Addiction potential of phentermine prescribed during long-term treatment of obesity.

OBJECTIVE: To investigate if phentermine treatment induces phentermine abuse, psychological dependence (addiction) or phentermine drug craving in overweight, obese and weight loss maintenance patients. To investigate whether amphetamine-like withdrawal occurs after abrupt cessation of long-term phentermine treatment. DESIGN: Clinical intervention trial with interruption of phentermine treatment in long-term patients. SUBJECTS: 269 obese, overweight or formerly obese subjects (age: 20-88 years, BMI: 21-74 kg m(-2)) treated with phentermine long-term (LTP, N=117), 1.1-21.1 years, or short-term (ATP, N=152), 4-22 days, with phentermine doses of 18.75-112.5 (LTP) and 15-93.75 (ATP) mg per day. MEASUREMENTS: Module K of the Mini International Neuropsychiatric Interview modified for phentermine (MINI-SUD), Severity of Dependence Scale (SDS), 45-item Cocaine Craving Questionnaire-NOW (CCQ-NOW) modified for phentermine (PCQ-NOW), and Amphetamine Withdrawal Questionnaire (AWQ) modified for phentermine (PWQ). RESULTS: MINI-SUD interviews were negative for phentermine abuse or psychological dependence in all LTP patients. SDS examination scores were low for all LTP and ATP patients, indicating they were not psychologically dependent upon phentermine. PCQ-NOW scores were low for all LTP and ATP patients, indicating neither short-term nor long-term phentermine treatment had induced phentermine craving. Other than an increase in hunger or eating, amphetamine-like withdrawal symptoms did not occur upon abrupt phentermine cessation as measured by sequential PWQ scores. CONCLUSIONS: Phentermine abuse or psychological dependence (addiction) does not occur in patients treated with phentermine for obesity. Phentermine treatment does not induce phentermine drug craving, a hallmark sign of addiction. Amphetamine-like withdrawal does not occur upon abrupt treatment cessation even at doses much higher than commonly recommended and after treatment durations of up to 21 years.

The effects of short-term overfeeding on energy expenditure and nutrient oxidation in obesity-prone and obesity-resistant individuals.

OBJECTIVE: The roles that energy expenditure (EE) and nutrient oxidation play in a predisposition for weight gain in humans remains unclear. SUBJECTS: We measured EE and respiratory exchange ratio (RER) in non-obese obesity-prone (OP; n=22) and obesity-resistant (OR; n=30) men and women following a eucaloric (EU) diet and after 3 days of overfeeding (1.4 × basal energy). RESULTS: Twenty-four hour EE, adjusted for fat-free mass and sex, measured while consuming a EU diet was not different between OP and OR subjects (2367±80 vs 2285±98 kcals; P=0.53). Following overfeeding, EE increased in both OP and OR (OP: 2506±63.7, P<0.01; OR: 2386±99 kcals, P<0.05). Overfeeding resulted in an increase in 24-hour RER (OP: 0.857±0.01 to 0.893±0.01, P=0.01; OR: 0.852±0.01 to 0.886±0.01, P=0.005), with no difference between groups in either the EU or overfeeding conditions (P>0.05). Nighttime RER (∼10pm-6:30am) did not change with overfeeding in OR (0.823±0.02 vs 0.837±0.01, P=0.29), but increased significantly in OP subjects (0.798±0.15 to 0.839±0.15, P<0.05), suggesting that fat oxidation during the night was downregulated to a greater extent in OP subjects following a brief period of overfeeding, as compared with OR subjects who appeared to maintain their usual rate of fat oxidation. Protein oxidation increased significantly in both OP (P<0.001) and OR (P<0.01) with overfeeding, with no differences between OP and OR. CONCLUSION: These results support the idea that overfeeding a mixed diet results in increases in EE and RER, but these increases in EE and RER are likely not responsible for obesity resistance. Adaptive responses to overfeeding that occur during the night may have a role in opposing weight gain.

Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema.

The composite physiologic index (CPI) was derived to represent the extent of fibrosis on high-resolution computed tomography (HRCT), adjusting for emphysema in patients with idiopathic pulmonary fibrosis (IPF). We hypothesised that longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (D(L,CO)) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema (CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n = 321), 6 months (n = 211) and 12 months (n = 144). Presence of CPFE was determined by HRCT. A five-point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p = 0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in D(L,CO) or an absolute increase in CPI of five points all discriminated median survival by 2.1 to 2.2 yrs versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV(1) predicted mortality (HR 3.7, p = 0.046). In IPF, a five-point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in D(L,CO). For CPFE patients, change in FEV(1) was the best predictor of mortality.

The ontogenesis of the forebrain commissures and the determination of brain asymmetries.

We have reviewed the organization and development of the interhemispheric projections through the forebrain commissures, especially those of the CC, in connection with the development of brain asymmetries. Analyzing the available data, we conclude that the developing CC plays an important role in the ontogenesis of brain asymmetries. We have extended a previous hypothesis that the rodent CC may exert a stabilizing effect over the unstable populational asymmetries of cortical size and shape, and that it participates in the developmental stabilization of lateralized motor behaviors.

Association between depression severity and cardiac autonomic modulation.

OBJECTIVE: Changes in autonomic modulation are found in depressive patients. QT dispersion is a convenient measure of cardiac autonomic modulation (CAM). As both QT dispersion and depression are related to changes in CAM, this study aimed to examine if there was an association between depression severity and QT dispersion. METHODS: The selected sample (n=60) derived from 236 women who were recruited via a campaign for breast cancer prevention. The women selected to participate were all non-smokers and were not taking any drug that could interfere with the results. After applying inclusion and exclusion criteria, 60 women were selected. QT dispersion (QTd) and rate-corrected QTd (QTcD) were calculated in 37 physically and mentally healthy women and 23 nontreated depressive women. Univariate ANOVA(s) were used to test group differences. The 17-item Hamilton Depression Rating Scale (HDRS17) was scored to measure depression severity. The relationship between depression severity and cardiac autonomic modulation was analyzed by the best curve that fit the raw data of the HDRS17 scores and the QT dispersion variables. RESULTS: The QTd and QTcD were significantly smaller in non-depressed in relation to the depressed women. The best curve that fit the raw data of depression severity (HDRS17) and the two measurements of cardiac autonomic modulation (QTd and QTcD) was a cubic equation for both QTd and QTcD. An increase in QTd and QTcD were observed until the HDRS17 score reached 20 points. CONCLUSION: There is a significant positive relationship between depression severity and cardiac autonomic modulation in mild and moderate depression.

Hypersensitivity pneumonitis and antigen identification--An alternate approach.

OBJECTIVES: Identification of the causal antigen for patients with hypersensitivity pneumonitis (HP) is challenging in a standard clinical setting. The purpose of this pilot study was to determine whether it was possible to evaluate the home/workplace of patients, and identify the causal antigen. METHODS: Using a case-control study design we compared the presence of antibody to antigen collected in the environment of individuals with HP and controls consisting of family members/co-workers. Based on patient interviews, homes/workplaces were evaluated and suspected sources of antigen collected for use in immunoassays. RESULTS: Nineteen individuals with HP participated with 15 classified as having fibrotic disease. Up to 54 bulk samples were collected from each patient's environment, with multiple isolates (antigens) cultured from each. Of the seven individuals who tested positive to one or more environmental samples, three had a positive response to more than 1 antigen from the environmental sample (range 1-9). Twelve individuals tested positive to antigen(s) on a standard panel, with only one overlapping with the antigen from the home/workplace sample. A significant association existed between results of interviews/site evaluations, and ability to collect antigen eliciting a positive response (p < 0.001). CONCLUSION: Antigen identification was successful for patients with 'active' disease. Antigens for which patients test positive on standard panels may not be present in their environment. One benefit to patient-centered testing is the ability to develop recommendations specific to their environment. As most individuals tested positive for >1 antigen, further investigation is warranted to determine the actual antigen responsible for disease.

Effects of prenatal irradiation on the development of cerebral cortex and corpus callosum of the mouse.

Defects of the cerebral cortex and corpus callosum of mice subjected prenatally to gamma irradiation were evaluated as a function of dose and of embryonic age at irradiation. Pregnant mice were exposed to a gamma source at 16, 17, and 19 days of gestation (E16, E17, and E19, respectively), with total doses of 2 Gy and 3 Gy, in order to produce brain defects on their progeny. At 60 postnatal days, the brains of the offspring were analyzed qualitatively and quantitatively and compared with those of nonirradiated animals. Mice irradiated at E16 were all acallosal. Those that were exposed to 2 Gy displayed an aberrant longitudinal bundle typical of other acallosals, but this was not the case in those irradiated with 3 Gy. The corpus callosum of animals irradiated at E17 with 3 Gy was pronouncedly hypotrophic, but milder effects were observed in the other groups. Quantitative analysis confirmed a dependence of callosal midsagittal area upon dose and age at irradiation, and, in addition, indicated an interaction between these variables. The neocortex of irradiated animals was hypotrophic: layers II-III were much more affected than layer V, and this was more affected than layer VI. Quantitative analysis indicated that this effect also depended on dose and age at irradiation and that it was due to a loss of cortical neurons. Furthermore, a positive correlation was found between the number of neurons within layers II-III, and V and the midsagittal area of the corpus callosum. Ectopic neurons were found in the white matter and in layer I of animals irradiated at E16 and E17, indicating that fetal exposure to ionizing radiation interfered with the migration of cortical neuroblasts.

The effects of hand preference and gender on finger tapping performance asymmetry by the use of an infra-red light measurement device.

We used an infra-red device to study the effects of gender and handwriting preference on manual asymmetry in tapping rate and intertap variability. Our sample (n=102) consisted of approximately equal number of subjects with respect to gender (52 women and 50 men) and handedness (52 right-handers and 50 left-handers). Data on overall performance indicated that men performed more quickly and regularly than women. The index used for measuring manual asymmetry was the difference between the hands as a proportion of the total. Therefore, the asymmetry index was adjusted to remove the influence of overall performance. The analyses based on asymmetry scores indicated a significant handedness effect: right-handers showed greater manual asymmetries than left-handers for both tapping rate and intertap variability. In addition, right handers exhibited a significant greater asymmetry for intertap variability than tapping rate. Taken together, these data may reflect greater hemispheric differences in right-handers, specially for intertap variability.

Dose-dependent occurrence of the aberrant longitudinal bundle in the brains of mice born acallosal after prenatal gamma irradiation.

Two groups of pregnant mice were gamma-irradiated at the 16th gestation day with doses of 2 or 3 Gy. All litters were born acallosal, but while the 3-Gy mice showed a severely hypotrophic neocortex without the aberrant longitudinal bundle typical of early disconnected rodents, in the 2-Gy group the cortex was less deranged and the aberrant bundle appeared consistently underneath the white matter.

The effects of total and partial callosal agenesis on the development of paw preference performance in the BALB/cCF mouse.

The relation between callosal defects and paw preference was investigated in 85 male mice of the BALB/cCF strain. Paw preference was also studied in 30 male Swiss mice. Directional laterality and magnitude of laterality devoid of directionality were evaluated independently. The study of the magnitude of paw preference showed that male BALB/cCF mice were more strongly lateralized than Swiss mice. There was no difference between BALB/cCF mice with callosal defects (abnormal group) and normal BALB/cCF mice. The analysis of directional laterality indicated a population tendency for left-paw use in BALB/cCF as compared to Swiss mice. Furthermore, the percentage of left-pawed animals in the abnormal group (78%) was significantly different from chance level, as opposed to an absence of such differences in the normal BALB/cCF and in Swiss mice. It was concluded that developmental disturbance of the corpus callosum is related to the appearance of a directional populational asymmetry in paw preference.

Effects of prenatal ionizing irradiation on the development of the ganglion cell layer of the mouse retina.

Prenatal exposure to ionizing irradiation has been shown to be an effective method to eliminate selectively certain neuronal population. This investigation studied the effects on the ganglion cell layer of the retinae of adult mice exposed to a gamma source (total dose=3 Gy) at 16 days gestation. There was a significant reduction in the total number of neurons (displaced amacrine+ganglion cells) in the ganglion cell layer (33%) that was mainly caused by a pronounced loss (59%) of displaced amacrine cells. The diameters of the surviving retinal ganglion cells were consistently larger than those of the controls. Prenatal irradiation is the first experimental approach that partially eliminates displaced amacrine cells. It is suggested that the morphogenesis of retinal ganglion cells may be affected by displaced amacrine cells.

Depletion of cortical target induced by prenatal ionizing irradiation: effects on the lateral geniculate nucleus and on the retinofugal pathways.

Studies using neonatal surgical lesions to reduce the target area of the retina have supported the idea that developing axons show only a limited specificity in their targeting. This investigation tested whether retinogeniculate axons adjust for partial target depletion by repositioning of axons. We used adult Swiss mice exposed to gamma rays at the time when layer IV cells are generated in the ventricular zone (16 days of gestation). Nissl-stained brain sections were used for histological analyses in thalamus and cortex. Retinal ganglion cells were backfilled from the optic tract with horseradish peroxidase. Intraocular injections of horseradish peroxidase were used to study the retinal projections. In the posterior cortex there was a nearly complete absence of layer IV. The irradiated animals showed a 75% reduction of the dorsal lateral geniculate nucleus. The ventral division, superior colliculus, and other visually related nuclei were not affected. The loss in the ganglion cells (15.7%) was significant but clearly smaller than that observed in the dorsal lateral geniculate nucleus (75%). Therefore, the shrinkage of the dorsal lateral geniculate nucleus led to a reduction in the area available for retinal projections. Despite partial target loss, pattern of retinal projections did not differ from that of the controls. The effect on the dorsal lateral geniculate nucleus is discussed in the light of differences between prenatal and neonatal damage of the presumptive visual cortex. The absence of aberrant retinal projections suggests that repositioning of axons is not the first mechanism employed by retinal axons to match connections in numerically disparate populations.

Morphological brain asymmetries in male mice with callosal defects due to prenatal gamma irradiation.

We have previously suggested a relationship between the development of the corpus callosum and the direction of cerebral asymmetries (Schmidt and Caparelli-Daquer, 1989; Schmidt et al., 1991). Here we report a study on morphological brain asymmetries using a distinct experimental approach. At embryonic day 16, mice were exposed to a gamma source, receiving a total dose of 2 Gy. At adulthood 32 irradiated and 28 normal male Swiss mice were evaluated for individual and populational interhemispheric asymmetries of weight, dorsal area, and neocortical volume. All irradiated mice showed callosal defects ranging from total absence to a partial reduction of the midsagittal callosal area. The normal and irradiated groups displayed a pronounced individual asymmetry in all measurements. In contrast, populational asymmetry could be identified only in the normal group. These results are consistent with our previous data in acallosal mutant mice and support the hypothesis that the corpus callosum may play a role in directing interhemispheric morphological brain asymmetries.

Effects of prenatal gamma irradiation on the development of the corpus callosum of Swiss mice.

The temporal sequence of events related to the effects of prenatal gamma irradiation on the development of the corpus callosum and cerebral cortex was studied in Swiss mice. Pregnant females on gestational day 16 were exposed to a 60Co source receiving total doses of 2 or 3 Gy. The offspring were analyzed at both prenatal and postnatal days. One day after irradiation, a great number of pyknotic figures was seen along the whole extension of the cerebral wall, especially in the proliferative zones. At perinatal ages, the thickness of the proliferative zones was reduced and the glial sling was never identified. From 5 days after birth onwards, we observed a severe shrinkage of layers II + III and IV. The majority of the irradiated mice were totally acallosal (particularly when the 3 Gy dose was used), but some animals presented callosal remnants. These remnants were identified above the ventral hippocampal commissure, except for two animals in which a larger callosal remnant extended from the columns of the fornix to the dorsal hippocampal commissure. The presence of callosal remnants in animals irradiated with 3 Gy was dependent on the age at which the animals were analyzed since remnants were observed in some animals analyzed at perinatal ages, but never in older animals. Callosal defects can be explained at least by three factors: (1) Death of a great part of callosal neurons located at layer III. (2) Postnatal axonal elimination. (3) Absence of the glial sling. The callosal agenesis in the absence of the glial sling indicates that this structure may play a crucial role in guiding callosal axons. However, the presence of callosal remnants indicates that surviving callosal axons can use structures other than the sling to cross the midplane. Our data indicate that axons of the middle portion of the callosum can cross the midplane using the ventral hippocampal commissure as a guide. Additionally, the dorsal hippocampal commissure may play a role in directing axons of the posterior part of the corpus callosum.

Time course of the effects of prenatal gamma irradiation on the dorsal lateral geniculate nucleus of Swiss mice.

A previous study reported that adult mice irradiated at the 16th embryonic day present a severe neuronal number reduction in the dorsal lateral geniculate thalamic nucleus. In the present study, we investigated the time course of the effects of prenatal irradiation on this thalamic nucleus. One day after irradiation, a great number of pyknotic figures were seen mainly in the cerebral proliferative zones. In the geniculate nucleus, only scattered pyknotic figures were identified. On the first week after birth, the geniculate nucleus presented frequent pyknotic figures. From five days after birth onwards, a severe shrinkage of the occipital cortex and a great reduction in the geniculate nucleus neuronal number were found. On the second week after birth this neuronal number reduction reached as high as 75%. At each postnatal analyzed age, severe volumetric geniculate nucleus shrinkage was combined to non-significant neuronal density variations. The presence of few pyknotic figures in the geniculate nucleus one day after irradiation and its delayed neuronal loss indicate an indirect effect of irradiation. We suggest that the effect upon the geniculate nucleus is secondary to the damage of the occipital cortex. A possible interpretation for thalamic neuronal loss is that geniculate neurons fail to establish cortical arbors after major target loss. In this case, the loss of trophic support should also be considered.

The effect of corpus callosum agenesis on neocortical thickness and neuronal density of BALB/cCF mice.

We used acallosal and normal adult BALB/cCF mice to test the hypothesis that the development of the corpus callosum is relevant for the establishment of a normal structure of the neocortex. Neuronal density and thickness of individual layers were analyzed in neocortical regions with abundant callosal connections (area 6 and the 17/18a border) and in the relatively acallosal area 17. In area 6, acallosal mice exhibited a total neocortical thickness smaller than that of normal mice, as well as thinner layers II+III and IV. Similar data were obtained at the 17/18a border, where the total thickness of the cortex and of layers II+III was smaller in the acallosal mice than in normal ones. In contrast, no significant thickness differences were documented in area 17 of acallosal versus normal mice. The quantitative data obtained in the analyzed neocortical regions did not show differences in neuronal density between acallosal and normal mice. The reduced cortical thickness, associated with the comparatively normal neuronal density in neocortical regions which normally have abundant callosal connections, provides indirect indication of a reduction in the number of cortical neurons in acallosal mice. This assumption was also supported by the lack of evidence of neocortical alterations in the acallosal area 17. The present findings suggest that during development neocortical neurons destined to receive a massive callosal input may die as a result of lack of afferents. Altogether the present data indicate that the input provided by callosal axons is necessary for a normal development of the neocortex.

Effects of sex and laterality on the rotatory swimming behavior of normal mice.

Clockwise and counterclockwise full turns are commonly used to assess lateralization in circling behavior. Although previous studies have reported that the rotatory swimming (ROSW) test is simple and reliable, little is known about lateralization of turns lower than 360 degrees and the amount of turning close to the wall, and even less is known about alternation of direction during a session. Here we investigated the effects of consistency of laterality and sex on 30 degree turns in center and in periphery of the swimming apparatus, and on alternation of direction upon three sessions. Approximately 80% of the turns occurred when mice swam along the wall. In side-consistent turners, this suggests the existence of an intrinsic sensorimotor asymmetry that determines the adhesion to the preferred side. Regarding categorization of side preferences, there was a high percentage of agreement between center and periphery, as well as between full turns and extra 30 degree turns (30 degree turns that do not contribute to full turns). Therefore, behavioral asymmetry in the ROSW can be assessed using 30 degree turns. There was no significant directional bias in the population, and side preference was found to be independent of sex. By contrast, after the second minute of each session, males exhibited a significantly higher number of reversal of direction (RD) as well as a higher number of RD per turn than females. The amount of RD presented by each animal is not predicted by the animal's side preference. Thus, RD is independent of preferred side of turning and depends on sex.

Sex differences in sensitivity to seizures elicited by pentylenetetrazol in mice.

Sex differences in sensitivity to seizures elicited by intraperitoneally injected pentylenetetrazol (PTZ) were studied in 240 (120 males and 120 females) adult Swiss mice. Animals were separated into four groups according to the dose that was injected: 40, 50, 60 and 70 mg/kg. Seizure severity was expressed by the following scoring scale: (0) no abnormal behavior; (1) myoclonus; (2) running bouncing (RB) clonus; (3) tonic hind limb extension (THE). The analyses of the dose-response curves indicated that females were more susceptible than males when the 50- and 60-mg/kg doses were used. Specifically, females often displayed RB clonus, while males frequently displayed only myoclonus or no abnormal behavior. No significant sex differences were demonstrated when either the 40- or the 70-mg/kg doses were used. These data indicate that, for a specific range of doses, sex differences in seizure susceptibility can be clearly demonstrated with the use of intraperitoneally injected PTZ. In this sense, this method could be used as a tool to investigate the role played by sexual hormones in regulating the sensitivity of the gamma-aminobutiric acid (GABA(A)) receptor complex (GRC).

The effects of total and partial callosal agenesis on the rotatory behavior of BALB/cCF mice.

We report a study on rotational behavior (free swim test) of 30 adult male mice of an inbred strain in which about 20% of the animals are born with callosal defects (the BALB/cCF strain). The experiment was designed to study the relationship between the development of the corpus callosum and the degree of lateralization in rotatory behavior. Most of the BALB/cCF mice (77%) were lateralized rotators. Although most animals with a normal callosal area presented individual asymmetry, there was no significant tendency for a populational asymmetry toward one side in this group. In contrast, 75% of the animals with abnormally small callosal areas were left rotators. These animals, therefore, presented not only individual asymmetry, but also a tendency for a populational asymmetry. It was concluded that disturbances in the development of the corpus callosum are related to the appearance of directional populational asymmetry in rotatory behavior.

Absence of population cerebral asymmetries in mice with callosal defects induced by prenatal gamma irradiation.

The development of the corpus callosum of 19 male Swiss mice was disturbed by exposure to a 60Co gamma source on embryonic day 16 with a total dose of 2 Gy (dose rate of 56 to 59 rads/min). At adulthood the animals were perfused with saline followed by formaldehyde and the cerebral hemispheres were weighed and photographed in dorsal, lateral and medial views. Brain asymmetries were evaluated by measurements of hemisphere weight, as well as dorsal and lateral areas. From the measurements of the midsagittal callosal areas, performed on the medial views, 2 subgroups could be identified: one with a small callosal remnant (N = 9) and another with a non-measurable callosal area (N = 10). In spite of a pronounced individual asymmetry, the irradiated mice (N = 19) did not show a populational asymmetry toward any side. A slight tendency favoring the left hemisphere was found in the small remnant subgroup. These results are consistent with our previous data for a strain of mice in which some animals present callosal defects. We conclude that the present data support the hypothesis that the corpus callosum may play a role in directing morphological hemispheric asymmetries.