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Aims: The clinical relevance of diabetes-distress is increasingly recognized, but little is known about the efficacy of interventions specifically targeted to treat elevated diabetes-distress. Therefore, this systematic review sought to determine the efficacy of psychological interventions aimed at treating elevated diabetes-distress in people with Type 1 or Type 2 diabetes. Methods: We systematically searched literature from five databases. Randomized controlled trials (RCTs) with an English abstract, describing the results of a psychological intervention in adults with diabetes were included. Articles were eligible for inclusion if the primary outcome was diabetes-distress measured by the Problem Areas in Diabetes Scale (PAID-5/PAID-20) or the Diabetes Distress Scale (DDS-17). Only mean group diabetes-distress values above cut-off at baseline or the results of a subgroup above cut-off (PAID-5 ≥ 8, PAID-20 ≥ 40 or DDS-17 ≥ 3) were included. Results: The search yielded 8907 articles. After removing 2800 duplicates, 6107 articles remained. Titles and abstracts were screened, leaving 394 potential articles of interest, nine of which were RCTs. In a random-effects meta-analysis, the pooled effect size for diabetes-distress was 0.48 (Cohen's d), Z = 3.91, P 1c (Cohen's d = 0.57), whereas mindfulness-based interventions did not (Cohen's d = 0.11). Conclusions: This systematic review shows that specifically diabetes-tailored psychological interventions are effective in reducing elevated diabetes-distress and HbA1c. More rigorous studies are warranted to establish the full potential of these interventions. PROSPERO database registration ID: CRD42017075290.

Contains fulltext : 198097.pdf (Publisher’s version ) (Closed access) AIM: Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self-measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies. MATERIAL AND METHODS: We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5-7 days every 6 weeks in the CGM group, while self-monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications. RESULTS: Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83-1.37). HbA1c levels were similar between treatment groups. CONCLUSIONS: In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome.

Secondary hyperparathyroidism is an almost inevitable complication of advanced kidney failure. The introduction of the calcimimetic cinacalcet for the treatment of secondary hyperparathyroidism in patients on dialysis was based on its ability to reduce elevated levels of parathyroid hormone (PTH). Subsequent clinical studies confirmed the beneficial effects of cinacalcet on biochemical parameters reflecting mineral disturbances and bone disease. In this review we summarise the impact of cinacalcet on biochemical, intermediate and clinical outcomes. We also present previously unpublished mineral metabolism data from 144 Dutch dialysis patients treated with cinacalcet who participated in the pan-European ECHO observational study. Although secondary hyperparathyroidism tended to be more severe in our Dutch cohort, compared with the entire ECHO cohort, cinacalcet was nevertheless effective in reducing PTH in these patients. Two recent clinical studies evaluated, respectively, the efficacy of cinacalcet in improving the intermediate endpoint of cardiovascular calcifications (ADVANCE trial), and its impact on clinical outcomes, including all-cause mortality and cardiovascular events (EVOLVE trial). The ADVANCE trial provided evidence that cinacalcet may indeed improve calcification in both large arteries and cardiac valves. The EVOLVE trial, however, did not meet its clinical primary endpoint (time to all-cause mortality, myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event), although secondary and sensitivity analysis suggested a beneficial effect. The clinical implications of these important studies are also addressed in this review.

A patient with acute cardiorespiratory failure caused by hyperleukocytosis due to chronic lymphocytic leukaemia (CLL) is described. Although acute pulmonary failure due to leukostasis is a known and often postmortem finding in patients with acute myelocytic leukaemia (AML) or chronic myelocytic leukaemia (CML) in blastic crises, it is rare in CLL.

To investigate the effects of a course of instruction in intraoral digital radiology on the knowledge, attitudes and beliefs of dental students.A questionnaire was administered to dental students at two institutions with (UL) and without (MCG) formal instruction in digital dental radiology, investigating their understanding of the principles of digital radiography, their attitudes to its use in the near future, and on the timing and suitability of the topic in the undergraduate dental curriculum. Differences in the responses between preclinical and clinical students at the two institutions were statistically assessed.The overall response rate was 66% (277) with rates of 52% (103) at MCG and 76% (174) at UL. UL students knew significantly more about digital radiography but they also had some significant misconceptions and differed in their perception of its future role. Most students (93%) believed that digital radiography should be included in the curriculum or offered as an elective course.Dental students want digital radiology to be introduced into the dental radiology curriculum, regardless of whether it is examined or not. The teaching methods and content of such a course need careful consideration.

Hypoglykemie is een symptomencomplex dat gepaard gaat met een te laag bloedsuikergehalte, veroorzaakt door een (relatieve) overmaat aan circulerende insuline. De hypoglykemie bij diabetespatienten die met insuline worden behandeld is genoegzaam bekend.

Spoedeisende hulp bij aandoeningen van de nieren of urinewegen is geboden wanneer de huisarts een afwijking waarneemt die gevaarlijk c.q. levensbedreigend kan zijn, of die bij de patient soortgelijke gevoelens of ten minste ongerustheid oproept.

The aim of this study was to compare the performance of direct digital radiography and traditional dental radiography for the detection of proximal surface dental caries in the mixed dentition.15 quadrants of extracted teeth, arranged from the primary canine to permanent first molar, were imaged using direct digital (Schick Technologies, Long Island City, NY, USA) and conventional films (D-speed and E-speed Plus; Eastman Kodak Co., Rochester, NY, USA). Five pediatric dentists viewed the images and scored the 270 proximal surfaces for presence of caries on a 5 point scale and extent of caries on a 4 point scale. The teeth were sectioned and viewed microscopically to determine the gold standard. Receiver operating characteristic (ROC) analysis and analysis of variance (ANOVA) were used to evaluate the viewer's performance for detecting proximal caries using the 3 different image receptor types.Experienced examiners were significantly more accurate in diagnosis of proximal surface caries using either D-speed or E-speed Plus films than they were using the direct digital receptor. The mean areas under the ROC curve (Az) for the viewers were 0.7595 for D-speed film, 0.7557 for E-speed Plus film, and 0.5928 for the direct digital receptor. The results also indicated that selected viewers' accuracy increased when viewing the direct digital images a second time.CCD based direct digital radiography was not as accurate as conventional film images for the purpose of diagnosing proximal surface caries in the mixed dentition. However, the results imply that with increased experience, direct digital images may be as accurate as conventional film based images for diagnosis.

Insulin-like growth factor (IGF)-I is a potent anabolic agent that plays an important role in regulating muscle protein balance. Alterations in one or more of the various components of the IGF system may be in part responsible for the muscle wasting that accompanies chronic alcohol consumption. The purpose of the present study was to characterize changes in the growth hormone-IGF axis produced by chronic alcohol consumption in rats. After 8 weeks of alcohol feeding, the IGF-I concentration was decreased in plasma (31%) as well as in the liver and skeletal muscle (40-50%), compared with pair-fed control animals. In addition, alcohol consumption decreased IGF-I mRNA abundance in liver and muscle (approximately 50%). IGF-I content in duodenum and kidney, however, was not altered by alcohol feeding. Concomitantly, the relative concentration of IGF binding protein (IGFBP)-1 was increased in plasma, liver, and muscle of alcohol-fed rats, compared with control values. In contrast, no changes in the plasma concentrations of IGFBP-2, -3, or -4 were detected in alcohol-fed rats at this time point Previous studies have indicated that elevations in glucocorticoids or decreases in insulin or growth hormone might be responsible for the decrease in IGF-I and/or the increase in IGFBP-1 in other catabolic conditions. However, there was no difference in the plasma concentrations of these hormones between alcohol-fed and control animals in this study. These data indicate that chronic alcohol feeding in rats decreases IGF-I and increases IGFBP-1 in the circulation and in skeletal muscle and that these changes appear to be independent of changes in classical hormonal regulators of the IGF system. The observed alterations in the IGF system are consistent with a reduction in the anabolic actions of IGF-I induced by chronic alcohol consumption.

To compare the effect of using regions of interest (ROIs) of different size and shape on the fractal index of alveolar bone.Two sets of clinical posterior bitewing radiographs were used to calculate the fractal index (S). Two comparisons were made. First, S was calculated from large interdental ROIs that included small amounts of root structure and compared with S from small ROIs that included no root structures. Then S was calculated from large interdental ROIs (similar to those used for the first set) and compared with S calculated from ROIs that included nearly all of the mandibular alveolar bone (and adjacent root) present on the bitewing.For the first comparison, paired t-tests showed that fractal indices calculated with the large ROIs were significantly different from the respective indices calculated from the small ROIs (P0.001). For the second comparison, the fractal indices calculated from the large quadrant ROIs were not significantly different from those calculated from the large ROIs (P = 0.120).ROI size and shape may affect the results of fractal analysis of alveolar bone.

von Willebrand factor (vWf) serves to bridge between receptors on the platelet cytoplasmic membrane and the extracellular matrix. In addition to circulating in plasma, vWf is deposited into the extracellular matrix of the subendothelium where it is associated with type VI collagen microfibrils, but not with the elastin-associated microfibrils which are present in the deepest portion of the subendothelium at the zone of the internal elastic lamina. The reaction of platelets to type VI collagen in flow systems is qualitatively different from the shear rate dependent adhesion and aggregation response which is observed with fibrillar type I collagen, exhibiting a response only at low shear rates. The adhesion response to type VI collagen is dependent upon vWf, GP Ib and the GP IIb-IIIa complex. Platelets exposed to purified fibrillin-containing elastin-associated microfibrils adhere and aggregate at low shear rates; this response appears to involve GP IIb-IIIa but not GP Ib. The data are consistent with the hypothesis that type VI collagen is a physiologically relevant binding site for vWf in subendothelium.

This pilot study was undertaken to determine whether spatial resolution affects radiometric analyses aimed at detecting progressive enamel loss. Four teeth were weighed, attached to a positioning device, and evaluated with radiography. A 1 mm strip of enamel was removed from each tooth, and the teeth were weighted again and reexamined by radiography. This process was repeated five times until 1/2 mm of dentin was removed. The radiographs were digitized twice with 59 and 200 microns pixels at 8 bits, providing two series of images with the optical densities converted into 256 gray levels. Each series of images was adjusted for contrast variation. Regions of interest were drawn on the crowns, and cumulative percent histograms (CPHs) were calculated. Within a series of CPHs enamel reduction resulted in shifts in the CPHs that were directly proportional to the amount of enamel removed. CPH shifts associated with the smaller 59 microns pixels accounted for 68% of the variation in weights caused by enamel reduction, whereas the shifts associated with the larger 200 microns pixels accounted for 50%. The results indicate that pixel size does affect radiometric determinations of enamel reduction.

Radiometric analysis can be used to identify small changes in grey levels taken from investigator-defined regions of interest (ROIs). To do this, standardization of the radiographic optical densities and image grey scales is considered essential. Rigid standardization is one of the impediments to applying existing radiometric techniques to clinical practice. The purpose of this study was to evaluate the use of grey-level variations from a series of intrafilm control regions of interest (ROIs) to adjust radiometric grey-level data taken from test ROIs.After digitization, ROIs were drawn on three locations: the background, anatomical crown, and tooth root. Mean grey levels, histograms and cumulative percent histograms (CPHs) were determined for each group. With the goal of decreasing the distribution of these curves from their unadjusted grey-level positions to zero (superimposing all curves), shifts required to align the control CPHs were applied to test CPHs. Changes between the pre- and post-adjusted CPH distributions were measured.Intrafilm controls provided a combined decrease of 45.3% in the grey-level distribution error.While CPHs can be adjusted using intrafilm controls, these adjustments may have limited benefit.

Two modalities of urate transport have been reported in rat kidney, a urate/anion exchanger and a potential sensitive, uricase-like uniporter. As an initial attempt to isolate and characterize the responsible transport protein(s), rat renal cortical membranes were harvested, solubilized, and subjected to affinity chromatography with urate or xanthine as the affinity ligand. Pig liver peroxisomal uricase was purified with the same system, and the enzymatically active protein was used to generate polyclonal antibodies in rabbit. Silver stain of SDS-polyacrylamide gel electrophoresis gels of the eluted fraction containing the affinity-purified renal membrane protein(s) demonstrated bands at 25, 32, 36, and 41 kDa. On Western blot, two of these bands (32 and 36 kDa) were immunoreactive to the polyclonal antibody to pig liver uricase. In 6 of 10 studies, the affinity-purified renal membrane protein(s) also oxidized urate. Anti-pig liver uricase produced a selective and dose-dependent inhibition of the uricase-like urate uniporter in renal membrane vesicles, but did not affect the urate/anion exchanger or the sodium-dependent glucose transporter. Immunocytochemical studies of rat renal cortex with the same antibody indicated that the immunoreactivity was localized to proximal tubules. These studies demonstrate that the renal cortical plasma membranes contain urate-binding proteins, which have some functional and immunological homology to the hepatic peroxisomal core protein, uricase. Within the renal cortex, these proteins are localized to proximal tubules, the site of urate transport. Since the antibody that reacts with the affinity-purified urate-binding proteins on Western blot selectively inhibits urate transport in intact membrane vesicles, it is concluded that at least one of the affinity-purified urate-binding proteins is a uricase-like urate transporter.

Bleeding abnormalities are common in patients with end-stage renal disease (ESRD). Although von Willebrand factor (vWF) abnormalities have been suspected in patients with ESRD, none have been clearly defined. Because vWF function is related to its collagen-binding capacity, we investigated whether this parameter might be altered in patients with ESRD. We measured vWF binding to type III collagen and levels of vWF antigen and ristocetin cofactor in 20 patients undergoing hemodialysis before and after routine hemodialysis sessions, in 10 patients with ESRD who had not previously undergone dialysis, and in 22 healthy, nonsmoking persons who served as controls. We found significant increases of vWF antigen levels in all patients with ESRD (undialyzed: mean, 6.4 +/- 3.0 U/ml, p0.001; before dialysis: mean, 5.1 +/- 4.0 U/ml, p0.001; after dialysis: mean, 4.8 +/- 3.4 U/ml, versus 0.81 +/- 0.26 U/ml in controls, p0.001). The ristocetin cofactor levels were increased in the patients who had not undergone dialysis (mean, 1.30 +/- 1.26 U/ml, p = 0.04), whereas both before and after hemodialysis groups (means, 0.71 U/ml and 0.75 U/ml, respectively) were not significantly different from controls (mean, 0.72 +/- 0.30 U/ml, p = 0.96 and p = 0.8, respectively). Patients with ESRD who had not undergone dialysis showed no difference in vWF binding to collagen (mean, 1.21 +/- 0.63 U/ml) compared with the control group (mean, 1.16 +/- 0.13).(ABSTRACT TRUNCATED AT 250 WORDS)

Typical 35-mm slide scanners use a photodiode array and software that allows for digital and analog controls that are manually adjustable. The digital controls provide brightness and contrast adjustments, whereas corresponding analog controls adjust the exposure time and black level that determines the clamping level of the charge-coupled device for the maximum black in the image. The objective of this study was to determine the effects of these controls on the radiometric data of intraoral dental radiograph images, to establish recommended settings, and to set specific standard guidelines for the digitization process. Three approaches were used. The results of this study demonstrate that brightness and contrast control alterations on the digitizer produces different optical densities and modulation transfer function values. The impact of these results is unresolved yet must be considered in analysis on quantitative radiometric studies.

A 35-mm slide scanner digital imaging system was tested for its suitability in digitizing intraoral dental radiographic film for quantitative studies. The system (Nikon model LS-3510AF Nikon Electronic Imaging, Nikon, Inc., Melville, N.Y.) uses a charge-coupled device linear photodiode array. The data content in the original film images was evaluated, and the system performance assessed objectively with the use of specially designed test films. Radiometric and geometric performances for the digitizing system were extracted from measurements and observations, and these were compared with published data for two other film digitizing systems (video camera DAGE MTI, Michigan City, Ind. and Barneyscan 35-mm film digitizer Barneyscan, Berkeley, Calif.). The techniques used to evaluate this system are easy and suitable for evaluation of any digitizing system. This scanner system (Nikon) was superior to previously evaluated systems in transforming and recording radiographic film densities across the range (0.3 to 2.0 optical density units) of clinically relevant optical densities. The scanner offers substantial advantage over the other digitizing systems for gray scale information from clinically important optical densities.

The cardiovascular risk factor plasminogen activator inhibitor type 1 (PAI-1) has been associated with abdominal obesity, hypertension, hypertriglyceridemia, hyperinsulinemia, glucose intolerance, and type II diabetes, conditions known to be linked with insulin resistance. To determine whether PAI-1 is related to insulin resistance, we studied nine obese nondiabetics and 10 obese type II diabetics by means of a sequential hyperinsulinemic euglycemic clamp study. Plasma PAI-1 antigen (Ag) correlated significantly with peripheral insulin resistance, represented by the insulin level at which peripheral glucose uptake (PGU) is half-maximal ([ED50PGU] r = .87, P < .001). Multiple regression analysis including indices of hepatic and peripheral insulin action, fasting plasma insulin levels, triglyceride levels, blood pressure (BP), waist to hip ratio (WHR), and body mass index (BMI) disclosed ED50PGU to account for 76% of the variance of PAI-1 Ag. We suggest that PAI-1 contributes to the increased cardiovascular risk encountered with insulin resistance.

The central giant cell granuloma is a tumor that has great potential for the displacement of teeth and the development of a facial deformity. Although its cause and behavior are still matters for discussion, its early diagnosis and treatment are a priority. We describe a patient with a large benign central giant cell granuloma of the anterior mandible. The clinical, radiographic, and histologic appearance, as well as the appropriate treatment, are discussed in light of the current literature.

Several studies have suggested that ACE-inhibition may be effective in postponing the onset of nephropathy in insulin-dependent diabetic subjects. In contrast, other drugs might have opposing effects. To study the long term effects of either captopril or nifedipine in normotensive, microalbuminuric patients with insulin-dependent diabetes mellitus, eighteen subjects received either placebo (n = 5, P), 20 mg nifedipine daily (n = 7, N) or 50 mg captopril daily (n = 6, C) for one year. Baseline clinical and laboratory variables were comparable in the three groups. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and blood pressure did not differ between groups before and after one years medication. UAER did not change in the captopril and the placebo group (C: -12.6% (-58.1 to 51.8%)' P: -17.3 (-55.9 to 99.3%), medians and ranges. In contrast, in the patients that received nifedipine, UAER rose by 43.1% (-8.5 to 261.8%), (p0.05 Baseline vs one year, and one year nifedipine vs captopril and placebo). We therefore conclude, that long-term use of nifedipine increases UAER in normotensive microalbuminuric insulin-dependent subjects, in contrast to captopril or placebo. Whether this enhancement of microalbuminuria exerts an adverse effect on renal function in the long-term is yet unknown, but caution seems warranted.

Insulin resistance contributes to the metabolic defects in non-insulin dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. In a double-blind placebo-controlled cross-over study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinaemic-euglycaemic clamp technique with infusion of 3-[3H]-glucose in eight obese NIDDM patients and in eight obese non-diabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu: 180.5 +/- 25.8 vs. 225.3 +/- 39.9 mU/l, P0.05), but not in non-diabetics (140 +/- 15.3 vs. 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and non-diabetics. When non-diabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production (HGP) is completely suppressed (HGP0) (P0.01). In conclusion, fluoxetine improves peripheral and hepatic insulin action in obese insulin-resistant subjects irrespective of its weight lowering effect.

A previously described 43-kDa plasma membrane fatty acid-binding protein (FABPPM) was not observed by immunohistochemical methods in proliferating 3T3-L1 fibroblasts. However, it was detectable in plasma membranes by the second day of confluent growth, prior to accumulation of visible lipid droplets, and was strongly expressed in 8-day differentiated adipocytes. These observations were confirmed by extraction of plasma membrane proteins and subsequent immunoblotting. Kinetics of initial [3H]oleate uptake by both fibroblasts and adipocytes consisted of the sum of a saturable and a non-saturable component. During differentiation the saturable component increased progressively. Vmax increased from 3 to 25 to 110 pmol.s-1.mg cell protein-1 between the fibroblast, the 4-day, and 8 day adipocyte stages; Km was 24 nM in fibroblasts and approximately 55 nM in both 4- and 8-day differentiated adipocytes. By contrast, the rate constant for nonsaturable oleate influx decreased progressively from 0.026 to 0.010 ml.s-1.mg protein-1 between the fibroblast and 8 day adipocyte stages. In 8-day adipocytes saturable oleate uptake was inhibited by up to 55% by antibodies against rat liver FABPPM; these antibodies had no effect on uptake of 2-deoxyglucose or the medium chain fatty acid octanoate. They also had no effect on oleate uptake by fibroblasts. These studies support the hypothesis that FABPPM is a component of a saturable transport mechanism for long chain fatty acids.

Insulin resistance contributes to the metabolic defects in non-insulin-dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. The serotonin-reuptake inhibiting agent fluoxetine has recently been recognized as an anorectic agent. The effect of fluoxetine on insulin action has not yet been determined. In a double blind placebo controlled crossover study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinemic euglycemic clamp technique with infusion of 3-3H-glucose in eight obese NIDDM and in eight obese nondiabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu 180.5 +/- 25.8 vs 225.3 +/- 39.9 mU/l, P less than 0.05), but not in nondiabetics (140 +/- 15.3 vs 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Basal hepatic glucose production (HGP) was reduced after fluoxetine in both NIDDM (9.45 vs 10.37 mumol/kg/min) and in nondiabetics (8.57 vs 9.16 mumol/kg/min), although the difference was only significant in nondiabetics (P less than 0.05). Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and nondiabetics. When nondiabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P less than 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production is completely suppressed (HGP0) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies have been carried out to investigate the role of maternal and fetal thyroid function in the effects of iodine deficiency on fetal brain development in sheep. Iodine deficiency was established with an especially prepared low-iodine diet of maize and pea pollard. The iodine-deficient sheep were mated and at the end of the second trimester of pregnancy (100 days gestation) were divided into groups which received either a sc injection of T4 or 3,5-dimethyl-3'-isopropyl-L-thyronine or an im injection of iodized oil. At 140 days gestation (10 days prior to parturition) comparison of the fetuses delivered by hysterotomy revealed that the retarded fetal brain development observed in iodine deficiency was greatly improved by T4 and by iodized oil. However, T4 and iodized oil failed to correct the reduction in the number and the increase in the length of synaptic appositions which were observed in the fetal cerebral cortex after iodine deficiency. In addition, the histological appearance of the fetal thyroid gland and the levels of plasma thyroid hormones were restored to normal. The administration of 3,5-dimethyl-3'-isopropyl-L-thyronine had no effect on the retarded fetal brain and body development of the iodine-deficient fetuses. The lack of response may be due to the inability of 3,5-dimethyl-3'-isopropyl-L-thyronine to cross the ovine placenta as no reduction in the abnormally elevated fetal plasma TSH was observed in spite of a fall in maternal plasma TSH and apparent restoration of maternal thyroid function. It is concluded that the retarded fetal brain development observed during iodine deficiency in sheep can be substantially improved by iodized oil or to a lesser extent by T4 administration at 100 days gestation and that this is dependent on the restoration of both maternal and fetal thyroid function which supports previous observations from this laboratory following fetal and maternal thyroidectomy. The persistence of some effects of iodine deficiency on the fetal brain suggests that irreversible damage may have occurred.

Foetal thyroidectomy and brain development in the sheep Sheep foetuses were surgically thyroidectomized at 50–60 days gestation, when thyroid function begins, and the pregnancy was then allowed to continue until 90, 120 or 150 days (term). At these times the foetuses were removed by caesarean delivery, exsanguinated, weighed and dissected. The central nervous system was divided—cerebral hemispheres, brain stem, cerebellum and spinal cord for subsequent analysis. Comparison was made with sham operations on seven foetuses. Thyroidectomy led to a fall in body weight (24.77;) and brain weight (11.7%) at 120 days and 150 days, 31.1% and 24.5% respectively. The hemispheres showed the greatest change and the cerebellum the least. DNA and protein contents were reduced in the hemispheres and cerebellum at 150 days, while in the brain stem and spinal cord the DNA content was not significantly affected. Protein content was, however, reduced indicating a reduced cell size, but not a reduced cell number as in the other two regions. Somatic changes included reduced wool growth, delayed osseous development in the limbs (X-ray assessment) a reduced heart weight (39.1%) and an increased pituitary weight (48.1%). The thyroidectomized lambs failed to survive for more than a few hours after birth or caesarean delivery at 150 days. The findings indicate significant effects of foetal thyroidectomy on brain development in the sheep late in pregnancy along with other evidence of foetal hypothyroidism.

The pattern of normal foetal brain development has been described for the Merino sheep. Controlled flock matings were used and foetuses removed by hysterotomy at 40, 54, 67, 81, 90, 95, 109, 121 and 150 days of gestation. Lambs at 7 days after birth and adults were also studied. The CNS was dissected, separated and weighed as four segments--cerebral hemispheres, brain stem, cerebellum and spinal cord. Determinations of DNA, RNA, protein, cholesterol and water content were subsequently carried out on each segment. Brain weight increased from 0.264 g (40 days) to 52.74 g at 150 days. The ratio to body weight decreased from 6.7% (40 days) to 1.5% (150 days). DNA increased more rapidly from 40 to 90 days in the cerebral hemispheres and brain stem than in the cerebellum and spinal cord and this increase preceded the main increase in weight. Increases in cholesterol and decreases in water content were also more marked in the cerebral hemispheres and brain stem. Increase in brain weight occurred in two phases, one up to 90 days followed by a more rapid and larger increase after 90 days which continued to birth. These two phases appear to reflect an increase in neuroblast multiplication followed by neuroglial multiplication and myelination respectively. At birth, brain weight had reached 50% of adult size, the cerebral hemispheres 52% of adult size, the cerebellum 40% and spinal cord 40%. The relative maturity of the brain at birth justifies the classification of the sheep as a prenatal brain developer.

Incubation of freshly isolated rat hepatocytes with highly purified radiolabeled rat transferrin in weakly buffered medium in the presence of 10 mM ethanol resulted in a marked diminution of iron uptake by these cells, associated with a greater pH depression than in ethanol-free control studies. This effect on iron uptake persisted, even when the cells were preincubated for 90 min with ethanol before the addition of transferrin. Increasing the buffering capacity of the system or the addition of a metabolic inhibitor of alcohol dehydrogenase (4-methylpyrazole) returned iron uptake to control values. Acetaldehyde, acetate, lactate (products of ethanol metabolism), and 3-butanol (an alcohol not metabolized by alcohol dehydrogenase) had no influence on iron uptake. Further investigation of iron uptake over the pH range 6-8.5 revealed a marked dependency of iron uptake on the extracellular pH. Leucine incorporation into cell protein was also found to be pH dependent. It is suggested that, in the light of current understanding of transferrin recycling by other cell types, the disturbances of iron homeostasis observed in alcoholics can be partially accounted for by alterations in their acid-base metabolism.

Global descriptive, epidemiological studies have established the relation of iodine deficiency to endemic cretinism which, in its fully developed form, is characterized by mental deficiency, deaf mutism and spastic diplegia. However, a second less common variant--myxedematous or hypothyroid cretinism--is characterized by severe hypothyroidism with dwarfism. Mixed forms occur. It has been shown that both conditions can be prevented by correction of the iodine deficiency before pregnancy. Cretinism and development--now termed iodine deficiency disorders (IDD). A number of recently developed animal models establish the effect of severe iodine deficiency on brain development. These include the rat, the marmoset monkey and the sheep. These models are all characterized by the production of severe maternal and fetal hypothyroidism which is associated with effects on the maturation of the cerebral cortex and cerebellum. There was a reduced brain weight with a reduced number of cells as indicated by reduced DNA, a greater density of cells in the cerebral cortex and reduced cell acquisition in the cerebellum. Studies of the mechanisms involved have been carried out in the sheep. The findings reveal significant, though less severe, effects of fetal thyroidectomy (late gestation) and a significant effect of maternal thyroidectomy on brain development in mid-gestation. A combination of maternal and fetal thyroidectomy has similar but more severe effects than iodine deficiency. In the light of current knowledge of the embryology of the brain it is suggested that the critical time for the effect of iodine deficiency is the mid-trimester (14-18 weeks) when the neurons of the cerebral cortex and basal ganglia are formed and could be damaged by the effect of iodine deficiency on maternal thyroid function. There is now recent evidence indicating transfer of maternal thyroxine across the placental barrier early in pregnancy. In this way, neurological cretinism might be produced. Impaired fetal thyroid function would follow in the third trimester and augment the effect of reduced maternal thyroid function. Impaired fetal thyroid function alone could produce the hypothyroid form of cretinism. Further experimental studies, particularly into the postnatal period, are required to substantiate these suggestions. Apart from this, further study of the effects of iodine deficiency on brain development at the subcellular and cellular levels are likely to be most productive.

Iodized oil was administered as a single intramuscular injection to pregnant iodine-deficient ewes at 100 days gestation and the subsequent growth of their fetuses compared with that of fetuses of severely iodine-deficient ewes and of iodine-replete ewes, all of which were fed the same low-iodine diet. The administered iodine produced a remarkable improvement in thyroid function and physical appearance of the fetuses, accompanied by an increase in brain growth and to a lesser extent in body growth, which at 140 days was only slightly (but significantly) less than that of the controls. There was restoration of the number of cells (DNA) and myelination (cholesterol/DNA) in the cerebellum and cerebral hemispheres which suggests a catch-up of neuroblast development during pregnancy. Histological examination, however, revealed that counts of synapses (density) in the cerebral cortex after iodized oil were still less than those of the control fetal brains. The relevance of these findings to the effects of iodine deficiency on human brain development is discussed.

1. A study was made of the changes in electrolyte concentrations and ruminal function which resulted from the provision of 1.3% sodium chloride solutions instead of fresh water to sheep consuming roughage rations in chaffed and in ground pelleted forms.2. Significantly higher osmotic pressures were observed in the rumen fluid of the sheep drinking saline water, the change being especially marked when the ration was ground and pelleted.3. Of the individual electrolytes measured, chloride showed a larger rise in concentration than did sodium plus potassium and it appeared that the sodium and chloride ions in the ingested saline water were differentially removed from the rumen.4. Provision of 1.3% NaCl solution in place of fresh water resulted in greater voluntary intakes of fluid and consequently in greater flows of fluid through the rumen.5. Based upon measurements of deoxyribonucleic acid and polysaccharide, there appeared to be a tendency for the total microbial populations in the rumens of sheep drinking 1.3% NaCl solution to be smaller than for the sheep drinking fresh water.6. The total metabolic activity of the rumen flora, measured calorimetrically, was not appreciably changed when saline water was drunk and the chaffed ration eaten, but was significantly reduced when the ration was ground and pelleted.7. Adaptation of the rumen microflora to high concentrations of NaCl was demonstrated in animals accustomed to drinking 1.3% NaCl solution.

1. Sheep, which had access to a solution containing 1.3% sodium chloride as their sole source of drinking water for 6 months or more, were infused with a hypertonic solution (10%) of sodium chloride, and their ability to tolerate this salt load was compared with that of a similar group of sheep which drank only rain water.2. The sheep which drank the rain water were often affected by the infusion and exhibited signs resembling potassium deficit. No such signs were apparent in the animals which consumed saline water.3. Glomerular filtration rates were increased in all sheep by the hypertonic saline infusion, the increases being greater in the sheep which were maintained on the saline water. Effective renal plasma flow rates, though extremely variable, behaved in a similar manner.4. Plasma values for sodium and chloride were increased in all sheep, but remained at a higher level for a longer period in the sheep which consumed rain water. The diuresis produced by hypertonic saline appeared to persist for a longer period in the sheep which drank rain water, while the excretion of sodium and chloride tended to be greater in the sheep maintained on saline water.5. Plasma potassium was reduced in all sheep and urinary excretion of potassium increased. The latter response was more pronounced in the sheep which drank the rain water.6. Filtered loads of sodium, chloride and potassium were greater in the sheep which were accustomed to drinking saline water. However, the amounts of potassium excreted were greater than those filtered in the rain water sheep and less than those filtered in the sheep which drank saline water. It therefore seems that secretion of potassium into the kidney tubules predominated in the former group and reabsorption prevailed in the latter.7. Reabsorption of free water in excess of solute was greater in the kidney tubules of the sheep which drank saline water.8. Increased blood volume and greater dilution of plasma proteins occurred in the sheep which drank rain water.

1. The ability of the sheep to tolerate excess sodium chloride has been investigated by subjecting sheep to an intravenous infusion of a 10% solution of sodium chloride. 2. Inulin and diodrast clearances failed to show any consistent changes in glomerular filtration rate but the effective renal plasma flow was slightly more. Plasma levels of sodium and chloride increased by 20-25% and potassium decreased by 30%. Urinary levels for sodium and chloride showed a corresponding increase and potassium excretion was reduced. 3. The rates of re-absorption of sodium and chloride from the renal tubules were found to be proportional to their rates of filtration at the glomerulus, but this ratio was reduced after the hypertonic saline infusion. No such correlation could be established for potassium. 4. Osmolar clearances indicated that continued re-absorption of osmotically free water from the kidney tubular fluid occurred during and after the hypertonic saline. Excretion of urine, hyperosmotic to plasma, was thus maintained and water conservation supported. 5. Possible renal mechanisms associated with these effects are discussed.

Total serum haemolytic complement activity (CH(50)) and the serum concentrations of both the third and fourth components of the complement system (C3 and C4) have been measured in 29 control subjects, 92 patients with chronic hepatocellular disease, and eight patients with large duct biliary tract obstruction. The mean C4 concentration was reduced in all types of chronic liver disease studied. However, the mean CH(50) and C3 values were increased in compensated primary biliary cirrhosis, were relatively normal in non-cirrhotic chronic active hepatitis, and were decreased in cryptogenic cirrhosis, particularly when ascites was present. There was a significant correlation between CH(50) and C3 in patients with chronic liver disease but no correlation between CH(50) and C4 or between C3 and C4. Raised values for CH(50) and C3 in primary biliary cirrhosis may be due at least in part to concomitant cholestasis since these values tend to be raised in patients with large duct biliary tract obstruction. Although primary biliary cirrhosis, chronic active hepatitis, and cryptogenic cirrhosis are considered to be part of a spectrum of chronic liver disease associated with disturbed immunity, the results of this study emphasize that there are clearly definable differences between these diseases in terms of the pattern of changes in serum complement.