Multitask methods for predicting molecular properties from heterogeneous data.

Data generation remains a bottleneck in training surrogate models to predict molecular properties. We demonstrate that multitask Gaussian process regression overcomes this limitation by leveraging both expensive and cheap data sources. In particular, we consider training sets constructed from coupled-cluster (CC) and density functional theory (DFT) data. We report that multitask surrogates can predict at CC-level accuracy with a reduction in data generation cost by over an order of magnitude. Of note, our approach allows the training set to include DFT data generated by a heterogeneous mix of exchange-correlation functionals without imposing any artificial hierarchy on functional accuracy. More generally, the multitask framework can accommodate a wider range of training set structures-including the full disparity between the different levels of fidelity-than existing kernel approaches based on Δ-learning although we show that the accuracy of the two approaches can be similar. Consequently, multitask regression can be a tool for reducing data generation costs even further by opportunistically exploiting existing data sources.

Prospective slice-by-slice motion correction reduces false positive activations in fMRI with task-correlated motion.

OBJECTIVE: We aimed to test the hypothesis that slice-by-slice prospective motion correction at 7T using an optical tracking system reduces the rate of false positive activations in an fMRI group study with a paradigm that involves task-correlated motion. MATERIALS AND METHODS: Brain activation during right leg movement was measured using a block design on 15 volunteers, with and without prospective motion correction. Clearly erroneous activations were compared between both cases, at the individual level. Additionally, conventional group analysis was performed. RESULTS: The number of falsely activated voxels with T-values higher than 5 was reduced by 48% using prospective motion correction alone, without additional retrospective realignment. In the group analysis, the statistical power was increased - the peak T-value was 26% greater, and the number of voxels in the cluster representing the right leg was increased by a factor of 9.3. CONCLUSION: Slice-by-slice prospective motion correction in fMRI studies with task-correlated motion can substantially reduce false positive activations and increase statistical power.

The effect of tin prefiltration on extremity cone-beam CT imaging with a twin robotic X-ray system.

INTRODUCTION: While tin prefiltration is established in various CT applications, its value in extremity cone-beam CT relative to optimized spectra has not been thoroughly assessed thus far. This study aims to investigate the effect of tin filters in extremity cone-beam CT with a twin-robotic X-ray system. METHODS: Wrist, elbow and ankle joints of two cadaveric specimens were examined in a laboratory setup with different combinations of prefiltration (copper, tin), tube voltage and current-time product. Image quality was assessed subjectively by five radiologists with Fleiss' kappa being computed to measure interrater agreement. To provide a semiquantitative criterion for image quality, contrast-to-noise ratios (CNR) were compared for standardized regions of interest. Volume CT dose indices were calculated for a 16 cm polymethylmethacrylate phantom. RESULTS: Radiation dose ranged from 17.4 mGy in the clinical standard protocol without tin filter to as low as 0.7 mGy with tin prefiltration. Image quality ratings and CNR for tin-filtered scans with 100 kV were lower than for 80 kV studies with copper prefiltration despite higher dose (11.2 and 5.6 vs. 4.5 mGy; p < 0.001). No difference was ascertained between 100 kV scans with tin filtration and 60 kV copper-filtered scans with 75% dose reduction (subjective: p = 0.101; CNR: p = 0.706). Fleiss' kappa of 0.597 (95% confidence interval 0.567-0.626; p < 0.001) indicated moderate interrater agreement. CONCLUSION: Considerable dose reduction is feasible with tin prefiltration, however, the twin-robotic X-ray system's low-dose potential for extremity 3D imaging is maximized with a dedicated low-kilovolt scan protocol in situations without extensive beam-hardening artifacts. IMPLICATIONS FOR PRACTICE: Low-kilovolt imaging with copper prefiltration provides a superior trade-off between dose reduction and image quality compared to tin-filtered cone-beam CT scan protocols with higher tube voltage.

Effect of inhaled dust mite allergen on regional particle deposition and mucociliary clearance in allergic asthmatics.

BACKGROUND: Acute exacerbations in allergic asthmatics may lead to impaired ability to clear mucus from the airways, a key factor in asthma morbidity. OBJECTIVE: The purpose of this study was to determine the effect of inhaled house dust mite challenge on the regional deposition of inhaled particles and mucociliary clearance (MCC) in allergic asthmatics. METHODS: We used gamma scintigraphy (inhalation of (99m) Tc -sulphur colloid particles) to measure the regional particle deposition and MCC in allergic asthmatics (n=12) 4 h following an inhaled dust mite allergen challenge (Dermatophagoides farinae extract; PD(max) =fall in forced expiratory volume in 1 s of 10%) for comparison with baseline non-challenge measures. RESULTS: In responders (n=9 PD(max) dose), lung function returned to pre-challenge values by 3 h but was significantly decreased at 6 and 24 h in three of the responders (i.e. late-phase response) and induced sputum eosinophils were increased at 24 h post-challenge (P<0.05). Responders showed enhanced bronchial airway deposition of inhaled particles (P<0.05) and slowed clearance from the central lung zone (P<0.01) at 4 h post-challenge compared with the baseline (no allergen challenge) that was predicted by the PD(max) allergen concentration (r=-0.70, P<0.05). The decline in lung function at 24 h post-challenge correlated with reduced MCC from the central lung zone (r=-0.78, P<0.02) and PD(max) . Non-responders (n=3) showed no change in lung function, regional deposition or MCC post-challenge vs. baseline. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that regional deposition and clearance of inhaled particles may be sensitive for detecting mild airway obstruction associated with early- and late-phase allergen-induced effects on mucus secretions. The study was listed on clinicaltrials.gov (NCT00448851).

Textured tetragonal ZrO2 film grown on (100) silicon surface by DLI metal-organic chemical vapor deposition.

Zirconia (ZrO2) thin films with micronic layer thickness are deposited on Si(100) substrates by MOCVD in a cold wall reactor using direct injection (DLI-CVD) process with Zr2(OiPr)6(thd)2 precursor diluted in cyclohexane. The effects of experimental parameters such as substrate's temperature, injection frequency, oxygen partial pressure in the reactive chamber and deposition duration of the process are investigated in order to produce a strongly textured tetragonal ZrO2 film. The films crystalline structure and crystallite size (several nm) are identified by Grazing incidence X-ray diffraction (GIXRD); the microstructure and morphology are observed with the use of FEG-SEM. GIXRD patterns showed the predominance of nano-crystallized tetragonal phase (or cubic) in the films. Pole figures have been analysed for both {111}(t-c) and {200}(t-c) planes in order to evaluate the relationship binding the preferential crystallographic orientation to the column-like growth structure. Besides, the internal stresses levels (with the use of sin2 psi method) within zirconia layers varied from a compressive to a tensile state depending on the experimental deposition conditions and are related to phase orientation and/or transformation into monoclinic one. It is demonstrated that high temperature, low pressure and low deposition time enhanced the tetragonal phase quality that became highly (200)t textured.

Future climate change will accelerate maize phenological development and increase yield in the Nemoral climate.

Climate change will bring warmer and wetter conditions and more frequent extreme events in the Nemoral climate zone. These changes are expected to affect maize growth and yields. In this study, we applied the AgroC model to assess climate change impact on changes in growing environmental conditions, growing season length, yield and potential yield losses due to multiple abiotic stresses. The model was calibrated and validated using data from dedicated field experiments conducted in Lithuania during four meteorologically contrasting years (2015, 2016, 2017 and 2019). We simulated the climate impacts on rainfed maize for long-term future climate conditions from 2020 to 2100 under the RCP2.6 (low), RCP4.5 (medium) and RCP8.5 (high) emission scenarios. As a result, we found that air temperature, sum of growing degree days and amount of precipitation during the growing season of maize will increase, especially under medium and higher emission scenarios (RCP4.5 and RCP8.5), with significantly positive effect on yields. The simulation results showed that average maize grain yield will increase under RCP2.6 by 69 kg ha-1 per decade, under RCP4.5 by 197 kg ha-1 per decade and under RCP8.5 by 304 kg ha-1 per decade. The future potential maize yield reveals a progressive increase with a surplus of +10.2% under RCP4.5 and +14.4% under RCP8.5, while under RCP2.6 the increase of potential yield during the same period will be statistically not significant. The yield gap under RCP2.6 and RCP4.5 will fluctuate within a rather narrow range and under RCP8.5, it will decrease.

Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer--a multi-centre randomised phase II study.

BACKGROUND: No standard treatment for locally advanced pancreatic cancer (LAPC) is defined. PATIENTS AND METHODS: Within a multi-centre, randomised phase II trial, 95 patients with LAPC were assigned to three different chemoradiotherapy (CRT) regimens: patients received conventionally fractionated radiotherapy of 50 Gy and were randomised to concurrent 5-fluorouracil (350 mg m(-2) per day on each day of radiotherapy, RT-5-FU arm), concurrent gemcitabine (300 mg m(-2)), and cisplatin (30 mg m(-2)) on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by sequential full-dose gemcitabine (1000 mg m(-2)) and cisplatin (50 mg m(-2)) every 2 weeks (RT-GC+GC arm). Primary end point was the overall survival (OS) rate after 9 months. RESULTS: The 9-month OS rate was 58% in the RT-5-FU arm, 52% in the RT-GC arm, and 45% in the RT-GC+GC arm. Corresponding median survival times were 9.6, 9.3, and 7.3 months (P=0.61) respectively. The intent-to-treat response rate was 19, 22, and 13% respectively. Median progression-free survival was estimated with 4.0, 5.6, and 6.0 months (P=0.21). Grade 3/4 haematological toxicities were more frequent in the two GC-containing arms, no grade 3/4 febrile neutropaenia was observed. CONCLUSION: None of the three CRT regimens tested met the investigators' definition for efficacy; the median OS was similar to those previously reported with gemcitabine alone in LAPC.

The effect of the arthroscopic augmentation of the subscapularis tendon on shoulder instability and range of motion: A biomechanical study.

BACKGROUND: Anterior shoulder dislocation is common. The treatment of recurrence with glenoid bone defect is still considered controversial. A new arthroscopic subscapularis augmentation has recently been described that functions to decrease the anterior translation of the humeral head. The purpose of the presented study was to examine the biomechanical effect on glenohumeral joint motion and stability. METHODS: Eight fresh frozen cadaver shoulders were studied by use of a force guided industrial robot fitted with a six-component force-moment sensor to which the humerus was attached. The testing protocol includes measurement of glenohumeral translation in the anterior, anterior-inferior and inferior directions at 0°, 30° and 60° of glenohumeral abduction, respectively, with a passive humerus load of 30N in the testing direction. The maximum possible external rotation was measured at each abduction angle applying a moment of 1Nm. Each specimen was measured in a physiologic state, as well as after Bankart lesion with an anterior bone defect of 15-20% of the glenoid, after arthroscopic subscapularis augmentation and after Bankart repair. FINDINGS: The arthroscopic subscapularis augmentation decreased the anterior and anterior-inferior translation. The Bankart repair did not restore the mechanical stability compared to the physiologic shoulder group. External rotation was decreased after arthroscopic subscapularis augmentation compared to the physiologic state, however, the limitation of external rotation was decreased at 60° abduction. INTERPRETATION: The arthroscopic subscapularis augmentation investigated herein was observed to restore shoulder stability in an experimental model.

Monitoring red blood cell aggregation with nuclear magnetic resonance.

We present a new application of nuclear magnetic resonance to monitor rouleaux formation in static blood suspensions of physiological hematocrit. The method measures the apparent mean residence time of water inside the rouleaux and yields the kinetics and the extent of red cell aggregation in units of cells per aggregate.

Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86.

PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy. PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54. 4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation). RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% +/- 3% and 69% +/- 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% +/- 5%; stage II, 69% +/- 6%; stage III, 57% +/- 4%; and stage IV, 19% +/- 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% +/- 5% v 44% +/- 6%; P =.053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site. CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.

Membrane potential dependent modulations of calcium oscillations in insulin-secreting INS-1 cells.

This study was undertaken to examine the role of K(+) channels on cytosolic Ca(2+) ([Ca(2+)](i)) in insulin secreting cells. [Ca(2+)](i) was measured in single glucose-responsive INS-1 cells using the fluorescent Ca(2+) indicator Fura-2. Glucose, tolbutamide and forskolin elevated [Ca(2+)](i) and induced [Ca(2+)] oscillations. Whereas the glucose effect was delayed and observed in 60% and 93% of the cells, in a poorly and a highly glucose-responsive INS-1 cell clone, respectively, tolbutamide and forskolin increased [Ca(2+)](i) in all cells tested. In the latter clone, glucose induced [Ca(2+)](i) oscillations in 77% of the cells. In 16% of the cells a sustained rise of [Ca(2+)](i) was observed. The increase in [Ca(2+)](i) was reversed by verapamil, an L-type Ca(2+) channel inhibitor. Adrenaline decreased [Ca(2+)](i) in oscillating cells in the presence of low glucose and in cells stimulated by glucose alone or in combination with tolbutamide and forskolin. Adrenaline did not lower [Ca(2+)](i) in the presence of 30mM extracellular K(+), indicating that adrenaline does not exert a direct effect on Ca(2+) channels but increases K(+) channel activity. As for primary b-cells, [Ca(2+)](i) oscillations persisted in the presence of closed K(ATP) channels; these also persisted in the presence of thapsigargin, which blocks Ca(2+) uptake into Ca(2+) stores. In contrast, in voltage-clamped cells and in the presence of diazoxide (50mM), which hyperpolarizes the cells by opening K(ATP) channels, [Ca(2+)](i) oscillations were abolished. These results support the hypothesis that [Ca(2+)](i) oscillations depend on functional voltage-dependent Ca(2+) and K(+) channels and are interrupted by a hyperpolarization in insulin-secreting cells.

Mutations of the androgen receptor coding sequence are infrequent in patients with isolated hypospadias.

Androgen receptor defects can cause severe hypospadias. To examine the possibility that androgen receptor defects are a common cause of such deficiencies, we have determined the coding sequence of the androgen receptor gene in nine patients with severe hypospadias. The analysis of the androgen receptor coding sequence predicts a normal amino acid sequence for the androgen receptor of eight of the nine patients, indicating that the observed defects in virilization are infrequently caused by mutations of the open-reading frame of the androgen receptor. These findings demonstrate the importance of family history and endocrine studies in identifying patients likely to harbor coding sequence mutations in the androgen receptor gene, and they serve to focus attention on other genes that may influence androgen action in this group of patients.

Adrenaline inhibits depolarization-induced increases in capacitance the presence of elevated [Ca2+]i in insulin secreting cells.

Cell capacitance (Cm), cell conductance (Gm), access conductance (Ga) and membrane voltage (Vm) were measured simultaneously in insulin secreting cells using the dual frequency method. Depolarization and stimulation of the cells with secretagogues increased Cm. EGTA abolished the increase in [Ca2+]i and prevented the rise of Cm. Adrenaline inhibited the augmentation of Cm without lowering [Ca2+]i. In pertussis toxin pretreated cells adrenaline had no effect. Thus, stimulation of insulin secretion is accompanied by an increase in Cm. Inhibition of exocytosis by adrenaline occurs even in the presence of elevated [Ca2+]i, i.e. at a more distal step of exocytosis.

Digital tumor fluoroscopy (DTF)--a new direct imaging system in the therapy planning for brain tumors.

Digital Tumor Fluoroscopy is an expanded x-ray video chain optimized to iodine contrast with an extended Gy scale up to 64000 Gy values. Series of pictures are taken before and after injection of contrast medium. With the most recent unit, up to ten images can be taken and stored. The microprogrammable processor allows the subtraction of images recorded at any moment of the examination. Dynamic views of the distribution of contrast medium in the intravasal and extravasal spaces of brain and tumor tissue are gained by the subtraction of stored images. Tumors can be differentiated by studying the storage and drainage behavior of the contrast medium during the period of examination. Meningiomas store contrast medium very intensively during the whole time of investigation, whereas astrocytomas grade 2-3 pick it up less strongly at the beginning and release it within 2 min. Glioblastomas show a massive but delayed accumulation of contrast medium and a decreased flow-off-rate. In comparison with radiography and MR-imaging the most important advantage of Digital Tumor Fluoroscopy is that direct information on tumor localization is gained in relation to the skull-cap. This enables the radiotherapist to mark the treatment field directly on the skull. Therefore it is no longer necessary to calculate the tumor volume from several CT scans for localization. In radiotherapy Digital Tumor Fluoroscopy a unit combined with a simulator can replace CT planning. This would help overcome the disadvantages arising from the lack of a collimating system, and the inaccuracies which result from completely different geometric relationships between a CT unit and a therapy machine.

Endorphins and pain perception in silent myocardial ischemia.

Evidence suggests that endogenous opioids, particularly the beta-endorphins and met-enkephalins, are closely involved in stress-induced analgesia and nociceptive pain control. Numerous investigations have been conducted to evaluate the role of opioids in silent vs symptomatic myocardial disease. There is good evidence to suggest that patients with asymptomatic ischemia have defective pain perception compared with those with angina; however, the precise role of the endorphin and enkephalin systems in this phenomenon remains to be elucidated. Possible sources for disparate study results include variation in patient populations, insensitive or improperly timed assay techniques, and differences in amount of ischemia.

A comparison of amplitude-modulated and frequency-modulated ambulatory monitoring systems.

To compare the results of monitoring for ischemia with amplitude-modulated (AM) and frequency-modulated (FM) ambulatory recorders, 22 patients with coronary artery disease were monitored during exercise and during 24 to 48 hours of daily activities. Simultaneous recordings were obtained with Oxford Medilog 4000-II and Medilog MR-35 systems from the same 2 bipolar leads. Each potential ischemic episode was interpreted blindly by 2 investigators. Significant ST depression was strictly defined as greater than or equal to 1 mm of horizontal or down-sloping ST depression persisting for 0.06 second beyond the J point and lasting greater than or equal to 1 minute. Of 82 episodes reviewed, 63 (77%) were either positive (37) or negative (26) for ischemia by both systems. However, 17 episodes were interpreted as positive on AM tracings but negative on FM tracings; the converse was true for only 2 episodes (p less than 0.01). For episodes read as positive with both systems, there were close correlations between recorders for duration (r = 0.80) and magnitude (r = 0.90) of ST depression. Because of the greater number of positive AM events, however, the mean total duration of ST depression for patients with ischemia during daily activities was greater on AM than on FM recordings (74 +/- 77 vs 39 +/- 42 minutes, p less than 0.10). Discrepancies between AM and FM tracings were invariably due to small differences in ST-segment morphology or in the magnitude of ST-segment depression. In summary, AM monitors generate complexes similar in appearance to those produced by FM devices in most instances.(ABSTRACT TRUNCATED AT 250 WORDS)

Appropriateness of the decision to transfer nursing facility residents to the hospital.

OBJECTIVES: To develop and test a standardized instrument, the purpose of which is to assess (1) whether skilled nursing facilities (SNFs) transfer residents to emergency departments (ED) inappropriately, (2) whether residents are admitted to hospitals inappropriately, (3) and factors associated with inappropriate transfers. DESIGN: A structured implicit review (SIR) of medical records. SETTING AND PARTICIPANTS: Using nested random sampling in eight community SNFs, we identified SNF and hospital records of 100 unscheduled transfers to one of 10 hospitals. MEASUREMENTS: Seven trained physician reviewers assessed appropriateness using a SIR form designed for this study (2 independent reviews per record, 200 total reviews). We measured interrater reliability with kappa statistics and used bivariate analysis to identify factors associated with assessment that transfer was inappropriate. RESULTS: In 36% of ED transfers and 40% of hospital admissions, both reviewers agreed that transfer/admit was inappropriate, meaning the resident could have been cared for safely at a lower level of care. Agreement was high for both ED (percent agreement 84%, kappa .678) and hospital (percent agreement 89%, kappa .779). When advance directives were considered, both reviewers rated 44% of ED transfers and 45% of admissions inappropriate. Factors associated with inappropriateness included the perceptions that: (1) poor quality of care contributed to transfer need, (2) needed services would typically be available in outpatient settings, and (3) the chief complaint did not warrant hospitalization. CONCLUSIONS: Inappropriate transfers are a potentially large problem. Some inappropriate transfers may be associated with poor quality of care in SNFs. This study demonstrates that structured implicit review meets criteria for reliable assessment of inappropriate transfer rates. Structured implicit review may be a valuable tool for identifying inappropriate transfers from SNFs to EDs and hospitals.

Diverse mechanisms of control of aromatase gene expression.

The synthesis of estrogens from androgens is catalyzed by a microsomal cytochrome P450 termed aromatase (P450arom). The expression of this enzyme is highly regulated in both a developmental and cell-type specific fashion. We have chosen to examine the molecular basis of aromatase gene regulation by studying two models of aromatase expression: the Sebright bantam chicken and the R2C rat Leydig tumor cell line. In the first model, affected (Sebright) chickens express aromatase in many extragonadal tissues, while normal Leghorn chickens express aromatase only in the ovary and hypothalamus. Our studies have demonstrated that in normal chickens the site of transcription initiation is located approx. 147 nucleotides upstream of the initiator methionine. While Sebright animals also express aromatase mRNA initiated at an analogous initiation site in the ovary, a distinctive species of aromatase mRNA is also detected and is present in ovary and extragonadal tissues. This mRNA contains an identical coding sequence, but contains an alternatively spliced 5' noncoding exon that is derived from a distinctive promoter. The second model, the R2C Leydig tumor cell line, provides ample contrast. This cell line expresses high basal levels of aromatase (150-200 pmol/h/mg protein) that is suppressed with administration of 8 bromo cAMP or forskolin but the activity is not altered by glucocorticoids or epidermal growth factor treatment. Despite this distinctive pattern of regulation, at least three species of aromatase mRNA are detected in Northern blots, each of which is also detected in rat ovary. Primer extension and S1 nuclease assays indicate that both granulosa cells and R2C cells utilize a promoter that is located approx. 97 nucleotides upstream of the initiator methionine. These studies suggest that the "ovarian" promoter is evolutionarily conserved in both rats and chickens. These results further imply that the genetic mechanisms controlling the diversity of aromatase expression among tissues and among different species are likely to fall into two groups: those that employ distinctive promoters and alternative splicing and those that effect different patterns of regulation through a common ("ovarian") promoter.

The real gordian knot: racemic mixtures versus pure enantiomers.

Many drugs exist as asymmetric three-dimensional (chiral) molecules and will therefore have several stereoisomers. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between enantiomers. The choice between developing a racemate or single enantiomers depends on therapeutic advances and developmental costs involved. Regarding the target environment for drug intervention, even if natural physiological mediators are achiral, their receptors may demonstrate a preference for the (-)- or (+)-enantiomer of agonists or antagonists. It is also obvious that the majority of enzymes and channels are stereospecific, at least to a variable extent. From a pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. With a few exceptions, toxicological differences between isomers of known drugs are less dramatic than thought to be and only seldom substantiate the necessity of a racemic switch. The pharmaceutical industry is currently very interested in the so-called "racemic switch." Before proceeding to a racemic switch it is necessary to determine if 1) it is chemically feasible to produce a single enantiomer; 2) a clinical advantage is obtainable through a racemic switch; and 3) a marketing advantage is obtainable. The real goal of a racemic switch should be the rational development of compounds that are profitable for the company and--first of all--beneficial for the patient.

Carcinogenicity study of lindane in the mouse.

Linadane (gamma-BHC) was investigated for its possible carcinogenic effect on 500 mice (250 males, 250 females) of the Chbi: NMRI (SPF) strain in a study lasting 80 weeks. A substance-related production of tumours was not evident at the dosage levels employed (12.5, 25 and 50 ppm). The tumours found corresponded in type and frequency to those occurring spontaneously in this strain. Electron-microscopical examination of livers, carried our at the same time, provided no evidence of Lindane-induced fine structural hepatocellular alterations.