Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of ischemic heart disease. An open-label study was conducted to test the efficacy and safety of atorvastatin, a new synthetic HMG-CoA reductase inhibitor in proven FH. After a 4-week placebo phase, 22 subjects were randomized to either 80 mg atorvastatin at night (n = 11) or 40 mg twice a day for 6 weeks. The two dosage groups were well matched and had no difference in lipoprotein responses. After 6 weeks, the LDL cholesterol concentration was reduced by 57%, from 8.16 +/- 1.15 to 3.53 +/- 0.99 mmol/L (P < .001). The total cholesterol concentration decreased from 9.90 +/- 1.32 to 5.43 mmol/L (P < .001). HDL cholesterol concentration increased from 1.19 +/- 0.31 to 1.49 +/- 0.43 mmol/L (P < .001). Triglyceride concentrations decreased from 1.34 +/- 0.66 to 0.88 +/- 0.36 mmol/L (P < .01). Three subjects had single, transient increases of serum transaminase of up to twice the upper limit of normal. Apolipoprotein B concentration decreased significantly by 42%. Changes in apolipoproteins AI and (a) were not statistically significant. Nondenaturing gradient gel electrophoresis revealed increases in the size of smaller LDL particles in four subjects. Plasma fibrinogen concentration increased by 44%. The drug was well tolerated. One subject withdrew for personal reasons. Atorvastatin is a powerful and safe lipid-modifying agent for LDL cholesterol; it also modifies HDL cholesterol and triglyceride concentrations, and may suffice as a single agent for many subjects with heterozygous FH.     

Expect the worse or hope for the best? Prenatal diagnosis of geleophysic dysplasia

Geleophysic dysplasia is a rare, autosomal recessive disorder which causes disproportionate short stature associated with severe physical handicaps, but is compatible with survival into adulthood. We present a case, a first-born child, where genetic counselling difficulties arose following ultrasound recognition of short-limbed dwarfism in association with polyhydramnios and an initial incorrect prenatal diagnosis of lethal chondrodysplasia. After birth of the surviving affected infant, the parents had great difficulty accepting that there had been a prenatal misdiagnosis and they were greatly disappointed by our inability to predict the postnatal survival of an infant to whom no hope of life had previously been given. The correct diagnosis was not made until the proband was nearly 1 year old, and the true prognosis then became clearer. This experience underlines the relative ease of prenatal recognition of skeletal growth abnormalities compared with the considerable difficulties experienced in reaching a precise diagnosis. Thus, following prenatal diagnosis of unspecified chondrodysplasia when parents seek definite information about the prognosis, the temptation to be either overpessimistic or overoptimistic should be avoided.     

Channeling of three newly introduced antidepressants to patients not responding satisfactorily to previous treatment

OBJECTIVE: Trifluoromethane and CO are produced simultaneously during the breakdown of isoflurane and desflurane by dry CO2 absorbents. Trifluoromethane interferes with anesthetic agent monitoring, and the interference can be used as a marker to indicate anesthetic breakdown with CO production. This study tests representative types of gas monitors to determine their ability to provide a clinically useful warning of CO production in circle breathing systems. METHODS: Isoflurane and desflurane were reacted with dry Baralyme at 45 degrees C. Standardized samples of breakdown products were created from mixtures of reacted and unreacted gases to simulate the partial degrees of reaction which might result during clinical episodes of anesthetic breakdown using 1% or 2% isoflurane and 6% or 12% desflurane. These mixtures were measured by the monitors tested, and the indication of the wrong agent or a mixture of agents due to the presence of trifluoromethane was recorded and related to the CO concentration in the gas mixtures. RESULTS: When presented with trifluoromethane from anesthetic breakdown, monochromatic infrared monitors displayed inappropriately large amounts of isoflurane or desflurane. Agent identifying infrared and Raman scattering monitors varied in their sensitivity to trifluoromethane. Mass spectrometers measuring enflurane at mass to charge = 69 were most sensitive to trifluoromethane. CONCLUSION: Monochromatic infrared monitors were unable to indicate anesthetic breakdown via interference by trifluoromethane, but did indicate falsely elevated anesthetic concentrations. Agent identifying infrared and Raman monitors provided warning of desflurane breakdown via the interference of trifluoromethane by displaying the wrong agent or mixed agents, but may not be sensitive enough to warn of isoflurane breakdown Some mass spectrometers provided the most sensitive warnings to anesthetic breakdown via trifluoromethane, but additional data processing by some patients monitor units reduced their overall effectiveness.     

Ca2+ differentially regulates conventional protein kinase Cs' membrane interaction and activation

The regulation of conventional protein kinase Cs by Ca2+ was examined by determining how this cation affects the enzyme's 1) membrane binding and catalytic function and 2) conformation. In the first part, we show that significantly lower concentrations of Ca2+ are required to effect half-maximal membrane binding than to half-maximally activate the enzyme. The disparity between binding and activation kinetics is most striking for protein kinase C betaII, where the concentration of Ca2+ promoting half-maximal membrane binding is approximately 40-fold higher than the apparent Km for Ca2+ for activation. In addition, the Ca2+ requirement for activation of protein kinase C betaII is an order of magnitude greater than that for the alternatively spliced protein kinase C betaI; these isozymes differ only in 50 amino acids at the carboxyl terminus, revealing that residues in the carboxyl terminus influence the enzyme's Ca2+ regulation. In the second part, we use proteases as conformational probes to show that Ca2+dependent membrane binding and Ca2+-dependent activation involve two distinct sets of structural changes in protein kinase C betaII. Three separate domains spanning the entire protein participate in these conformational changes, suggesting significant interdomain interactions. A highly localized hinge motion between the regulatory and catalytic halves of the protein accompanies membrane binding; release of the carboxyl terminus accompanies the low affinity membrane binding mediated by concentrations of Ca2+ too low to promote catalysis; and exposure of the amino-terminal pseudosubstrate and masking of the carboxyl terminus accompany catalysis. In summary, these data reveal that structural determinants unique to each isozyme of protein kinase C dictate the enzyme's Ca2+-dependent affinity for acidic membranes and show that, surprisingly, some of these determinants are in the carboxyl terminus of the enzyme, distal from the Ca2+-binding site in the amino-terminal regulatory domain.     

Paradigms in obstetric nursing]

Recent finding suggest that many fetuses have to adapt to a limited supply of nutrients and in doing so they permanently change their physiology and metabolism. These 'programmed' changes may be the origins of a number of diseases in life, including coronary heart disease and the related disorders stroke, diabetes and hypertension.     

Synergistic effect of glucose and prolactin on GLUT2 expression in cultured neonatal rat islets

We studied the synergistic effect of glucose and prolactin (PRL) on insulin secretion and GLUT2 expression in cultured neonatal rat islets. After 7 days in culture, basal insulin secretion (2.8 mM glucose) was similar in control and PRL-treated islets (1.84 +/- 0.06% and 2.08 +/- 0.07% of the islet insulin content, respectively). At 5.6 and 22 mM glucose, insulin secretion was significantly higher in PRL-treated than in control islets, achieving 1.38 +/- 0.15% and 3.09 +/- 0.21% of the islet insulin content in control and 2.43 +/- 0.16% and 4.31 +/- 0.24% of the islet insulin content in PRL-treated islets, respectively. The expression of the glucose transporter GLUT2 in B-cell membranes was dose-dependently increased by exposure of the islet to increasing glucose concentrations. This effect was potentiated in islets cultured for 7 days in the presence of 2 micrograms/ml PRL. At 5.6 and 10 mM glucose, the increase in GLUT2 expression in PRL-treated islets was 75% and 150% higher than that registered in the respective control. The data presented here indicate that insulin secretion, induced by different concentrations of glucose, correlates well with the expression of the B-cell-specific glucose transporter GLUT2 in pancreatic islets.     

Assessment of anastomotic reliability with pulse oximetry in graded intestinal ischemia: an experimental study in dogs

BACKGROUND/PURPOSE: Pulse oximetry has been proposed as an appropriate and feasible technique in the assessment of intestinal ischemia in recent years. In this study the authors aimed to assess the reliability of anastomoses in the dog small intestine in which there is graded irreversible ischemia as measured by pulse oxymeter. METHODS: In a control group of four dogs, without any devascularization, three small bowel anastomoses were formed in each dog. The study group consisted of 12 dogs. In each animal three intestinal segments with different levels of ischemia were created by ligating the marginal vessels proximally and distally in sequence beginning from the midpoint of the segmental vascular arcade. Preanastomotic pulse oximeter readings between 80% and 90% were assigned to mild ischemia, 70% and 80% to moderate, and 60% and 70% to severe ischemia group. Pulse oximetry measurements were obtained from probes applied to the antimesenteric serosal surfaces at the midpoint of small intestinal segments. A total of 48 intestinal segments (12 nonischemic in the control group and 36 with three different levels of ischemia in the study group) were transected in the midpoint and anastomosed in double layers. Postanastomotic SaO2 values were also noted. The anastomoses were evaluated 48 hours later macroscopically if there was any leakage, and biopsy specimens were obtained for histopathologic ischemic gradings. All results were studied statistically. RESULTS: Histopathologic grades between each group were statistically different (P < .01 for each comparison) except for control and mild ischemia groups (P > .05), worsening as the level of ischemia increased. Pre- and postanastomotic pulse oximetry measurements correlated very well with the histological gradings (r = -0.90, P < .001 and r = -0.93, P < 0.001 respectively). Number of anastomotic leakages were none in control, one in mild, nine in moderate, and 12 (all of the anastomoses) in severe ischemia groups. In the moderate ischemia group with an average preanastomotic pulse reading of 76.75%, each of the leaking anastomoses had a postanastomotic pulse measurement of lower than 70%. The finding that the difference between histopathologic grades of control and mild ischemia groups with average preanastomotic pulse measurements of 96% and 85%, respectively is not statistically significant enables us to suggest that a saturation of at least 85% is necessary for a reliable anastomosis. CONCLUSION: These results suggest clearly that anastomotic reliability can be predicted objectively with pulse oximetry.     

Modulation of TCDD-induced fetotoxicity and oxidative stress in embryonic and placental tissues of C57BL/6J mice by vitamin E succinate and ellagic acid

Secretory middle ear otitis is of difficult assessment in children with severe hearing impairment. This otitis, very frequent in infants and children, influences negatively the auditive capacity and apprenticeship as well. Our study deals with the prevalence and severity of the secretive middle ear otitis in an scholar population handicapped by a heavy hypoacusia. Demographically, etiologic and seasonal correlations are considered in the paper. The outcome shows a high incidence of the condition, an inversely relation with the age, an evident seasonal distribution and the absence of correlation between etiology of middle ear disease and sensorineural deafness.