French Sleepiness Scale for Adolescents-8 items: A discriminant and diagnostic validation.

The objective of the present study was to validate the Short Version of French Sleepiness Scale for Adolescents (FSSA) with eight items (FSSA8). METHODS: A total of 384 adolescents, aged between 12 and 18 years, completed the FSSA8. These included 269 nonclinical adolescents and 115 adolescents admitted for overnight polysomnography and Multiple Sleep Latency Test (MSLT) because of suspected hypersomnia (85 patients with narcolepsy and 30 with other sleep disorders). Item response theory (IRT) assumptions were tested and psychometric properties were analysed. Matching on sex ratio and age was conducted to estimate concurrent criterion, diagnostic validity and cut-offs. RESULTS: IRT assumptions were validated confirming the one-dimensionality of the FSSA8. The latent continuum sleepiness for which the scale and its items are reliable encompassed most of the clinical subjects. FSSA8 is weakly correlated with MSLT. Distribution of scores for the nonclinical group and the clinical group differed significantly; the FSSA8 had very good screening validity in sleep disorders. The cut-off was seven points. CONCLUSION: The FSSA8 appeared to be more reliable for patients than for nonclinical participants and to be a good tool for screening excessive daytime sleepiness in sleep disorders.

The role of sleep laboratory polygraphy in the evaluation of obstructive sleep apnea syndrome in Robin infants.

OBJECTIVE/BACKGROUND: Currently, obstructive sleep apnea syndrome (OSAS) management in Robin sequence (RS) infants has not been standardized. Sleep laboratory polysomnography (PSG) is the gold standard for OSAS diagnosis, however, access is restricted. This study aimed to compare the respiratory indexes measured in a sleep laboratory using PSG as well as a possible alternative, polygraphy (PG). PATIENTS/METHODS: This retrospective study was conducted between 2015 and 2017 in a tertiary hospital. PSG performed in RS infants in the sleep laboratory was analysed by a single reviewer. After sleep data removal, anonymized raw data were analysed to obtain only PG data. Respiratory indexes were compared for (i) PSG and PG and (ii) patients with or without OSAS clinical signs. RESULTS: Among the 20 RS (median [IQR] age: 43 [25-114] days at evaluation), 70% of the patients had OSAS clinical signs but all of them had severe OSAS. The median mixed obstructive apnea hypopnea index was not significantly different between PSG and PG (27/h [18-38] versus 26/h [18-56], p = 0.43). The median obstructive apnea index was higher with no significant difference between PG and PSG (19/h [15-31] versus 7/h [4-25], p = 0.05). The median obstructive hypopnea index was significantly lower on PG than on PSG (2/h [0-3] versus 8/h [8-19], p = 0.01). No difference on PSG or PG was observed for patients with and without clinical signs of OSAS. CONCLUSION: Although PSG remains the gold standard for OSA evaluation, a PG seems to be a useful alternative to measure OSA in RS infants because of their OSAS severity. This evaluation should be recommended in all RS infants, even in the absence of OSAS clinical signs. CLINICAL TRIAL REGISTRATION: Not applicable.

Impact of prone positioning in infants with Pierre Robin sequence: a polysomnography study.

OBJECTIVE/BACKGROUND: Obstructive sleep apnea syndrome (OSA) is frequent in Pierre Robin sequence (PRS) infants. Prone positioning (PP) is commonly recommended but has never been studied by polysomnography (PSG). This study aimed to evaluate the impact of the PP on sleep and breathing outcomes measured by PSG. PATIENTS/METHODS: Retrospective study conducted between 2015 and 2017 in a tertiary hospital. A PSG with pulse oximetry and transcutaneous carbon dioxide was performed in PRS infants in the supine position (SP) and the PP. Sleep and breathing outcome measures were compared between SP and PP. RESULTS: Among the 18 PRS (mean ± SD age: 44 ± 26 days at evaluation), 11 had clinical manifestations of OSA. All had severe OSA diagnosed on PSG. In the PP, infants had a significantly higher sleep efficiency (median [IQR]: 83% [69-90]) than in the SP (70% [55-77], p = 0.04). During REM, there was a trend towards lower OAHI in the PP (50/h [28-82] versus 61/h [40-103], p = 0.05). For 13, the PP was the best sleep position (72%), and for four the SP was the best sleep position (22%; p < 0.01). The PP was sufficient alone to decrease OSA index <10 events/hour in three infants. CONCLUSION: Positioning infants in the PP led to an improvement of sleep quality and an incomplete correction of OSAS in the vast majority of PRS infants. A nocturnal sleep recording seems to be indicated systematically in the early evaluation of these young patients to choose the best therapeutic option for OSAS. CLINICAL TRIAL REGISTRATION: Not applicable.

Stromal-cell-derived factor 1alpha /CXCL12 modulates high-threshold calcium currents in rat substantia nigra.

Dopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal-cell-derived factor 1alpha (CXCL12) but, to date, no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated. We tested the effects of CXCL12 on whole-cell currents of dopaminergic neurons recorded in patch clamp in substantia nigra slices and showed that CXCL12 (0.01-10 nm) increased the amplitude of total high-voltage-activated (HVA) Ca currents through CXCR4 activation. This effect was reversibly reduced by varpi-conotoxin-GVIA, suggesting that CXCL12 acted on N-type Ca currents, known to be involved in dopamine (DA) release. We therefore investigated the effects of CXCL12 on DA release from cultured dopaminergic neurons from the rat mesencephalon. In basal conditions, CXCL12 alone had no effect on DA release. When neurons were depolarized with KCl (20 mm), and thus when HVA Ca currents were activated, low CXCL12 concentrations (1-50 nm) increased DA release via CXCR4 stimulation. These data strongly suggest that the chemokine CXCL12 can act directly as a neuromodulator of dopaminergic neuronal electrical activity through the modulation of HVA currents.

Pathology underrates colon cancer extranodal and nodal metastases; ex vivo radioimmunodetection helps staging.

PURPOSE: Colorectal carcinoma is frequently accompanied by small lymph nodes metastases that often escape pathologic examination. We evaluated whether ex vivo radioimmunodetection with the Affinity Enhancement System (AES) could improve detection of mesocolonic metastases. EXPERIMENTAL DESIGN: A bivalent 111In-labeled hapten was injected (16 patients) 4 days after a bispecific antibody (anticarcinoembryonic antigen, antihapten). Surgery was done 1 to 3 days later, and radioactive uptake in the mesocolon was recorded. Extensive pathologic examination of the mesocolon (reference method) was done after fat dissolution. This method visualizes all lymph nodes but is not in routine use. RESULTS: The reference method disclosed 705 nodes. There was no significant difference between the number of node metastases detected by AES or by the reference method (16 versus 17). Better detection would have been obtained by AES than by routine pathology (P<0.01). In addition 12 extranodal metastases were found in this study of which eight were detected by AES. The prognostic importance of such extranodal metastases has been underlined in the literature. Routine pathology combined with AES would have disclosed all node metastases and 86% of total metastases versus 35% by routine pathology alone. CONCLUSIONS: Ex vivo radioimmunodetection could improve nodal and extranodal metastases detection in patients with colorectal cancer. Its value for improving pathologic analysis, together with the effect of these small metastases on prognosis, should be further evaluated. The benefit of adjuvant chemotherapy for patients upstaged with radioimmunodection should also be assessed because adjuvant chemotherapy improves the 5-year survival of stage III patients.

Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice.

Antibody conjugates were prepared by coupling F(ab')2 or Fab' fragments of an antibody specific for the human high molecular weight-melanoma associated antigen to Fab' fragments of an antibody specific for indium-diethylenetriaminepentaacetate complexes. Monovalent and bivalent haptens were synthesized by reacting the dipeptide tyrosyl-lysine with diethylenetriaminepentaacetic cyclic anhydride. In vitro, the antibody conjugate mediated binding of the 111In-labeled haptens to melanoma cells. In vivo, it allowed specific localization of the haptens in A375 tumors. The bivalent hapten exhibited much higher efficiency at targeting 111In onto cells, both in vitro and in vivo. Antibody conjugate and hapten doses (2 micrograms and 1 pmol, respectively) and the delay between antibody conjugate and tracer injections (24 h) were adjusted to maximize tumor uptake (4% injected dose/g) and tumor to normal tissue contrast (greater than 3) obtained 3 h after injection of the 111In-labeled bivalent hapten. This two-step technique, when compared to direct targeting of 111In-labeled F(ab')2 fragments, provided lower localization of injected activity into the tumor (x 0.25), but higher tumor/tissue ratios, especially with respect to liver (x 7), spleen (x 8), and kidneys (x 10). In addition, high contrast images were obtained within 3 hours, instead of days. Thus, antibody conjugate-mediated targeting of small bivalent haptens, labeled with short half-life isotopes, is proposed as a general method for improving tumor radioimmunolocalization.

Recent advances in pretargeted radioimmunotherapy.

Pretargeted delivery of radionuclides is based upon bispecific immunoconjugates that bind a target tumor antigen and a small molecule carrying the active payload. This strategy is supposed to combine the advantage of antibodies to track tumor cells in vivo and of small radiolabeled molecules that clear rapidly from normal organs and minimize toxicity. Many pretargeting approaches have been proposed, but only those using the biotin/avidin recognition system and those using bispecific anti-tumor x anti-hapten antibodies have been tested in the clinic for both immunoscintigraphy and radioimmunotherapy. Their respective advantages and drawbacks, as well as hurdles in the way of an effective therapy against solid tumors, are discussed. In the light of the encouraging results obtained so far in the clinic, pretargeting remains a most promising challenge for chemistry and biotechnology.

Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and radioimmunoguided surgery.

Patients with recurrent or metastatic medullary thyroid carcinoma (MTC) were referred for pretargeted immunoscintigraphy (Affinity Enhancement System; AES) and radioimmunoguided surgery (RIGS). Data collected from 13 patients establish that whole-body AES immunoscintigraphy revealed metastases < 360 mg and RIGS detected micrometastases (5-15 mg). All tissue samples removed by the surgeon were diagnosed by histology and immunohistochemistry of calcitonin to check the accuracy of IS and RIGS results. AES immunoscintigraphy is very sensitive. Of 34 metastases or recurrences detected, 22 had escaped physical examination or conventional imaging. The accuracy of RIGS was 86%, its sensitivity 75%, and its specificity was 90% (n = 208). IS and RIGS detected occult tumors that would have escaped surgery, clearly demonstrating clinical benefit. Serum calcitonin (normal, 10 pg/ml) and carcinoembryonic antigen (normal, 5 ng/ml) of two patients were restored to normal. In patients whose tumors were discovered, progression of their disease was slowed, as evidenced by the large decrease in serum calcitonin and carcinoembryonic antigen, an important prognostic factor. Surgery was canceled in one case where IS detected distant metastases out of surgical reach. Thus, AES immunoscintigraphy and RIGS might be of valuable help for the surgical management of medullary thyroid carcinoma.

Oral immunization with a free peptide from cholera toxin: local protection and IgA production.

It is frequently of great benefit for good protection against pathogens to elicit a local immunization. For example the importance of antibacterial as well as antitoxin local secretory IgA, for protection against cholera, has been underlined in several studies. We have already reported that oral administration of the peptide corresponding to the 50-75 sequence of cholera toxin (CT) B subunit elicits serum antibodies neutralizing CT activity. In this study we demonstrate that IgA with specificity to CT are present in intestinal secretions of mice immunized orally with the P50-75 or P30-50 peptides of CT B subunit. In addition local protection is observed in the intestine of P50-75 orally immunized mice. These results point out the potential of synthetic peptides as immunogens at the mucosal level.

Robust estimation of the motile cilia beating frequency.

The estimation of the cilia beating frequency (CBF) is of great interest in understanding how the CBF modulates liquid fluxes and how it is controlled by the ciliated cell intra- and/or extracellular medium composition in physiological processes. Motion artifacts and camera defaults may hinder the computation of the frequency variations during long-lasting experiments. We have developed a new analysis approach consisting of a preliminary corrective step (removal of a grid pattern on the image sequence and shift compensation), followed by a harmonic model of the observed cilia using a maximum likelihood estimator framework. It is shown that a more accurate estimation of the frequency can be obtained by averaging the squared Fourier transform of individual pixels followed by a particular summation over the different frequencies, namely the compressed spectrum. Robustness of the proposed method over traditional approaches is shown by several examples and simulations. The method is then applied to images of samples containing ciliated ependymal cells located in the third cerebral ventricle of mouse brains, showing that even small variations in CBF in response to changes in the amount of oxygenation, pH or glucose were clearly visible in the computed frequencies. As a conclusion, this method reveals a fine metabolic tuning of the cilia beating in ependimocytes lining the third cerebral ventricle. Such regulations are likely to participate in homeostatic mechanisms regulating CSF movements and brain energy supply.

(68)Ga-AMBA and (18)F-FDG for preclinical PET imaging of breast cancer: effect of tamoxifen treatment on tracer uptake by tumor.

INTRODUCTION: AMBA is a bombesin analogue that binds to GRPr. In a mouse model of estrogen-dependent human breast cancer, we tested whether (68)Ga-AMBA can be used for PET detection of GRPr-expressing tumors and could be more accurate than (18)F-FDG to monitor tumor response to hormone therapy. METHODS: The radiolabeling of (68)Ga-AMBA was automated using a R&D Synchrom module. ZR75-1, a breast cancer cell line, was xenografted in nude mice. (68)Ga-AMBA tumor uptake was compared with that of (18)F-FDG before and after treatment with tamoxifen. RESULTS: AMBA was (68)Ga-radiolabelled in 30min with 95.3% yield and purity≥98%. Prior to treatment, (68)Ga-AMBA was highly concentrated into tumors (tumor to non-tumor ratio=2.4 vs. 1.3 with (18)F-FDG). With tamoxifen treatment (n=6) (68)Ga-AMBA uptake plateaued after 1week and decreased after 2weeks, with a significant reduction compared to controls (n=4). In contrast the effect of tamoxifen treatment could not be appreciated using (18)F-FDG. CONCLUSIONS: (68)Ga-AMBA appeared better than (18)F-FDG to visualize and monitor the response to hormone treatment in this breast cancer model.

Alpha2-adrenoceptor activation increases a cationic conductance and spontaneous GABAergic synaptic activity in dopaminergic neurones of the rat substantia nigra.

Noradrenaline (NA) plays an important role in compensating for the loss in dopaminergic (DA) function following lesions of the DA neurones of the substantia nigra (SN). Alpha2-adrenoceptors are largely expressed in these neurones, but the cellular response to their activation is unknown. Whole-cell patch-clamp recordings were made from DA neurones of rat SN. At a holding potential of -60 mV, bath application of NA (50 microM) induced an inward current (-20.3+/-10.0 pA) in 50% of the recorded neurones. This effect was mimicked by UK-14304 (50 microM), a specific alpha2-adrenoceptor agonist, whereas alpha1-adrenoceptor and beta-adrenoceptor agonists failed to induce a response. Surprisingly, alpha2-adrenoceptor antagonists (idazoxan, RX-811059, SKF-86466 and yohimbine) also induced an inward current that could occlude the one induced by UK-14304, suggesting that they may act as alpha2-adrenoceptor agonists. The inward current results from an increase in cationic conductance identical to the one previously described in these neurones, as neurotensin (1 microM), known to activate it, occluded the inward current induced by UK-14304. In addition, GABAergic miniature inhibitory postsynaptic current frequency was increased by activation of presynaptic alpha2-adrenoceptors. We conclude that the effects of NA on alpha2-adrenoceptors can contribute to the previously described composite action of NA on DA neurone firing and can be pharmacologically differentiated from the effect of NA on DA and neighbouring neurones known to be mediated through alpha1-adrenoceptors.

Two-step targeting of xenografted colon carcinoma using a bispecific antibody and 188Re-labeled bivalent hapten: biodistribution and dosimetry studies.

UNLABELLED: Radioimmunotherapy (RIT) is currently being considered for the treatment of solid tumors. Although results have been encouraging for pretargeted 131I RIT with the affinity enhancement system (AES), the radionuclide used is not optimal because of its long half-life, strong gamma emission, poor specific activity, and low beta particle energy. 188Re, though unsuitable for direct antibody labeling, could be used with the AES two-step targeting technique. The purpose of this study was to compare the distribution and dosimetry of a bivalent hapten labeled with 188Re or 125I. For dosimetry calculations and biodistribution data, 125I was substituted for 131I. METHODS: After preliminary injection of a bispecific anticarcinoembryonic antigen (CEA) or antihapten antibody (Bs-mAb F6-679), AG 8.1 or AG 8.0 hapten radiolabeled with 188Re or 125I was injected into a nude mouse model grafted subcutaneously with a human colon carcinoma cell line (LS-174-T) expressing CEA. A dosimetry study was performed for each animal from the concentration of radioactivity in tumor and different tissues. RESULTS: Radiolabeling of AG 8.1 with 125I afforded a 40% yield with a specific activity of 11.1 MBq/nmol after purification. Radiolabeling of AG 8.0 with 188Re afforded a 72% yield with a specific activity of 31.82 MBq/nmol. In all experiments, the percentage of tumor uptake of 125I-AG 8.1 was always significantly greater than that of 188Re-AG 8.0. The corresponding tumor-to-tissue ratios reflected uptake values. The least favorable tumor-to-normal tissue ratios in the dosimetry study were 8.1 and 8.5 for 131I (tumor-to-blood ratio and tumor-to-kidney ratio, respectively) and 2.3 for 188Re (tumor-to-intestine ratio). CONCLUSION: This study indicates that 188Re can be used for radiolabeling of hapten in two-step radioimmunotherapy protocols with the AES technique. 188Re has a greater range than 131I, which should allow the treatment of solid tumors around 1 cm in diameter. Although the method used for hapten radiolabeling did not provide optimal tumor uptake, the use of a bifunctional chelating agent associated with AG 8.1 should solve this problem.

Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEA/anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer.

Two-step radioimmunotargeting using a bispecific anti-CEA/anti-in-DTPA monoclonal antibody and an 111In-labeled DTPA dimer (diDTPA-TL) was evaluated nine times in eight patients with medullary thyroid cancer (MTC). Immunoscintigraphy was performed 5 and 24 hr after injection of 111In-diDTPA-TL. For five patients, radioimmunoguided surgery (RIGS) was performed using a hand-held gamma probe (sodium iodine), and a biodistribution study was performed 48 hr (four times) and 24 hr (one time) after injection of 111In-diDTPA-TL. Mean tumor uptake (%ID/kg in tumor) was 39 (range 2.75-139). In these five patients, immunoscintigraphy visualized all known tumors and detected unknown foci (US and CT were negative) in the neck (once) and neck and liver (once). Immunoscintigraphy, performed four times in search of a recurrence, detected unknown localizations in the mediastinum and neck (twice) and was negative twice. There were no false-positives. In three of five patients who had surgery, RIGS localized tumor foci not detected by the surgeon. RIGS failed to detect two small lesions (10 x 10 mm) corresponding to sites of fibrosis and microscopic cancer infiltration. Bispecific anti-CEA/anti-In-DTPA mediated targeting of 111In-diDTPA-TL provided elevated tumor uptake and tumor-to-normal tissue ratios. Radioimmunodetection of small MTC lesions is thus possible even when morphological imaging techniques prove negative.

Bispecific monoclonal antibody-mediated targeting of an indium-111-labeled DTPA dimer to primary colorectal tumors: pharmacokinetics, biodistribution, scintigraphy and immune response.

Eleven patients with primary colorectal carcinoma tumors (4 +/- 2 cm) were given intravenous injections of 1-10 mg of an anti-CEA, anti-In-DTPA bispecific Fab'-Fab monoclonal antibody, and 2-8 days later, were injected with 1.2-4.2 nmol of an 111In-labeled DTPA dimer (6 mCi). The bispecific antibody exhibited good stability and F(ab)'2-like pharmacokinetics. After injection, the 111In-DTPA dimer distributed in a large volume (88 ml/kg-180 ml/kg) and cleared through the kidneys (mean residence time in the whole body: 9 hr-16 hr). Uptake of 111In by the tumor using this two-step technique (1.8%-17.5% injected dose ID/kg, measured from surgical samples 48 hr after hapten injection) was not found significantly lower than that achieved with our reference 111In-labeled anti-CEA F(ab)'2 1 to 4 days after injection in six patients with similar clinical status (5.5%-30.2% ID/kg). In addition, tumor-to-blood and tumor-to-liver uptake ratios were significantly improved (blood 7.8 versus 4.2, liver 2.8 versus 0.8). As a result, low background images allowed detection of 12 of 13 lesions, 4 hr and 24 hr after hapten injection. However, 7 of 11 patients developed HAMA.

Potentiation by low doses of selected neuroleptics of food-induced conditioned place preference in rats.

Numerous data support the hypothesis that dopamine (DA) plays a crucial role in reward-related processes and in incentive learning in animals and man. The possibility that various neuroleptics exhibiting a high affinity for the dopaminergic D2 (and D3) receptors could reinforce DA transmission was studied using the conditioned place preference paradigm (CPP) in rats. This was done by examining the ability of these compounds to potentiate the reinforcing properties of food in hungry rats subjected to a version of the CPP paradigm which consisted of repeated pairings of food with a single environmental cue, the floor texture of an open field. During the test session when food was no longer available in the open field, the increase in the time spent by drug-free rats on the food-paired texture was assumed to indicate the perceived rewarding value of the food. This time was significantly lengthened when the specific D2 (D3)-receptor antagonists sulpiride (4 mg/kg), amisulpride (0.5, 1 mg/kg) or pimozide (0.03, 0.06 mg/kg) were administered before the food conditioning sessions. Larger doses of these compounds as well as haloperidol, metoclopramide and the non-specific D1-D2 antagonist, chlorpromazine, regardless of the doses tested, did not exhibit this effect, but rather reduced the food-induced CPP, an action usually associated with neuroleptics. The positive effects of amisulpride was reversed by a D1 receptor antagonist, SCH 23390 (0.01 mg/kg). These results suggest that, as with amphetamine (0.5 mg/kg), some D2-specific neuroleptics enhance the incentive value of food in a narrow range of low doses, an effect proposed to reflect a "prohedonic" property.(ABSTRACT TRUNCATED AT 250 WORDS)

Thalamic low threshold calcium current in a genetic model of absence epilepsy.

The low threshold calcium current (IT) in thalamo-cortical neurones contributes to the generation of spike and wave discharges (SWDs) characteristic of generalized, non-convulsive absence epilepsy. The biophysical properties of this current were analysed in dorsal lateral geniculate neurones from the Genetic Absence Epilepsy Rats from Strasbourg (GAERS+). No difference was found in the voltage dependence and kinetics of IT between GAERS+ and rats of the non epileptic control strain (GAERS-). Thus, a dysfunction of IT does not appear to underlie the occurrence of SWDs in absence epilepsy.

Pretargetted imaging of colorectal cancer recurrences using an 111In-labelled bivalent hapten and a bispecific antibody conjugate.

In 11 patients recurrence of colorectal cancer was suspected by a rise in serum carcinoembryonic antigen (CEA) (nine cases), by a subocclusive clinical situation (one case) or by endoscopy (on an anastomosis, one case). Two-step tumour targetting was performed by a first injection of 0.1 mg kg-1 of unlabelled bispecific antibody conjugate (an anti-CEA Fab' fragment chemically coupled to an anti-diethylene triamine pentaacetate (DTPA)-indium fragment) followed 4 to 5 days later by injection of the bivalent DTPA hapten labelled with 5 to 8 mCi 111In. Planar scintigraphy, single photon emission computed tomographic (SPECT) 360 degrees acquisitions and whole-body scans were obtained 4.5 and 24 h after injection of the radiolabelled hapten. Biodistribution was determined for eight patients at 48 h. The final diagnosis was confirmed histologically in nine patients (eight by second-look surgery, one by laparotomy). Overall, results were one true negative (1-year follow-up) and 10 true positive; however, for the three large liver metastases (3 to 6 cm), only the periphery of the metastasis had high uptake compared to normal liver. For pelvic recurrences, immunoscintigraphic (IS) contrast was better for small tumours. The highest tumour uptake was found for a 1 cm diameter pelvic recurrence (7.2% i.d. kg-1). Mean tumour-to-blood ratios were 6.4. Thus, this two-step tumour targetting technique, which uses a bispecific antibody conjugate and an 111In-labelled bivalent hapten injected sequentially without chasing the excess bispecific antibody, provided satisfactory results in this preliminary clinical trial for detection of recurrent colorectal cancers.

[Immunotargeting of tumors: state of the art and prospects in 2000]. / Immunociblage des tumeurs: situation et perspectives en 2000.

Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal antibodies directed against tumor associated antigens shows now important clinical developments. This is mainly due to encouraging therapeutic results which have obtained using humanized antibodies such as the anti-CD20 rituximab in follicular B lymphomas and the anti-DrbB2 herceptin in breast carcinomas. Thanks to genetic engineering it is possible to graft variable or hypervariable regions from murine antibodies to human IgG, and even to obtain fully human antibodies by using either transgenic mice containing a large part of the human repertoire of human IgG, or selection of human antibody fragments expressed by phages. Radiolabeling of antibodies played a major role to demonstrate the tumor immunotargeting specificity and remains attractive for the diagnosis by immunoscintigraphy as well as for the treatment by radioimmunotherapy of some cancers. In this review, the current results and the prospects of diagnostic and therapeutic uses of anti-tumor antibodies and their fragments will be described. Concerning diagnosis, 123-iodine or 99m-technetium labeled Fab fragments allowed very demonstrative tumor images but this technique has a limited effect upon the therapeutic attitude. Immuno-PET (positron emission tomography) could enhance the sensitivity of this imaging method. Radio-immunoguided surgery and immunophotodetection are attractive techniques still under evaluation. Concerning therapy, 131-iodine labeled anti-CD20 antibodies gave spectacular results in non-Hodgkin's B lymphomas. In solid tumors which as less radiosensitive, radioimmunotherapy could concern small tumors and need the use of two-steps targeting and/or alpha emitters radioisotopes. Some other strategies will be described such as bispecific antibodies directed against tumors and immune effector cells, some antibody fragments expressed on T cells called T-bodies or some biological studies using intrabodies. Published data and works in progress demonstrate that immunotargeting of tumors will have a growing place in the treatments of cancer patients.

Adverse effects of two nights of sleep restriction on the hypothalamic-pituitary-adrenal axis in healthy men.

CONTEXT: Insufficient sleep is associated with increased cardiometabolic risk. Alterations in hypothalamic-pituitary-adrenal axis may underlie this link. OBJECTIVE: Our objective was to examine the impact of restricted sleep on daytime profiles of ACTH and cortisol concentrations. METHODS: Thirteen subjects participated in 2 laboratory sessions (2 nights of 10 hours in bed versus 2 nights of 4 hours in bed) in a randomized crossover design. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 9:00 am to midnight to measure ACTH and total cortisol. Saliva was collected every 20 minutes from 2:00 pm to midnight to measure free cortisol. Perceived stress, hunger, and appetite were assessed at hourly intervals by validated scales. RESULTS: Sleep restriction was associated with a 19% increase in overall ACTH levels (P < .03) that was correlated with the individual amount of sleep loss (rSp = 0.63, P < .02). Overall total cortisol levels were also elevated (+21%; P = .10). Pulse frequency was unchanged for both ACTH and cortisol. Morning levels of ACTH were higher after sleep restriction (P < .04) without concomitant elevation of cortisol. In contrast, evening ACTH levels were unchanged while total and free cortisol increased by, respectively, 30% (P < .03) and 200% (P < .04). Thus, the amplitude of the circadian cortisol decline was dampened by sleep restriction (-21%; P < .05). Sleep restriction was not associated with higher perceived stress but resulted in an increase in appetite that was correlated with the increase in total cortisol. CONCLUSION: The impact of sleep loss on hypothalamic-pituitary-adrenal activity is dependent on time of day. Insufficient sleep dampens the circadian rhythm of cortisol, a major internal synchronizer of central and peripheral clocks.