Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30.

We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004). The higher the entry serum leptin, the greater its reduction on metformin therapy (partial R(2) = 29%, P =.002). The greater the reduction in insulin on metformin, the greater the reduction in leptin (partial R(2) = 8%, P =.03). The higher the entry PAI-Fx, the greater the reduction in PAI-Fx on metformin (partial R(2) = 43%, P =.0001). Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action.

Applicability of the third-generation, thyroid-stimulating hormone assay in pregnancy.

Use of the third-generation, thyroid-stimulating hormone (TSH) assay in gravid patients has not been validated. We obtained serum from 93 healthy women with a singleton gestation and measured TSH using a two-site immunochemiluminescent ("sandwich") assay. Standard immunoassays were employed for total T4, free T4, and T3 levels. Reference ranges (RR) established by the kit manufacturer were used for comparison. Although the mean TSH level for our population was within the RR, 12/93 women (13%) had a TSH value below the lower limit of normal. None, however, had clinical hyperthyroidism or an elevated free T4. Established RR for the third-generation TSH assay may not apply to pregnant women, and isolated TSH measurements during pregnancy should be interpreted with caution.

Pupillographic assessment of sleepiness in sleep-deprived healthy subjects.

Spontaneous pupillary-behavior in darkness provides information about a subject's level of sleepiness. In the present work, pupil measurements in complete darkness and quiet have been recorded continuously over 11-minute period with infrared video pupillography at 25 Hz. The data have been analyzed to yield three parameters describing pupil behavior; the power of diameter variation at frequencies below 0.8 Hz (slow changes in pupil size), the pupillary unrest index, and the average pupil size. To investigate the changes of these parameters in sleep deprivation, spontaneous pupillary behavior in darkness was recorded every 2 hours in 13 healthy subjects from 19:00 to 07:00 during forced wakefulness. On each occasion, comparative subjective sleepiness was assessed with a self-rating scale (Stanford Sleepiness Scale, SSS). The power of slow pupillary oscillations (< or = 0.8 Hz) increased significantly and so did the values of SSS, while basic pupil diameter decreased significantly. Slow pupillary oscillations and SSS did not correlate well in general but high values of pupil parameters were always associated with high values in subjective rating. Our results demonstrate a strong relationship between ongoing sleep deprivation and typical changes in the frequency profiles of spontaneous pupillary oscillations and the tendency to instability in pupil size in normals. These findings suggest that the results of pupil data analysis permit an objective measurement of sleepiness.

[Pupillography for objective vigilance assessment. Methodological problems and possible solutions]. / Pupillographie zur objektiven Vigilanzprüfung. Methodische Probleme und Lösungsansätze.

To measure vigilance disorders in healthy normals or in patients (narcolepsy, sleep apnea syndrome) is difficult, time-consuming and hardly objective with present methods. Recording and analysis of spontaneous pupillary behaviour in darkness by infrared video pupillography is an objective and time-saving method to measure daytime sleepiness. However, certain external conditions must be satisfied (avoid light, noise, stress) to get reliable results. Spontaneous pupillary oscillations are recorded in darkness over 10 min and data are analyzed by fast Fourier transformation, with additional calculation of the mean pupillary diameter for each time segment (approx. 1 min). While in the alert normal, pupil remains dilated during the measurement in darkness and oscillates with an amplitude below 0.3 mm and a frequency about 1 Hz, there are characteristic changes in fatigue: (1) low-frequency components dominate the spontaneous pupillary oscillations, with an amplitude reaching several millimeters, and (2) pupil diameter decreases with time. Infrared video pupillography could play a role as a screening method and therapy control for hypersonic patients (most frequent: sleep apnea syndrome) with excessive daytime sleepiness. An objective, time-saving method like infrared video pupillography would be useful in sleep medicine and psychiatry when testing the level of vigilance, and in psychology or industrial medicine as well, providing informations about acute vigilance problems in healthy normals.

[Pupillography as an objective attention test]. / Pupillographie als objektiver Vigilanztest.

Infrared video pupillography (IVP) allows continuous recording of spontaneous pupillary oscillations in darkness which change characteristically with fatigue. Pupil size in darkness is age-related, has its maximum in the second decade and subsequently decreases during life time. Normally, the pupil oscillates in darkness with a frequency of about 1 Hz and amplitudes of less than 0.3 mm. Excessive daytime sleepiness causes instability of this pupillary behaviour which is constant in alert normals, and so called fatigue waves appear with an amplitude reaching several millimeters. The frequency profile is dominated by slow frequencies below 0.5 Hz, while average pupil size decreases continuously with time. As IVP is an objective and time-saving method it could become an important supplement to test procedures used in sleep medicine and sleep research to measure daytime sleepiness.

Improvement in symptoms of depression and in an index of life stressors accompany treatment of severe hypertriglyceridemia.

In 14 men and nine women referred because of severe primary hypertriglyceridemia, our specific aim in a 54-week single-blind treatment (Rx) period was to determine whether triglyceride (TG) lowering with a Type V diet and Lopid would lead to improvement in symptoms of depression, improvement in an index of life stressors, change in locus of control index, and improved cognition, as serially tested by Beck (BDI), Hassles (HAS) and HAS intensity indices, Locus of Control index, and the Folstein Mini-Mental status exam. On Rx, median TG fell 47%, total cholesterol (TC) fell 15%, and HDLC rose 19% (all p < or = 0.001). BDI fell at all nine Rx visits (p < or = 0.001), a major reduction in a test of depressive symptoms. The HAS score also fell at all nine visits (p < or = 0.05 - < or = 0.001). Comparing pre-Rx baseline BDI vs BDI at 30 and 54 weeks on Rx, there was a major shift towards absence or amelioration of depressive symptoms (chi 2= 5.9, p = 0.016). On Rx, the greater the percent reduction in TG, the greater the percent fall in BDI (r = 0.47, p < or = 0.05); the greater the percent reduction in TC, the greater the percent fall in HAS (r = 0.41, p < or = 0.05). Improvement in the BDI and HAS accompanied treatment of severe hypertriglyceridemia, possibly by virtue of improved cerebral perfusion and oxygenation. There may be a reversible causal relationship between high TG and symptoms of depression.

Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives.

To assess relationships of serum phytosterols (plant sterols [P]) to serum cholesterol (C), P were measured by gas-liquid chromatography (GLC) in 595 hypercholesterolemics (top C quintile in screening of 3,472 self-referred subjects). A second specific aim was to determine whether high serum P would track over time and whether they would predict familial aggregation of high C, high low-density lipoprotein cholesterol (LDLC), high apolipoprotein (apo) B, and increased premature coronary heart disease (CHD) in hyperphytosterolemic probands and their first-degree relatives. Mean +/- (SD) C was 260 +/- 56 mg/dL, campesterol (CAMP) was 2.10 +/- 1.6 micrograms/mL, stigmasterol (STIG) 1.71 +/- 1.67, sitosterol (SIT) 2.98 +/- 1.61, and total P 6.79 +/- 3.66 micrograms/mL. Serum C correlated with CAMP (r = .15, P less than or equal to .001), STIG (r = .10, P less than or equal to .02), SIT (r = .34, P less than or equal to .0001), and total P (r = .29, P less than or equal to .0001). High serum CAMP and STIG were associated with a personal or family history of CHD in subjects less than or equal to age 55 years (premature CHD). In 21 hyperphytosterolemic probands who initially had at least one P at or above the 95th percentile and a second P at or above the 75th percentile, P were remeasured 2 years later. Initial and 2-year follow-up CAMP, STIG, and SIT did not differ (P greater than .7). Initial and follow-up CAMP were correlated (r = .47, P = .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure lowering in elderly subjects: a double-blind crossover study of omega-3 and omega-6 fatty acids.

In 46 elderly (aged greater than or equal to 60 y) hypertensive subjects with entry systolic blood pressure (SBP) greater than or equal to 160 or diastolic blood pressure (DBP) greater than or equal to 90 mm Hg, our specific aim in a randomized, double-blind, crossover study (two 8-wk treatment periods separated by a 3-wk washout) was to compare blood pressure-lowering effects of 9 g fish oil/d [omega-3 (n-3) fatty acid] vs 9 g corn oil/d [omega-6 (n-6) fatty acid]. After a 4-wk baseline period, 22 subjects were randomly assigned to receive fish oil and 24 to receive corn oil. For both 8-wk treatments there were no between-group differences in the change in blood pressure. There was a treatment difference for standing DBP when baseline values were compared with those after treatment 2; DBP decreased by 5.1 mm Hg in the fish-oil group vs 0.72 mm Hg in the corn-oil group (P = 0.024). Within groups during the first treatment, both fish oil and corn oil lowered all four blood pressure measures (P less than 0.05); blood pressures were not further lowered during the second treatment compared with the washout period. There were no significant between-group differences in laboratory safety tests or categorical side effects. Fish oil lowered triglycerides by 0.47 mmol/L (P less than 0.001). In elderly subjects, diet plus both omega-3 and omega-6 supplements (9 g/d) safely and effectively lower SBP and DBP.

Nonanesthetic alcohols dissolve in synaptic membranes without perturbing their lipids.

While many theories of general anesthesia postulate a lipid site of action, there has been no adequate explanation for the lack of anesthetic potency of the highly hydrophobic primary alkanols with more than 12 carbons (the cut-off). Some work suggests that these nonanesthetic alcohols do not dissolve in membranes. Other work contradicts this and suggests that an anesthetic site on a protein provides a better explanation. Here we show that both the anesthetic dodecanol and the nonanesthetic tetradecanol are taken up equally well into the tissues of animals and into isolated postsynaptic membranes. When a group of Rana pipiens tadpoles were treated with dodecanol, half were anesthetized by 4.7 microM (free aqueos concentration), and the corresponding concentration in the tissues was found to be 0.4 mmol per kg wet weight. Prolonged exposure (92 hr) to tetradecanol produced even higher tissue concentrations (0.7 mmol per kg wet weight), yet no anesthetic effects were observed. Furthermore, general anesthetics are thought to act on postsynaptic membranes but both alkanols partitioned into postsynaptic membranes from Torpedo electroplaques. The spin label, 12-doxyl stearate, was incorporated into these membranes. The lipid order parameter it reported was decreased by the anesthetic alcohols (octanol, decanol, and dodecanol), whereas the nonanesthetic alcohols either did not change it significantly (tetradecanol) or actually increased it (hexadecanol and octadecanol). Thus, although lipid solubility is unable to account for the pharmacology of the cut-off in potency of the long-chain alcohols, lipid perturbations provide an accurate description.