Engineering of trypsin and its impact on beta-casein processing

Reactivation of fetal hemoglobin synthesis in adulthood can be seen in hematological disorders affecting the erythropoietic system. The objective of the present study was to evaluate the incidence and prognostic significance of increased hemoglobin F in patients with myelodysplastic syndrome. Hemoglobin F concentrations and Ggamma/Ggamma + A gamma-globin chain ratios were determined in 26 patients with primary myelodysplastic syndrome. Median age of the patients was 65 years; all FAB subtypes were included. Increased hemoglobin F concentration of up to 20% of total hemoglobin (normal: below 2%) was seen in 16 patients; ten patients had normal values. There was a significant relation between hemoglobin F concentration and the course of disease, e.g., 12 of the 16 patients with elevated hemoglobin F survived at least 1 year after the examination, in contrast to only three of the ten patients with normal hemoglobin F (p < 0.025). All of six patients with hemoglobin F above 5% survived at least 1 year. There was no significant difference in the hemoglobin F concentration between patients with and without cytogenetic anomalies. The Ggamma/Ggamma + A gamma-globin chain ratio was slightly elevated in all patients, with a weak correlation to the degree of hemoglobin F elevation. The values were not of additional prognostic significance. The data of the present study suggest that the hemoglobin F concentration may be a prognostic parameter in myelodysplastic syndrome; increased hemoglobin F concentration may indicate a better prognosis.     

Evidence for photoreceptor changes in patients with diabetic retinopathy

PURPOSE: To determine whether the rod and cone photoreceptors are affected in patients with diabetic retinopathy. METHODS: Twelve patients with diabetes and varying levels of retinopathy and nine age-similar control observers participated in this study. Two-color (500 versus 650 nm) dark-adapted thresholds were measured as a function of retinal eccentricity. Full-field flash electroretinograms were obtained using brief, high-intensity flashes. Dark-adapted rod-isolated (Wratten 47B filter) and light-adapted cone-isolated (Wratten 26 filter) electroretinographic responses were measured as a function of flash intensity. The a-wave data were fitted with a model based on photopigment transduction to obtain values for the parameters of Rmax (the maximal response) and log S (sensitivity). Standard clinical 30-Hz flicker electroretinographic responses were also measured. RESULTS: Psychophysically measured dark-adapted thresholds were elevated primarily at eccentricities of 5 degrees and 10 degrees from the fovea. Analysis of rod and cone a-wave data showed that Rmax was normal in most of the patients, but log S was reduced. Analysis of b-wave and oscillatory potential parameters showed rod and cone postreceptoral abnormalities, including changes in the rod-isolated semisaturation constant (log k), cone-mediated 30-Hz flicker, and cone-isolated oscillatory potentials. The electrophysiological results were not significantly correlated with blood glucose or glycosylated hemoglobin level. CONCLUSIONS: The results provide evidence for rod and cone receptoral and postreceptoral deficits in patients with diabetic retinopathy. The photoreceptor changes are primarily in the log S (sensitivity) parameter and are attributed to transduction abnormalities.     

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes

OBJECTIVE: To examine the 14-year incidence and progression of diabetic retinopathy and macular edema and its relation to various risk factors. DESIGN: Population-based incidence study. SETTING: The study was conducted in an 11-county area in southern Wisconsin. PARTICIPANTS: Six hundred thirty-four insulin-taking persons with diabetes diagnosed before age 30 years participated in baseline, 4-year, 10-year, and 14-year follow-up examinations. MAIN OUTCOME MEASURES: The 14-year progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema were detected by masked grading of stereoscopic color fundus photographs using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study retinopathy severity scheme. RESULTS: The 14-year rate of progression of retinopathy was 86%, regression of retinopathy was 17%, progression to proliferative retinopathy was 37%, and incidence of macular edema was 26%. Progression of retinopathy was more likely with less severe retinopathy, being male, having higher glycosylated hemoglobin or diastolic blood pressure at baseline, an increase in the glycosylated hemoglobin level, and an increase in diastolic blood pressure level from the baseline to the 4-year follow-up. Increased risk of proliferative retinopathy or incidence of macular edema was associated with more severe baseline retinopathy, higher glycosylated hemoglobin at baseline, and an increase in the glycosylated hemoglobin between the baseline and 4-year follow-up examination. The increased risk of proliferative retinopathy was associated with the presence of hypertension at baseline, whereas the increased risk of a participant having macular edema develop was associated with the presence of gross proteinuria at baseline. Lower glycosylated hemoglobin at baseline was associated with improvement in retinopathy. CONCLUSIONS: These data suggest relatively high 14-year rates of progression of retinopathy and incidence of macular edema. These data also suggest that a reduction of hyperglycemia and hypertension may result in a beneficial decrease in the progression to proliferative retinopathy.     

Retinopathy and vision loss in insulin-dependent diabetes in Europe. The EURODIAB IDDM Complications Study

PURPOSE: To assess the frequency of retinopathy and vision loss in patients with insulin-dependent diabetes mellitus and their relations to potentially modifiable risk factors. METHODS: The authors conducted a multicenter cross-sectional study of diabetic complications and their risk factors using standardized methods of assessment. The sample was comprised of 3250 insulin-dependent diabetic patients (1668 men, 1582 women) aged 15 to 60 years with mean (standard deviation) duration of diabetes of 14.7 (9.3) years from 31 European diabetes centers; 2991 of the patients were eligible for retinal photography. Visual acuity was measured using the Snellen chart. Retinopathy was evaluated by retinal photographs (two fields per eye) graded at a central facility. Glycated hemoglobin (HbA1c), cholesterol, triglyceride, fibrinogen, von Willebrand factor, and urinary albumin excretion rate were assessed at a single location. RESULTS: Corrected visual acuity was greater than or equal to 1.0 in both eyes in 69.7% of patients and less than or equal to 0.1 in the best eye in 2.3%. Factors significantly related to vision loss were age, duration of diabetes, glycated hemoglobin (HbA1c), and level of retinopathy. Mild nonproliferative retinopathy was found in 25.8% of the patients, moderate-severe nonproliferative retinopathy in 9.8% of the patients, and proliferative retinopathy in 10.6% of the patients. After adjustment for age, duration of diabetes, HbA1c, and albumin excretion rate, significant risk factors for moderate-severe nonproliferative retinopathy were blood pressure and triglyceride, and risk factors for proliferative retinopathy were triglyceride and fibrinogen. CONCLUSION: Vision loss is a common complication of patients with insulin-dependent diabetes, with diabetic retinopathy an important cause. Apart from poor glycemic control, several other potentially modifiable risk factors for retinopathy may be important, including elevated blood pressure, plasma triglyceride, and fibrinogen. In view of the possible barriers to the full implementation of strict glycemic control in this type of diabetes, additional strategies for the prevention and slowing of progression of retinopathy should be investigated, such as blood pressure and lipid lowering therapies.     

Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18

PURPOSE: To identify risk factors for the development of high-risk proliferative diabetic retinopathy (PDR) and for the development of severe visual loss or vitrectomy (SVLV) in eyes assigned to deferral of photocoagulation in the Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: Multivariable Cox models were constructed to evaluate the strength and statistical significance of baseline risk factors for development of high-risk PDR and of SVLV. RESULTS: The baseline characteristics identified as risk factors for high-risk PDR were increased severity of retinopathy, decreased visual acuity (or increased extent of macular edema), higher glycosylated hemoglobin, history of diabetic neuropathy, lower hematocrit, elevated triglycerides, lower serum albumin, and persons with mild to moderate nonproliferative retinopathy, younger age (or type 1 diabetes). The predominant risk factor for development of SVLV was the prior development of high-risk PDR. The only other clearly significant factor was decreased visual acuity at baseline. In the eyes that developed SVLV before high-risk proliferative retinopathy was observed, baseline risk factors were decreased visual acuity (or increased extent of macular edema), older age (or type 2 diabetes), and female gender. CONCLUSIONS: These analyses supported the view that the retinopathy-inhibiting effect of better glycemic control extends across all ages, both diabetes types, and all stages of retinopathy up to and including the severe nonproliferative and early proliferative stages and the possibility that reducing elevated blood lipids and treating anemia slow the progression of retinopathy.     

Early macular dysfunction detected by focal electroretinographic recording in non-insulin-dependent diabetics without retinopathy

The focal electroretinogram, which measures the functional integrity of the distal retina of the macula, was recorded with a hand-held stimulator-ophthalmoscope in 26 eyes from patients with non-insulin-dependent diabetes mellitus with normal fundus photography, and in 52 control eyes of similar age range. Implicit time and amplitude of the responses were studied as a function of the age, glycemic control through glycosylated hemoglobin measurement and duration of diabetes. Implicit time and amplitude were significantly delayed (F=5.05, p=0.028) and reduced (F=11.26, p=0.013) in diabetic patients without diabetic retinopathy compared to control subjects. Moreover, there was a significant relationship between the implicit time (r=0.57, p=0.002) and amplitude (r=-0.65, p=0.0004) with the duration of diabetes but not with hemoglobin Alc. These results strongly suggest an early macular dysfunction in non-insulin-dependent diabetes mellitus before the appearance of diabetic retinopathy.     

Diabetic retinopathy: a review

In the United States, diabetic retinopathy is the leading cause of new blindness in those of occupational age. We present an overview of risk factors, including renal disease, uncontrolled blood pressure, pregnancy, poor glucose control, elevated glycosylated hemoglobin, duration of disease, and age at time of diagnosis; pathogenesis, addressing the involvement of aldose reductase, nonenzymatic glycosylation of proteins, vasoproliferative factors, ischemia and vasodilation, systemic growth factors, and platelets and blood viscosity; pathology, including nonproliferative, preproliferative, and proliferative retinopathy; and the management of this condition.     

Reversible diabetes mellitus during growth hormone therapy in chronic renal failure

A 12-year-old girl with short stature due to idiopathic Fanconi syndrome and chronic renal failure was treated with recombinant human growth hormone (rhGH). There was no family history of diabetes mellitus and the glucose tolerance before treatment was normal. Intravenous glucose tolerance tests were performed before, during and after treatment. Two months after starting rhGH the early phase of insulin secretion (1-+3-min values) was diminished, and the patient developed manifest diabetes mellitus with hyperglycemia and an elevated hemoglobin A1c. Following discontinuation of rhGH, glucose tolerance slowly returned to normal.     

Retinopathy in African Americans and whites with insulin-dependent diabetes mellitus

BACKGROUND: The development and progression of diabetic retinopathy in African Americans with insulin-dependent diabetes mellitus is not known. METHODS: Two hundred subjects with insulin-dependent diabetes mellitus with duration of diabetes 16 years or less at first visit were studied; 58 were African Americans and 142 were whites. All had gradable stereoscopic color fundus photographs (seven standard fields) from at least two visits (mean time between first and second visit was 4.1 years). Subjects with hemoglobinopathy or proliferative retinopathy or subjects who had evidence of treatment for proliferative retinopathy at first visit were excluded. Masked grading of photographs was conducted using the modified Airlie House classification scheme. RESULTS: African Americans were older, heavier, had higher systolic blood pressure (all P < .05), and marginally higher hemoglobin A1 (HbA1) values (P = .06) than the whites at first visit. African Americans had a lower rate of two steps or more progression from preexistent retinopathy (19%) than whites (43%). Progression to proliferative retinopathy or treatment was similar by race. Multivariate analysis predicting development oe progression of retinopathy, while controlling for length of follow-up, found higher HbA1 (odds ratio [OR] = 2.15), longer duration of insulin-dependent diabetes mellitus (OR = 1.69), higher serum creatinine concentration (OR = 1.59), and white race (OR = 2.62) to be independent risk factors. CONCLUSIONS: These data suggest a previously unsuspected reduction in the adjusted risk for development and progression of retinopathy in African Americans. The reason for this apparently reduced risk are not known.     

Fetal hemoglobin levels in sudden infant death syndrome

OBJECTIVE: The aim of this study was to determine and compare fetal hemoglobin levels from infants dying of the sudden infant death syndrome (SIDS) with aged-matched control infants dying of other causes. Similar previous studies have reported both elevated and normal levels of fetal hemoglobin in whole blood samples from infants dying of SIDS. DESIGN: Triton-acid-urea gel electrophoresis and densitometry were used to determine fetal hemoglobin levels in postmortem whole blood samples from infants dying of SIDS and from appropriately age-matched control infants. Whole blood samples were analyzed blindly and matched for postgestational age. Infant ages at death ranged from birth to less than 1 year. MAIN OUTCOME MEASURES: Fetal hemoglobin in whole blood from infants dying of SIDS and control infants. RESULTS: During the period of postnatal development most associated with SIDS cases (2 to 6 months after birth), fetal hemoglobin levels were found to be significantly elevated in postmortem whole blood samples from SIDS infants compared with gestational age-matched control infants dying of causes other than SIDS. CONCLUSION: We conclude that levels of fetal hemoglobin are elevated in postmortem whole blood of SIDS infants compared with controls. Furthermore, the apparent conflict in the literature regarding fetal hemoglobin levels in SIDS infants and controls is most likely due to variability in the control data of some studies.     

Iron sufficiency in breast-fed infants and the availability of iron from human milk

Four infants were studied who had been exclusively breast-fed for periods varying from 8 to 18 months. All had grown sufficiently to have exhausted their prenatally acquired iron endowment with respect to meeting current needs for maintaining normal hemoglobin levels. All infants had normal hemoglobin values and normal serum iron values. Studies of iron absorption from breast milk and cow's milk were performed in ten normal adults. The absorption of iron from the human milk was significantly higher. These findings suggest that the iron present in human milk is sufficient to meet the iron requirements of the exclusively breast-fed infant until he approximately triples his birthweight.     

Season and migration alters the corticosterone response to capture and handling in an Arctic migrant, the white-crowned sparrow (Zonotrichia leucophrys gambelii)

PURPOSE: Blood pressure in individuals who have sickle cell disease has been reported to be lower than published normal values. We determine whether and to what degree this is true, using data obtained as part of a large natural history study. PATIENTS AND METHODS: Blood pressure was measured annually for 3,317 subjects with sickle cell disease who were 2 years old or older. Values obtained were compared with those reported by the National Health and Nutrition Examination Survey I and II (NHANES I and II). They were further analyzed with respect to age, sex, height, weight, hematologic diagnosis, blood urea nitrogen and creatinine, stroke, and death. RESULTS: Blood pressure was significantly lower in subjects with sickle cell anemia than published norms for age, race, and sex, a difference that increased with age. It correlated with body mass index, hemoglobin, measures of renal function and age, but the strength of the correlation varied among age and sex subgroups. The risk for occlusive stroke increased with systolic but not diastolic pressure. Mortality was related to elevated blood pressure in males (P < 0.05) and to a lesser extent in females (P = 0.10). In subjects with hemoglobin SC disease, blood pressure also deviated from normal but to a lesser degree. CONCLUSION: Blood pressure is generally lower than normal in individuals with sickle cell anemia. Those with high values relative to this population had an increased risk of stroke and death. Blood pressure should be monitored but values obtained must be assessed relative to the lower values expected for patients with this disease. Those with blood pressure values above 140/90 mm Hg should be evaluated and considered for treatment.     

Asymmetry of retinitis pigmentosa-related to initial optic disc vasculitis

A case of highly asymmetric retinitis pigmentosa is reported. Signs of pigmentary retinopathy appeared in the first eye following optic disc vasculitis or neuroretinitis of unknown etiology. Within 2 years the visual field became markedly restricted and the dark adaptation thresholds elevated. Twelve years later this eye was almost blind and the ERG was non-recordable. In the fellow eye, the first pigmentary changes were observed 5 years after the initial presentation, and the progression was slow. Nineteen years after the initial examination the visual field of the less affected eye was constricted to 30 degrees nasally and 60 degrees temporally, the dark adaptation threshold was only slightly elevated, and the full-field ERG was within normal range. It is possible that neuroretinitis or vasculitis of the optic disc caused the earlier onset and the more progressive course of pigmentary retinopathy in the initially affected eye.     

Colour vision in AIDS patients without HIV retinopathy

Patients suffering from AIDS develop ocular complications, the most frequent being HIV retinopathy. It is however not clear, if functional visual impairments can be observed as early indicators of ocular complications, before clinical diagnosis of HIV retinopathy is made at fundus examination. To address this issue, we measured colour vision in a group of 49 AIDS subjects with normal clinical fundi using the 'two equation method'. This method, combining red-green Rayleigh and the blue-green Moreland metameric matches, enables more complete and quantitative assessments of colour vision than those based on pigmentary tests. Data were collected on our computer controlled colorimeter and compared to those of normal subjects. While most AIDS subjects without HIV retinopathy demonstrated normal colour vision, a significant portion of them had wider matches than normal subjects (11% for the Rayleigh equation and 16% for the Moreland equation). Furthermore, matching ranges of the Moreland equation were significantly correlated with CD4 lymphocyte counts. Patients with low CD4 values tended to produce larger matching ranges than the patients with high CD4 values. A within subject study on 17 patients confirmed this trend and showed that the patients who increased/decreased their CD4 blood counts generally improved/impaired their colour discrimination in the Moreland match. No such correlation was found between the matching ranges of the Rayleigh equation and the CD4 counts. These results show that colour discrimination is slightly reduced in some AIDS subjects, although there are no detectable ocular complications. They also suggest two different types of colour vision impairments in AIDS patients without retinopathy: one reversible process affecting colour discrimination in the blue-green range; and another irreversible process affecting colour discrimination in the red-green range.     

The instant formulated parenteral solution Fresubin in the postoperative feeding of patients after maxillofacial surgery

21 patients who underwent maxillofacial surgery received daily 6-8 packets of the instant formula diet Fresubin (2,100-2,800 kcal = 8,790-11,720 J). In 1 patient nutrition with Fresubin had to be interrupted due to vomiting. Under nutrition with Fresubin, mean body weight decreased significantly by about 3.5 kg. Serum electrolytes, blood gases, pH, base excess, serum-urea-nitrogen and creatinine, albumin content, serum transaminases, glucose content, hemoglobin and hematocrit did not show any significant change. It was evident that the sodium and potassium content of Fresubin was not high enough to guarantee normal serum values. In 8 of 21 patients potassium had to be substituted parenterally. Concentrations of lipids and triglycerids increased during nutrition with Fresubin and became elevated over normal values without statistic significance.     

White blood cell count is a poor predictor of severity of disease in the diagnosis of appendicitis

The white blood cell (WBC) count is considered to be a useful test in the diagnosis of appendicitis. The purpose of this study was to examine the clinical features of patients with normal WBC appendicitis and also to determine whether a higher WBC count correlates with a more advanced stage of appendicitis. Patients with pathologically confirmed appendicitis from January 1989 to December 1994 were included in the study (n = 1919). The age, gender, temperature, length of hospital stay, and severity of disease (1 = acute appendicitis; 2 = gangrenous appendicitis; 3 = perforated appendicitis with abscess formation; 4 = appendicitis with diffuse peritonitis) were compared for patients with a normal WBC count (range, 3.8-10.9) versus those who had an elevated WBC count. A normal WBC count was seen in 11 per cent of patients (n = 209). There was no difference in age, temperature, gender, or severity of disease in the patients with a normal WBC count compared with those with an elevated WBC count (P > 0.05). The severity of disease of patients with a normal WBC count were: 1 = 58 per cent; 2 = 13 per cent; 3 = 7 per cent; and 4 = 22 per cent. For patients with an elevated WBC count the scores were: 1 = 57 per cent; 2 = 17 per cent; 3 = 13 per cent; and 4 = 14 per cent. The proportion of gangrenous and perforated appendicitis in the patients with a normal WBC count is the same as in the patients with an elevated WBC count.     

Visual fields at different stages of diabetic retinopathy

Available studies on visual field disturbances in diabetic retinopathy have shown conflicting results, obtained with different and often non-comparable techniques. We have studied visual fields at different stages of diabetic retinopathy with modern sensitive computerized technique taking precautions to limit disturbing effects of random field variation and lack of perimetric experience. Sixty-three diabetic patients, insulin-dependent and non-insulin dependent, were each subject to three test sessions using the 30-2 full threshold program of the Humphrey perimeter. Retinopathy levels ranged from 10 to 65 in the ETDRS Final scale. In eyes without retinopathy or with very mild and mild disease (levels 10-35) mean deviation values exceeding the p < 5% level occurred in only 4% of eyes in trained sessions, and the number of test points with significantly reduced sensitivity did not exceed that expected in normal eyes. In moderate and moderately severe diabetic retinopathy (level 43-47) and in severe non-proliferative and proliferative retinopathy (levels 53-65) there was clear evidence of field loss, however, with significantly reduced mean deviation values in 44% of the eyes and 6.5% of tested points showing reproducible loss of sensitivity. Thus, there was no evidence of field loss in eyes with mild disease, but clear field defects in eyes with more advanced disease. Significantly reduced sensitivity was often correlated with retinal non-perfusion and there was seen a tendency towards more correlation in the midperiphery than paracentrally.     

Intraerythrocytic adaptation (2,3 DPG,P50) in thalassemia minor

P50 and 2,3 DPG content of erythrocytes were determined in 25 patients with heterozygous beta thalassemia minor to assess the adaptive mechanisms to anemia. 2,3 DPG levels were appropriately elevated for the degree of anemia. However, P50 values were not proportionately increased. No correlations were noted between hemoglobin level, 2,3 DPG, or P50 and the presence of symptomatic complaints of fatigue or weakness in these heterozygous patients.     

The development and progression of diabetic retinopathy in type I diabetic patients: a cohort study

To describe the course and risk factors for development and progression of retinopathy, we studied a cohort of 333 Israeli Jewish patients with Type 1 (insulin-dependent) diabetes mellitus. The median age at diagnosis was 9.5 (range 0.04-26.2) years and the median duration of follow-up was 14 (range 1.6-30) years. Evaluation of both retinae was performed yearly since referral and HbA1 values were tested every 3 months since 1978. During a follow-up of 4070 patient-years, 162 patients developed non-proliferative retinopathy. The median retinopathy-free interval was 14.9 years and after 30 years all patients were affected. Pre-pubertal duration of diabetes was relevant. Independent and significant risk factors for early onset of non-proliferative retinopathy were: poor cumulative glycaemic control (median retinopathy-free interval in the 1st vs 4th quartiles of mean HbA1 values over all years: 18.0 vs 12.5 years, p = 0.0001); onset of diabetes during or after puberty (median retinopathy-free interval in patients with onset of diabetes before, during or after pubescence: 16.3, 13.2 and 14.0 years, respectively, p = 0.0001); and non-Ashkenazi Jewish origin (median retinopathy-free interval 15.8 years in Ashkenazi vs 14.0 in non-Ashkenazi patients, p = 0.0004). Of 162 patients with non-proliferative retinopathy, progression to proliferative retinopathy occurred in 37, during 707 patient-years. The first event of proliferative retinopathy was diagnosed within the 1st year after non-proliferative retinopathy evolved, and at 6.3 years since onset of non-proliferative retinopathy 75% of the patients were still free of proliferative changes. Risk factors significantly and independently associated with an early progression to the proliferative stage were: poor glycaemic control in the last 3 years prior to the development of proliferative retinopathy and non-Ashkenazi Jewish origin. All patients in the 4th quartile of HbA1 values were affected by proliferative retinopathy within 11.6 years after onset of non-proliferative retinopathy.     

Erythropoietin in hepatocellular carcinoma

Hemopoietic alterations may occur during tumoral diseases, determining anemia. In most cases, serum EPO levels were lower than normal values. Hepatocellular carcinoma (HCC), one of the most frequent malignancies world-wide, is often characterized by mild anemia and increased serum EPO levels. We studied 30 HCC patients and 20 healthy subjects. We found that HCC patients presented higher serum EPO levels than healthy controls. In HCC patients, there was a significant inverse correlation between serum EPO levels and red blood cell count or hemoglobin levels. We postulated that the elevated serum EPO levels observed in these patients may be due to reduced hepatic clearance of EPO, and to the influence of cytokine-mediated inflammatory factors.