Social isolation at adolescence: a systematic review on behaviour related to cocaine, amphetamine and nicotine use in rats and mice.

Adolescence is known for its high level of risk-taking, and neurobiological alterations during this period may predispose to psychoactive drug initiation and progression into more severe use patterns. Stress is a risk factor for drug consumption, and post-weaning social isolation increases drug self-administration in rodents. This review aimed to provide an overview of the effects of adolescent social isolation on cocaine, amphetamine and nicotine use-related behaviours, highlighting the specific period when animals were submitted to stress and these drugs. We wondered if there was a specific period during adolescence that isolation stress would increase drug use vulnerability. A total of 323 publications from the Scopus, Web of Science and PubMed (Medline) electronic databases were identified using the words "social isolation" and "adolescence" and "drug" or "cocaine" or "amphetamine" or "nicotine", resulting in 24 articles after analyses criteria following the PRISMA statement. The main points raised were social isolation during adolescence increased cocaine self-administration, amphetamine and nicotine locomotor activity. We did not observe a pattern of a specific moment during the adolescent period that could lead to an increased vulnerability to drug use. The precise conditions under which adolescent social stress alters drug use parameters are complex and likely depend on several factors.

[Cardiorespiratory effects of perioperative positioning techniques]. / Kardiorespiratorische Effekte perioperativer Positionierungsmaßnahmen.

The supine position is still the most frequently used type of positioning during surgical procedures. Positions other than the supine position lead to physiological alterations that have a relevant influence on the course of anesthesia and surgery. As a matter of principle, hemodynamic stability is at risk because venous blood is pooled in the lower positioned body parts. In addition, head down positions (Trendelenburg position) may lead to an impairment of respiratory function by reducing lung volumes as well as lung compliance. Upright positions (beach chair position) are characterized by a relative hypovolemia accompanied by a reduction of mean arterial pressure, cardiac output and stroke volume, whereas pulmonary functions remain unchanged. Some severe adverse events have been described in the literature (e.g. intraoperative apoplexy, postoperative blindness). The pathophysiological principles and effects of hemodynamic alterations as well as potential strategies to avoid complications are presented and discussed in this lead article. Head down positions, especially the Trendelenburg position, cause a relative (intrathoracic) hypervolemia and an increase in cardiac preload that is usually well-tolerated in patients without heart problems; however, the Trendelenburg position, especially if combined with a capnoperitoneum, significantly impairs pulmonary function, can have a negative effect on intracerebral pressure and may reduce blood flow of intra-abdominal organs. The pathophysiological intraoperative changes caused by Trendelenburg positioning are described and approaches suitable for risk reduction are discussed. The prone position and lateral decubitus position have little influence on the intraoperative homeostasis. Nevertheless, there is an ongoing discussion concerning the efficacy of a 15° left lateral position during caesarean section, which is also discussed in a separate section of this review.

Intrauterine Growth Restriction Modifies the Accumbal Dopaminergic Response to Palatable Food Intake.

Intrauterine growth restriction (IUGR) associates with increased preference for palatable foods and altered insulin sensitivity. Insulin modulates the central dopaminergic response and changes behavioral responses to reward. We measured the release of dopamine in the accumbens during palatable food intake in IUGR rats both at baseline and in response to insulin. From pregnancy day 10 until birth, gestating Sprague-Dawley rats received either an ad libitum (Control), or a 50% food restricted (FR) diet. In adulthood, palatable food consumption and feeding behavior entropy was assessed using an electronic food intake monitor (BioDAQ®), and dopamine response to palatable food was measured by chronoamperometry recordings in the nucleus accumbens (NAcc). FR rats eat more palatable foods during the dark phase, and their eating pattern has a higher entropy compared to control rats. There was a delayed dopamine release in the FR group in response to palatable food and insulin administration reverted this delayed effect. Western blot showed a decrease in suppressor of cytokine signaling 3 protein (SOCS3) in the ventral tegmental area (VTA) and an increase in the ratio of phospho-tyrosine hydroxylase to tyrosine hydroxylase (pTH/TH) in the NAcc of FR rats. Administration of insulin also abolished this latter effect in FR rats. FR rats showed metabolic alterations and a delay in the dopaminergic response to palatable foods. This could explain the increased palatable food intake and behavioral entropy found in FR rats. IUGR may lead to binge eating, obesity and its metabolic consequences by modifying the central dopaminergic response to sweet food.

Energy drinks and their component modulate attention, memory, and antioxidant defences in rats.

PURPOSE: This study aimed to evaluate the effects of the subchronic consumption of energy drinks and their constituents (caffeine and taurine) in male Wistar rats using behavioural and oxidative measures. METHODS: Energy drinks (ED 5, 7.5, and 10 mL/kg) or their constituents, caffeine (3.2 mg/kg) and taurine (40 mg/kg), either separately or in combination, were administered orally to animals for 28 days. Attention was measured though the ox-maze apparatus and the object recognition memory test. Following behavioural analyses, markers of oxidative stress, including SOD, CAT, GPx, thiol content, and free radicals, were measured in the prefrontal cortex, hippocampus, and striatum. RESULTS: The latency time to find the first reward was lower in animals that received caffeine, taurine, or a combination of both (P = 0.003; ANOVA/Bonferroni). In addition, these animals took less time to complete the ox-maze task (P = 0.0001; ANOVA/Bonferroni), and had better short-term memory (P < 0.01, Kruskal-Wallis). The ED 10 group showed improvement in the attention task, but did not differ on other measures. In addition, there was an imbalance in enzymatic markers of oxidative stress in the prefrontal cortex, the hippocampus, and the striatum. In the group that received both caffeine and taurine, there was a significant increase in the production of free radicals in the prefrontal cortex and in the hippocampus (P < 0.0001; ANOVA/Bonferroni). CONCLUSIONS: Exposure to a combination of caffeine and taurine improved memory and attention, and led to an imbalance in the antioxidant defence system. These results differed from those of the group that was exposed to the energy drink. This might be related to other components contained in the energy drink, such as vitamins and minerals, which may have altered the ability of caffeine and taurine to modulate memory and attention.

[Ankle joint prosthesis for bone defects]. / Sprunggelenkprothese bei Knochendefekten.

Large defects of the talus, i.e. due to tumors, large areas of osteolysis in total ankle replacement (TAR) and posttraumatic talus body necrosis are difficult to manage. The gold standard in these circumstances is still tibiocalcaneal arthrodesis with all the negative aspects of a completely rigid hindfoot. We started 10 years ago to replace the talus by a custom-made, all cobalt-chrome implant (laser sintering). The first patient with a giant cell tumor did very well but the following patients showed all subsidence of the metal talus into the tibia due to missing bony edges. Therefore, we constructed a custom-made talus (mirrored from the healthy side) and combined it with a well functioning total ankle prosthesis (Hintegra). So far we have implanted this custom-made implant into 3 patients: the first had a chondrosarcoma of the talus (1 year follow-up), the second had massive osteolysis/necrosis of unknown origin (6 months follow-up) and the third massive osteolysis following a correct TAR (2 months follow-up). The results are very encouraging as all of the patients are practically pain free and have a good range of movement (ROM): D-P flexion 15°-0-20° but less motion in the lower ankle joint: ROM P-S 5°-0-5°. No subsidence was detected in the tibia or the calcaneus. The custom-made talus combined with the Hintegra total ankle replacement will probably be an interesting alternative to a tibiocalcaneal arthrodesis in selected cases with massive defects of the talus.

Long-term outcome after supination-external rotation type-4 fractures of the ankle.

We have compared the results at a mean follow-up of 13 years (11 to 14) of two groups of supination-external rotation type-4 fractures of the ankle, in one of which there was a fracture of the medial malleolus and in the other the medial deltoid ligament had been partially or completely ruptured. Of 66 patients treated operatively between 1993 and 1997, 36 were available for follow-up. Arthroscopy had been performed in all patients pre-operatively to assess the extent of the intra-articular lesions. The American Orthopaedic Foot and Ankle Society hind-foot score was used for clinical evaluation and showed a significant difference in both the total and the functional scores (p < 0.05), but not in those for pain or alignment, in favour of the group with a damaged deltoid ligament (p < 0.05). The only significant difference between the groups on the short-form 36 quality-of-life score was for bodily pain, again in favour of the group with a damaged deltoid ligament. There was no significant difference between the groups in the subjective visual analogue scores or in the modified Kannus radiological score. Arthroscopically, there was a significant difference with an increased risk of loose bodies in the group with an intact deltoid ligament (p < 0.005), although there was no significant increased risk of deep cartilage lesions in the two groups. At a mean follow-up of 13 years after operative treatment of a supination-external rotation type-4 ankle fracture patients with partial or complete rupture of the medial deltoid ligament tended to have a better result than those with a medial malleolar fracture.

Comparison of in vitro and in vivo acute fish toxicity in relation to toxicant mode of action.

Acute toxicity to fish hepatoma cell line PLHC-1 and to juvenile rainbow trout was examined for 18 plant protection products. The main objective was to explore whether hepatoma cells could be used to predict acute toxicity in fish taking into account the mode of toxic action and compound properties. Acute fish toxicity was determined using the OECD guideline test 203 and compared to predicted baseline LC50 of acute fish toxicity calculated with a quantitative structure-activity relationship (QSAR) derived for guppy fish. Cytotoxicity was determined through the inhibition of neutral red uptake (NR(50)) into lysosomes and compared to predicted baseline cytotoxicity derived for goldfish GFS cells. In general, NR50 values were higher by a factor ranging from 3 to 3000 than the corresponding acute LC50. A weak correlation between NR50 and LC50 values was found (log/log: r2=0.62). Also the lipophilicity (log K(ow)) was not a good predictor for cytotoxicity (r2=0.43) and lethality (r2=0.57) of these pesticides. The neutral red assay is detecting general baseline toxicity only. Comparing LC50 data to QSAR results, the compounds can be classified to act as narcotics or reactive compounds with a specific mode of toxic action in fish. The results indicate that limitation of the neutral red assay in predicting acute fish toxicity. A promising alternative might be the assessment of toxicity in a set of in vitro systems addressing also cell-specific functions which are related to the mode of toxic action of the compound.

Lessons learned from investigations on case study level for modelling of nutrient emissions in the Danube basin.

In the framework of the project daNUbs (Nutrient Management in the Danube Basin and its Impact on the Black Sea) the MONERIS emission model is used for the basin wide calculation of nutrient (nitrogen and phosphorus) emissions in the Danube Basin. The MONERIS model was developed and successfully applied for German river catchments. Based on investigations in selected test regions (case studies) the daNUbs approach is to check the applicability of the MONERIS emission model for the specific conditions of the Danube Basin in more detail than is possible with a basin wide application. Six case studies with areas of 400-3,500 km2 and several subcatchments have been selected in order to represent different conditions along the Danube Basin. In this study region intensive data collection and enhanced monitoring has been performed in order to raise the database significantly above the generally available data. Water balance as well as nutrient balance calculations have been performed with the MONERIS model as well as with other approaches. Results are compared to each other and to data from monitoring. Results up till now showed the applicability and sensitivity of the MONERIS approach in different conditions of the Danube Basin (e.g. emissions via groundwater). They indicated that the nitrogen retention in the catchments is well described with the MONERIS model.

Selected requirements on a sustainable nutrient management.

Nutrients are a limited resource and call for management. A sustainable nutrient management strategy reintegrates nutrients in the environment without accumulating harmful substances above an acceptable level. In this study a methodology to assess the environmental compatibility was developed. For this assessment both the (i) enrichment of pollutants in the soils and (ii) the area specific nutrient demand of the crops were taken into account. The method considers, that products applied on soils also contain stable substances, and as a consequence the accumulation of pollutants diminishes. Additionally, it is considered, that increasing substance concentrations in the soil will lead to an increase of substance flows out of the soil by percolation, plant-removal (and erosion). In practice long term management strategies are restricted by the time span considered, the accepted accumulation of substances, the plants real needs and legal constraints. The rating of various goods can be made with the ratio of the added nutrients, considering the pollution criteria, the legal constraints and the plants real needs.

[Treatment of trochanteric fractures with the gamma nail]. / Die Versorgung trochanterer Frakturen mit dem Gammanagel.

The osteosynthesis of trochanteric fractures requires a minimal invasive technique to guarantee fully weight bearing and early rehabilitation in elderly patients. In this retrospective study we want to prove if the gamma nail meets all requirements and if the results improved after initiation of the new instrumentarium and standardization of the operative technique. From January 1992 until April 2000 we treated 387 patients with a gamma nail. The average age was 79.4 years. We used the new instrumentarium suitable for radiography since June 1996, the operative technique was standardized since the same time. The evaluation occurred on the basis of clinical and radiological findings included analysis of complications. We've seen intraoperative problems in 29% before June 1996, this rate could be reduced to 9%. General postoperative complications presented in equal frequency. After improvement of the technique dislocations of the neck screw and relevant sinking of the fractures were more rarely. The rate of reoperations after complications of the implant was 8% in both groups. In consideration of technical standards the postoperative full weight bearing and early mobilisation is possible even in old patients.

Arthroscopy of the elbow joint-video analysis of the anatomy and function.

The anatomical structures of the elbow joint were dissected in layers in human cadavers. The surgical dissection was divided into to deep and superficial areas. Each step was documented by digital video and photographs. The functional and anatomical preparation allowed us to establish the limits and scope of diagnostic and therapeutic procedures by arthroscopy.

Males with anorexia nervosa: a controlled study of eating disorders in first-degree relatives.

OBJECTIVE: To compare lifetime rates of full and partial anorexia nervosa and bulimia nervosa in first-degree relatives of males with anorexia nervosa and in relatives of never-ill comparison subjects. METHODS: Rates of eating disorders were obtained for 747 relatives of 210 probands from personal structured clinical interviews and family history. Best-estimate diagnoses were determined blind to proband diagnosis and pedigree status. RESULTS: Full and partial syndromes of anorexia nervosa aggregated in female relatives of ill probands. For the full syndrome of anorexia nervosa, the crude relative risk was 20.3 among female relatives and for partial syndrome anorexia nervosa, the crude relative risk was 3.3. In contrast, bulimia nervosa was relatively uncommon among relatives of ill probands. CONCLUSION: Although anorexia nervosa in males is exceedingly rare, there is a pattern of familial aggregation that is highly similar to that observed in recent family studies of affected females. On the basis of these findings, there is no evidence that familial-genetic factors distinguish the occurrence of anorexia nervosa in the two sexes.

C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABA(b) receptors.

Assembly of fully functional GABA(B) receptors requires heteromerization of the GABA(B(1)) and GABA(B(2)) subunits. It is thought that GABA(B(1)) and GABA(B(2)) undergo coiled-coil dimerization in their cytoplasmic C termini and that assembly is necessary to overcome GABA(B(1)) retention in the endoplasmatic reticulum (ER). We investigated the mechanism underlying GABA(B(1)) trafficking to the cell surface. We identified a signal, RSRR, proximal to the coiled-coil domain of GABA(B(1)) that when deleted or mutagenized allows for surface delivery in the absence of GABA(B(2)). A similar motif, RXR, was recently shown to function as an ER retention/retrieval (ERR/R) signal in K(ATP) channels, demonstrating that G-protein-coupled receptors (GPCRs) and ion channels use common mechanisms to control surface trafficking. A C-terminal fragment of GABA(B(2)) is able to mask the RSRR signal and to direct the GABA(B(1)) monomer to the cell surface, where it is functionally inert. This indicates that in the heteromer, GABA(B(2)) participates in coupling to the G-protein. Mutagenesis of the C-terminal coiled-coil domains in GABA(B(1)) and GABA(B(2)) supports the possibility that their interaction is involved in shielding the ERR/R signal. However, assembly of heteromeric GABA(B) receptors is possible in the absence of the C-terminal domains, indicating that coiled-coil interaction is not necessary for function. Rather than guaranteeing heterodimerization, as previously assumed, the coiled-coil structure appears to be important for export of the receptor complex from the secretory apparatus.

[Tibial torsion deformities]. / Tibiale Torsionsfehler.

Tibial torsion defects are usually not clinically evident and, hence, are often overlooked. Clinical examination and CT scan have proved to be the best ways of measuring static tibial torsion, whereas dynamic measurements are usually performed in the clinic and the "gait laboratory." Only few studies have determined there to be a connection between a torsion defect in the lower leg and expected pathological conditions of the knee and ankle joints. However, patellofemoral instability, Osgood-Schlatter disease, osteochondrosis dissecans are increasingly being found in cases of increased external tibial torsion and arthrosis in reduced torsion. Although spontaneous correction may occur in certain cases, in others the only way to correct the condition is by employing physiologic torsion. Conservative treatment methods such as bandages or orthosis have been shown to not have any effect on torsion; thus, surgical treatment is the only successful way to correct a pathologic angle of rotation of the tibia. For this, supramalleolar osteotomy with fixation using Kirscher wires and plaster or an external fixator are the most common treatments.

Toxin production in cyanobacterial mats from ponds on the McMurdo ice shelf, Antarctica.

Cyanobacteria are known to produce hepatotoxic substances, the functional and ecological role of these toxins, however, remains largely unclear. Toxic properties of cyanobacteria collected in Antarctica were investigated to determine whether toxin-producing species can also be found under these environmental conditions. Samples were collected from meltwater ponds on the McMurdo Ice Shelf, Antarctica in the summers of 1997 to 1999. These ponds are colonized by benthic algae and cyanobacterial mats. Oscillatoriales, Nodularia sp., and Nostoc sp. constituted the major taxa in freshwater ponds, while Nostoc sp. was missing from brackish and saline ponds. Samples were taken from either floating, submerged or benthic mats, and extracted for in vitro toxicity testing. The presence of toxins was determined by the phosphatase-inhibition assay and by high performance liquid chromatography. The cytotoxic properties of the extracts were investigated in hepatocytes determining 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide metabolism and trypan blue dye exclusion. The results show that all cyanobacterial extracts display phosphatase-inhibiting activity, of which approximately half had significantly greater than 50% inhibiting activity. The presence of nodularin and microcystin-LR was established by high performance liquid chromatography. Cytotoxic properties, independent of the phosphatase inhibiting activity, were also detected. Toxic strains of cyanobacteria can therefore also be found in Antarctica and this finding may lead to further insight into potential ecological roles of cyanobacterial phosphatase inhibiting toxins.

Arthroscopic findings in acute fractures of the ankle.

We have evaluated prospectively the arthroscopic findings in acute fractures of the ankle in 288 consecutive patients (148 men and 140 women) with a mean age of 45.6 years. According to the AO-Danis-Weber classification there were 14 type-A fractures, 198 type B and 76 type C. Lesions of the cartilage were found in 228 ankles (79.2%), more often on the talus (69.4%) than on the distal tibia (45.8%), the fibula (45.1%), or the medial malleolus (41.3%). There were more lesions in men than in women and in general they were more severe in men (p < 0.05). They also tended to be worse in patients under 30 years and in those over 60 years of age. The frequency and severity of the lesions increased from type-B to type-C fractures (p < 0.05). Within each type of fracture the lesions increased from subgroups 1 to 3 (p < 0.05). The anterior tibiofibular ligament was injured with increased frequency from type-B.1 to type-C3 fractures (p < 0.05), but it was not torn in all cases. While lateral ligamentous injuries were seen more often in type-B than in type-C fractures (p < 0.05), no difference was noted in the frequency of deltoid ligamentous lesions. Our findings show that arthroscopy is useful in identifying associated intra-articular lesions in acute fractures of the ankle.

Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes.

OBJECTIVE: Lifetime rates of full and partial anorexia nervosa and bulimia nervosa were determined in first-degree relatives of diagnostically pure proband groups and relatives of matched, never-ill comparison subjects. METHOD: Rates of each eating disorder were obtained for 1,831 relatives of 504 probands on the basis of personal structured clinical interviews and family history. Best-estimate diagnoses based on all available information were rendered without knowledge of proband status and pedigree identity. Only definite and probable diagnoses were considered. RESULTS: Whereas anorexia nervosa was rare in families of the comparison subjects, full and partial syndromes of anorexia nervosa aggregated in female relatives of both anorexic and bulimic probands. For the full syndrome of anorexia nervosa, the relative risks were 11.3 and 12.3 in female relatives of anorexic and bulimic probands, respectively. Bulimia nervosa was more common than anorexia nervosa in female relatives of comparison subjects, but it, too, aggregated in the families of ill probands; the corresponding relative risks for bulimia nervosa were 4.2 and 4.4 for female relatives of anorexic and bulimic probands, respectively. When partial syndromes of anorexia nervosa and bulimia nervosa were considered, relative risks fell by one-half in each group of ill probands. CONCLUSIONS: Both anorexia nervosa and bulimia nervosa are familial. Their cross-transmission in families suggests a common, or shared, familial diathesis. The additional observation that familial aggregation and cross-transmission extend to milder phenotypes suggests the validity of their inclusion in a continuum of familial liability.

[Comparative periprosthetic bone density measurements of the proximal femur shaft using dual energy x-ray absorptiometry (DEXA) with experimental "Press Fit-gliding Stem Prosthesis"]. / Vergleichende periprothetische Knochendichtemessungen am proximalen Femurschaft mittels Dual Energy X-ray-Absorptiometry (DEXA) mit experimenteller "Press Fit-Gleitschaftprothese".

PROBLEM: Periprosthetic bone atrophy caused by stress shielding is one of the problems of non-cemented femoral stems of hip arthroplasty. Stress shielding and thus the loss of bone mass and their dissemination in the proximal part of the femur of conventional non-cemented femoral stems depends on stiffness (E-modules of the material and the geometry) of the implant and on the bonding between implant and bone. All currently implanted non-cemented femoral stems lead to proximal bone loss which goes up to 40-50% of the original bone mineral content. The senior author (E. M.) developed a femoral stem (Press Fit-Gliding Stem PFGS) which shifts relative movements of force-transmission from the bone-implant interface into the interior of the prosthetic system (Inner Bearing-System) and which only transfers forces proximal into the femur. METHOD: The examinations were made in 21 patients between 1 and 6 years after implantation of a Press Fit-Gliding Stem compared with a normal contralateral femur (12), with bilateral PFGS (3) and other bilateral arthroplasty (6). RESULTS: In all 21 patients supplied with a PFGS an increase of bone mineral content (BMC) and bone mineral density (BMC) in zone 7 as well as a marked smaller deviation around the mean value in all zones respectively could be noticed. CONCLUSIONS: With the Dual Energy X-ray Absorptiometry (DEXA)-measurement of bone mineral content (BMC) and bone mineral density (BMD) in all zones according to Gruen could be shown that it is not only possible with regard to a favorable force transmission to avoid the inevitable bone atrophy but on the contrary to induce an increase of bone at the point of local force transmission that is in the region of the calcar femorale (zone 7). CLINICAL RELEVANCE: The Press Fit-Gliding Stem is still in the clinical test-program.

Intensity and predictors of treatment received by adolescents with unipolar major depression prior to hospital admission.

We sought to characterize the type and intensity of treatment received in the community by 80 adolescents with unipolar major depressive disorder prior to hospital admission for this index episode of illness. Structured clinical interviews were used to rate the presence and severity of a wide range of depressive symptoms and to derive global measures of episode subtype and degree of impairment. Multiple sociodemographic and clinical variables were considered as predictors of level of antidepressant treatment exposure. Although the majority of patients sought help prior to admission, only 58% received antidepressant medication, and fewer than half of these treated patients received levels of treatment deemed adequate by conventional standards. More aggressive levels of pharmacotherapy were received by only a small minority of the sample, and overall severity of illness had little effect on intensity of treatment. Specific clinical features associated with endogeneity were the most robust predictors of more intense antidepressant pharmacotherapy. A disturbingly high proportion of adolescents with serious depressive illness receive less than optimally aggressive treatment in the community relative to the seriously handicapping nature of their illness. The potential implications of these observations are considered.

Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania.

We compared the response to acute lithium therapy in 30 adolescents, 13-17 years of age, with mania and a prior history of early childhood attention deficit hyperactivity disorder (ADHD) to a sex- and age-matched control group of adolescent manics without premorbid psychiatric illness. Response to treatment was assessed daily over the course of 28 days using measures of global clinical improvement and severity ratings on the Bech-Rafaelsen Mania Scale (BRMS). BRMS scores decreased by a mean of 24.3 in the subgroup without prior ADHD compared to 16.7 in patients with ADHD (P = 0.0005). The average percent drop in BRMS scores over the study period in these two subgroups was 80.6% and 57.7%, respectively (P = 0.0005). Time to onset of sustained global clinical improvement was also assessed using Kaplan-Meier survival methods and possible covariates of time to improvement were tested in a Cox proportional hazards model. Median time to onset of sustained improvement was lengthened significantly in patients with early ADHD (23 days) compared to those without it (17 days; log rank chi2 = 7.2, P = 0.007). The results suggest that early childhood ADHD defines an important source of heterogeneity in bipolar illness with developmental, clinical, and neuropharmacogenetic implications.