 months, 33% of parents would accept the medial vaccine (one injection in the thigh, with some children getting a red, sore injection site and a few having a fever of < or = 102 degrees F for one day). Seventeen percent accepted a vaccine requiring two injections (influenza vaccine-like) or having increased adverse effects (pneumococcal vaccine-like) despite the vaccine only preventing one episode of otitis media over the next 6 months. No substantial differences in these proportions were found when compared among groups by reason-for-visit, recent occurrence of otitis media, or a history of recurrent otitis media in a sibling. CONCLUSION: Many parents will accept low efficacy vaccines for otitis media prevention. Parental acceptance does not vary with the child's otitis media experience but does vary with severity of adverse effects and administration mode of the vaccine.

Extended photoreceptor viability by light stress in the RCS rats but not in the opsin P23H mutant rats.

PURPOSE: To determine the effect of light stress on retinal function and long-term photoreceptor viability in Royal College of Surgeons (RCS) rats and the applicability of the light treatment to the opsin P23H mutant rats. METHODS: RCS rats at postnatal day (P)23 were illuminated with 120 foot-candles (fc) white light for 10 hours. Photoreceptor survival and basic fibroblast growth factor (bFGF) expression were measured at P60 and P83. Retinal function was evaluated by electroretinography. Opsin P23H transgenic rats were treated with light at P28 and analyzed at P70 for photoreceptor viability, ultrastructure, and bFGF expression. RESULTS: Light-treated RCS rats at P60 had four to five rows of nuclei versus one to two rows in untreated littermates. The average amplitude of the ERG b-wave was 28 microV in treated rats, compared with 6 microV in untreated littermates. By P83 there was still significant preservation of the ONL in treated rats. Immunoblot analysis showed a high expression of bFGF in the treated retinas even 2 months after treatment. Illumination of P23H rats at P28 with 120 fc white light for 10 hours caused substantial photoreceptor cell death, although bFGF expression was upregulated. Lowered illumination dosages continued to cause photoreceptor damage until levels were reached that neither caused damage nor enhanced survival. CONCLUSIONS: Although light stress promotes photoreceptor survival and function in the RCS rat, it elicits death signals in the P23H rats that may not be overcome by survival-promoting factors. Therefore, use of light stress to promote photoreceptor survival should be considered with regard to sensitivity of the mutation to light damage.

The pattern ERG in man following surgical resection of the optic nerve.

Pattern electroretinogram (PERG) results recorded in different laboratories from patients with unilateral traumatic transections of the optic nerve have led investigators to opposite conclusions about the sources of this response. There was no absolute demonstration of complete transection in any of these studies. In the present study, PERGs and flash ERGs were recorded from a patient who, 30 months earlier, had undergone surgical resection of the right optic nerve to remove a glioma. The histological section of the biopsied nerve confirmed complete optic nerve transection. Ophthalmoscopically and angiographically, the right eye was normal except for marked optic atrophy. PERGs were produced by 10 Hz reversal of high contrast checks with check widths from 13 deg 30 min to 12 min arc. Field size was 27 deg X 21 deg and space-averaged screen luminance was 110 cd/m2. Smaller checks (3 deg 23 min to 12 min) produced responses in both eyes, but the responses in the right eye were much smaller than those in the left eye. Large checks and diffuse flashes produced approximately equal responses in the two eyes. The implicit times of the PERGs produced by stimulation of the right eye with smaller checks were shorter than those of the left eye. The authors conclude that, in humans, there is a contribution to the high contrast pattern reversal ERG from cells which are not dependent upon the integrity of the ganglion cell layer. These cells and cells dependent upon ganglion cells may both contribute to the high contrast PERG in the normal human eye.

Lipids and Lp(a) lipoprotein levels and coronary artery disease in subjects with non-insulin-dependent diabetes mellitus.

OBJECTIVE: To determine whether increased Lp(a) lipoprotein levels are associated with either non-insulin-dependent diabetes mellitus (NIDDM) or coronary artery disease (CAD) in patients with NIDDM and to examine the relationship between Lp(a) levels and glycemic control. DESIGN: We conducted a cross-sectional study of subjects with NIDDM who were participants in the Rochester Diabetic Neuropathy Study and healthy control subjects from the population of Rochester, Minnesota. MATERIAL AND METHODS: Lipids and Lp(a) lipoprotein levels were compared in 227 subjects with NIDDM and 163 control subjects and, among the subjects with NIDDM, in those with (N = 96) and without (N = 131) CAD. The correlation between Lp(a) levels and glycosylated hemoglobin was investigated. RESULTS: Subjects with NIDDM had higher triglyceride and lower high-density lipoprotein cholesterol levels than did control subjects. Subjects with NIDDM and CAD had higher total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels and lower high-density lipoprotein cholesterol levels than did subjects with NIDDM without CAD. Subjects with NIDDM had significantly higher Lp(a) levels than did control subjects, but subjects with NIDDM and CAD did not have significantly higher Lp(a) levels than did those without CAD. Among subjects with NIDDM, the level of Lp(a) was not significantly correlated with glycosylated hemoglobin. CONCLUSION: Although subjects with NIDDM have higher Lp(a) levels than do control subjects, Lp(a) does not seem to be associated with CAD in subjects with NIDDM. In this study, no association was found between Lp(a) level and glycemic control.

Studies of binaural detection in the rabbit (Oryctolagus cuniculus) with Pavlovian conditioning.

A Pavlovian conditioned eyeblink response in rabbits (Oryctolagus cuniculus) was used to study psychoacoustical phenomena previously demonstrated in human listeners and other animals. This article contains the results of a tone-in-noise detection study to examine 2 psychoacoustical phenomena in rabbit and in human listeners: (a) the binaural masking level difference (BMLD) and (b) differential performance across reproducible noise masker waveforms. The rabbits demonstrated a BMLD comparable in size to other species. Significant differences in performance across reproducible noise masker waveforms were seen in the rabbits. This performance was compared with the performance of human listeners using the same set of waveforms.

The role of portosystemic shunts for variceal bleeding in the liver transplantation era.

OBJECTIVE: To review our experience with portosystemic shunts during the era of liver transplantation at the Mayo Clinic to provide insight into the selection of patients for these procedures. DESIGN: We reviewed the charts of a cohort of 57 patients who underwent portosystemic shunting between 1985 and 1990 for the management of variceal bleeding. A follow-up survey by letter and telephone was also conducted. SETTING: The Mayo Clinic, a tertiary referral center. PATIENTS: These patients were not considered transplantation candidates at the time of the shunt because of active alcoholism, extensive portal vein thrombosis, coexistent myelodysplastic syndromes, or malignant neoplasms. INTERVENTION: Portosystemic shunts; the exact type was at the surgeon's discretion. OUTCOME: Survival after shunt surgery among patients with various liver diseases. RESULTS: Twenty-two patients died during follow-up after being shunted for bleeding, and one of the shunted patients subsequently required liver transplantation. Comparison of Kaplan-Meier survival curves between various groups of patients indicated that patients who were actively alcoholic had a poorer chance of survival (P < .003) than did those who were abstinent. Patients with portal vein obstruction or chronic cholestatic liver disease appeared to do better after shunt surgery than did patients with other causes of portal hypertension. Other factors such as age, Child-Pugh score, or presence of malignant neoplasms did not reliably predict outcome from portosystemic shunts. CONCLUSIONS: In well-selected patients who may not be deemed candidates for liver transplantation, portacaval shunts can be effectively employed to prevent bleeding from esophageal varices that are resistant to obliteration by sclerotherapy.

Antibiotic susceptibilities of streptococci from the mouth and blood of patients treated with penicillin or lincomycin and clindamycin.

Patients undergoing dental extractions were non-randomly allocated to three groups, one of which received no antibiotic, one benzylpenicillin followed by oral penicillin for 5 days, and the third intramuscular lincomycin followed by oral clindamycin. Dental extraction was performed at the beginning of the course of chemotherapy. Streptococci were isolated from the extracted teeth, from blood cultures collected before and immediately after dental extraction, and from sutures removed from the gums 5-7 days after the operation. The species of these organisms was determined, and their susceptibilities to penicillin, clindamycin, cephaloridine, erythromycin and tetracycline were assessed. The majority of streptococci isolated from teeth belonged to the species Streptococcus sanguis, S. mitior, S. mutans and S. milleri. Occasional isolates of each of these organisms collected before the antibiotic could take effect were resistant to penicillin. Three of these species, but not S. mutans, were the commonest streptococci to be isolated from the blood after dental extraction. Penicillin completely suppressed dental bacteriaemia under the conditions of our investigation, and lincomycin reduced the incidence by about 60 per cent. The commonest streptococci from sutures were also S. sanguis, S. mitior, S. mutans and S. milleri. S. faecalis was also isolated, but only in patients who had received antibiotics. Among the non-faecalis organisms, penicillin resistance was significantly more frequent among isolates from patients given penicillin than from patients not given this antibiotic, and clindamycin resistance was significantly more frequent among isolates from patients given lincomycin and clindamycin than from patients not given these antibiotics.

Oxidative stress indices in IDDM subjects with and without long-term diabetic complications.

BACKGROUND: Numerous animal and population studies of diabetes have identified markers of oxidative stress. However, for most markers that have been measured the results are not consistent. In addition, it is less clear whether oxidative stress is related to the development of diabetic complications. The objective of this study was to evaluate a series of plasma markers and leukocyte markers to test the hypothesis that type 1 Insulin Dependent Diabetes Mellitus (IDDM) subjects experience oxidative stress. A related question was whether markers of oxidative stress are higher in IDDM subjects who have developed long-term complications. METHODS: The study population consisted of 22 IDDM subjects with diabetic complications and 22 IDDM subjects without complications, both groups matched by age and gender and with similar HbA1c levels, and 16 nondiabetic control subjects. Plasma levels of organoperoxides were determined by the ferrous oxidation/xylenol orange (FOX) assay, malondialdehyde by the thiobarbituric acid (TBARS) assay, and vitamin E by HPLC. Mononuclear cells and polymorphonuclear cells were analyzed for ascorbic acid by HPLC and for glutathione (GSH) by enzymatic recycling. In addition, GSH peroxidase, GSH transferase and glucose-6-phosphate dehydrogenase levels were determined in both cell fractions. RESULTS: Plasma organoperoxides were significantly elevated in the IDDM subjects compared to controls (p = 0.02) while TBARS and vitamin E levels were not significantly different. In the IDDM subjects, mononuclear cell levels of ascorbic acid were significantly lower (p < 0.02) and levels of GSH were lower, approaching significance (p = 0.07), compared to controls. Ascorbic acid and GSH levels in polymorphonuclear cells were not significantly different between IDDM subjects and controls, nor were enzyme levels different. In addition, the plasma and intracellular indices of oxidative status in IDDM subjects were not different when IDDM subjects with complications were compared to IDDM subjects without complications. CONCLUSION: Demonstration of oxidative stress in IDDM subjects depends upon which markers are measured. This is in agreement with previous studies of oxidative stress in various disease states including diabetes. Plasma levels of organoperoxides may be the most reliable indicators of oxidative stress. However, it is unclear whether elevated plasma organoperoxides indicate a generalized systemic stress or are produced in localized areas. By comparison, oxidative stress indices determined with isolated blood cells may provide a clearer picture. Depressed levels of ascorbic acid and GSH were observed only in mononuclear cells, which are mainly long-lived T lymphocytes. Mononuclear cells antioxidant status may reflect systemic oxidative stress. In this study, neither plasma markers nor intracellular markers of oxidative stress were different in IDDM subjects with long-term diabetic complications compared to subjects without complications.

Molecular, morphometric and functional analyses demonstrate that the growth hormone deficient little mouse is not hypomyelinated.

To study the effects of naturally occurring growth hormone deficiency type I on CNS myelination, we compared the myelination of brains from little and wild-type littermate mice using molecular, histological, morphometric, and functional analyses. The little mouse produces only 6-8% of normal levels of growth hormone (GH) and approximately 20% of normal circulating levels of insulin-like growth factor 1 (IGF-1). Our data show that the expression of myelin basic protein (MBP) and proteolipid protein (PLP) of the little brain exhibit the same temporal pattern and amount as that of the wild-type brain. Furthermore, the density and size of myelinated axons and the myelin sheath thickness in the corpus callosum, anterior commissure and the optic nerve are comparable in the little and wild-type brains. These regions are reduced in size in the little mouse brain proportionate to the overall reduction in brain size implying a reduction in the total number of neurons. Therefore, it follows that the total myelin content is reduced, but when normalized to brain size, the myelin concentration is unchanged. Myelin staining patterns of whole brains were identical. Moreover, functional analysis of the visual pathway indicated no difference between the little and control mice. These results are inconsistent with previous reports of hypomyelination in the little mouse and suggest that this form of GH deficiency does not adversely affect the myelination process except possibly through neuronal proliferation. However, since axon size and density are maintained, the neuronal growth may conversely be inherently limited by other restricted brain growth.