Gastrectomy with or without omentectomy for cT3-4 gastric cancer: a multicentre cohort study.

BACKGROUND: Omentectomy is performed widely for locally advanced gastric cancer to prevent disease recurrence. However, its clinical benefit is unknown. METHODS: This retrospective cohort study compared the outcome of gastrectomy with preservation of the omentum (GPO) and gastrectomy with resection of the omentum (GRO) among patients with cT3-T4 gastric cancer who underwent gastrectomy between 2006 and 2012 in one of five participating institutions. A consensus conference identified 28 variables potentially associated with outcome after gastrectomy for the estimation of propensity scores, and propensity score matching (PSM) was undertaken to control for possible confounders. Postoperative surgical outcomes, overall survival and disease recurrence were compared between GPO and GRO. RESULTS: A total of 1758 patients were identified, of whom 526 remained after PSM, 263 in each group. Median follow-up was 4·9 (i.q.r. 3·1-5·9) years in the GRO group and 5·0 (2·5-6·8) years in the GPO group. The incidence of postoperative complications of Clavien-Dindo grade III or more was significantly higher in the GRO group (17·5 versus 10·3 per cent; P = 0·016). Five-year overall survival rates were 77·1 per cent in the GRO group and 79·4 per cent in the GPO group (P = 0·749). There were no significant differences in recurrence rate or pattern of recurrence between the groups. CONCLUSION: Overall survival and disease recurrence were comparable in patients with cT3-4 gastric cancer who underwent GPO or GRO.

ANTECEDENTES: La omentectomía se realiza ampliamente en el cáncer gástrico localmente avanzado para prevenir la recidiva de la enfermedad. Sin embargo, se desconoce su beneficio clínico. MÉTODOS: Este estudio retrospectivo comparó el resultado de la gastrectomía con preservación del omento (gastrectomy with preservation of the omentum, GPO) con la gastrectomía con resección del omento (gastrectomy with resection of the omentum, GRO) para el cáncer gástrico con estadio clínico T3/T4. Se incluyeron pacientes sometidos a gastrectomía por cáncer gástrico clínico T3/T4 (2006-2012) y se recogieron datos relevantes de 5 hospitales participantes. A través de una conferencia de consenso se identificaron 28 variables potencialmente asociadas con el resultado tras la gastrectomía, mediante las cuales se estimaron las puntuaciones de propensión, utilizándose el emparejamiento por puntuación de propensión (propensity score matching, PSM) para el control de posibles factores de confusión. Los resultados quirúrgicos postoperatorios, la supervivencia global y la recidiva de la enfermedad se compararon entre las gastrectomías con GPO y GRO. RESULTADOS: En total, se identificaron 1.758 pacientes, seleccionándose 526 (263 GRO y 263 GPO) tras el PSM. La mediana (rango intercuartílico) de seguimiento fue de 4,9 años (3,1-5,9) en el grupo GRO y de 5,0 años (2,5-6,8) en el grupo GPO. La incidencia de complicaciones postoperatorias de Clavien-Dindo grado III o más alto fue significativamente más elevada en el grupo GRO que en el grupo GPO (17,1% versus 9,1%; P = 0,010). La supervivencia global a los 5 años fue del 77,1% para el grupo GRO y del 79,4% para el grupo GPO (P = 0,749). No hubo diferencias estadísticamente significativas en la tasa de recidiva o patrón de recidiva entre ambos grupos. CONCLUSIÓN: La supervivencia global y la recidiva de la enfermedad son comparables en pacientes con cáncer gástrico estadio clínico T3-4 sometidos a GPO o GRO.

12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs.

BACKGROUND: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. METHODS: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. RESULTS: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. CONCLUSION: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer.

BACKGROUND: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). PATIENTS AND METHODS: Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set. RESULTS: Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate. CONCLUSIONS: We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.

Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylate.

Imatinib mesylate (IM) is currently used as the first therapeutic choice against chronic myelogenous leukaemia (CML). Because IM poorly penetrates the blood-brain barrier, IM-treated CML patients may have a potential risk of central nervous system (CNS) involvement. Here we report a case with lymphoid blast crisis isolated only in CNS after bacterial meningitis, although the patient achieved and maintained complete cytogenetic response by IM therapy. It is important to consider isolated CNS blast crisis as a possible event in IM-treated CML patients.

Epstein-Barr virus renders the infected natural killer cell line, NKL resistant to doxorubicin-induced apoptosis.

We established two Epstein-Barr virus (EBV)-infected NKL sublines, which acquired stress resistant phenotype against DNA damage and starvation compared with EBV-negative NKL. EBV-rendered doxorubicin resistance at least partially through NF-kappaB activation and the resultant sustenance of antiapoptotic proteins including Bcl-X(L) and FLIP(L/S).

Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia.

Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3ach/SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3ach mice was significantly ameliorated in Fgfr3ach/SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic potential of CNP for treatment of midfacial hypoplasia and foramen magnum stenosis in achondroplasia.

Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp.

Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54±0.094 U/mg protein and 0.57±0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75±0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III ß-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen.

Cloning of cDNA for rat eosinophil major basic protein.

We have determined the complete nucleotide sequence for the cDNA encoding rat eosinophil major basic protein (MBP) using the rapid amplification of cDNA ends (RACE) procedure. The deduced amino acid sequence revealed that the rat prepro-MBP has three functional domains, namely the signal peptide, the acidic peptide that contains numerous acidic amino acids, and the mature MBP, as in human and guinea pig MBP.

Establishment of a CD4-positive plasmacytoma cell line (AMO1).

A human plasmacytoma cell line (AMO1) was established. The AMO1 cells had the light and electron microscopic characteristics typical of plasmacytoma cells and did not harbor Epstein-Barr virus. These cells expressed cytoplasmic immunoglobulin A kappa and the immunoglobulin heavy-chain gene (JH) and kappa light-chain gene (C kappa) were rearranged. Coexpression of a CD4 antigen and plasma cell antigens (CD38 and PCA-1) was an unusual and sustained feature. Neither the T-cell receptor beta nor the gamma chain gene displayed the rearranged form. Other lineage-specific surface antigens, namely T, B, monocytoid, and myeloid antigens, were all negative in AMO1. In accordance with the surface CD4 expression, polymerase chain reaction analysis indicated constitutive expression of CD4 mRNA, and the cytogenetic findings revealed that AMO1 cells had a derivative chromosome 12, which had a structural abnormality of the short arm carrying the CD4 gene locus. These findings provide strong evidence for the presence of CD4-positive malignant plasma cells and raise the possibility that the CD4 expression in the AMO1 cell line is closely associated with the derivative chromosome.

DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions.

Natural killer (NK) cell-type lymphoproliferative disease of granular lymphocytes (LDGL) is characterized by the outgrowth of CD3(-)CD16/56(+) NK cells, and can be further subdivided into two distinct categories: aggressive NK cell leukemia (ANKL) and chronic NK lymphocytosis (CNKL). To gain insights into the pathophysiology of NK cell-type LDGL, we here purified CD3(-)CD56(+) fractions from healthy individuals (n=9) and those with CNKL (n=9) or ANKL (n=1), and compared the expression profiles of >12 000 genes. A total of 15 'LDGL-associated genes' were identified, and a correspondence analysis on such genes could clearly indicate that LDGL samples share a 'molecular signature' distinct from that of normal NK cells. With a newly invented class prediction algorithm, 'weighted distance method', all 19 samples received a clinically matched diagnosis, and, furthermore, a detailed cross-validation trial for the prediction of normal or CNKL status could achieve a high accuracy (77.8%). By applying another statistical approach, we could extract other sets of genes, expression of which was specific to either normal or LDGL NK cells. Together with sophisticated statistical methods, gene expression profiling of a background-matched NK cell fraction thus provides us a wealth of information for the LDGL condition.

Nitric oxide blocks the cell cycle of mouse macrophage-like cells in the early G2+M phase.

The effects of nitric oxide produced by macrophage-like cells (Mm1) on the cell cycle were investigated. Mm1 cells lost proliferative activity in the presence of interleukin-6 (IL-6) and a subpopulation accumulated in the G2+M phase. This level increased in proportion to the incubation time. The DNA content of the cells was slightly lower than that of Mm1 cells treated with vinblastine or demecolcine, drugs which block the cell cycle in the M phase. The peak of the early G2+M phase was reduced by treatment with NG-mono-methyl-L-arginine. However, after treatment with exogenous nitric oxide or sodium nitroprusside, the G0/G1 phase increased, but the early-G2+M and the S phase decreased. The flow cytometry pattern in IL-6-treated Mm1 was the same as that of cytochalasin B-treated Mm1. These data suggest that endogenous nitric oxide affects the microfilament system of IL-6-treated Mm1 cells and blocks the cell cycle in the early G2+M phase.

Polyamine inhibition of gastric ulceration and secretion in rats.

The effect of polyamines on gastric ulceration and secretion in rats was studied. Stress-induced gastric ulceration and ulceration in pylorus-ligated rats were inhibited by subcutaneous or oral administration of spermine; spermidine's inhibitory effect was somewhat less. Histamine-induced ulceration was also inhibited by the subcutaneous injection of spermine. In addition, the daily oral administration of spermine for 10 days was therapeutic against an acetic acid-induced ulcer (chronic ulcer). Gastric secretion in pylorus-ligated rats and in rats with fistulae and stimulated by histamine injection was decreased by the subcutaneous injection of spermine.

Structure-activity characterization of an H2-receptor antagonist, 3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-++ +butenylamino]- 3-cyclobutene-1,2-dione hydrochloride (T-066), involved in the insurmountable antagonism against histamine-induced positive chronotropic action in guinea pig atria.

IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino]-3-cyclobutene-1,2-dione hydrochloride), an H2-receptor antagonist, shows highly potent, time-dependent, and irreversible antagonism at H2-receptors. We identified the structurally important parts of IT-066 involved in its interaction with the H2-receptor, and explored its unique mode of action by investigating the H2-receptor blocking action of IT-066 and related compounds in guinea pig isolated atria. IT-066 is structurally divided into three different parts: a tertiary amine and hydrophobic group, a connecting carbon chain, and a polar group. Though the replacement of its pyridine ring with a benzene ring maintained the mode of the H2-receptor blocking action of IT-066, the oxidation of the piperidine ring completely attenuated this blocking action. By replacing the connecting carbon chain of IT-066, cis-2-butene, with butane, trans-2-butene, or 2-butyne, the irreversible antagonism disappeared and the potency was reduced. On the other hand, BMY25368, whose connecting carbon chain is trimethylene, showed irreversible antagonism comparable to that of IT-066. Hydrolysis of the polar group of IT-066 completely attenuated the H2-receptor blocking activity. Among the compounds tested, only the compound that had 3,4-diamino-3-cyclobutene-1,2-dione as a polar group showed time-dependent and insurmountable H2-receptor blocking action. These data suggest the importance of the following structural features of IT-066: the piperidine ring of IT-066 and -NH2 in its polar group are essential for the interaction with the H2-receptor; and the 3,4-diamino-3-cyclobutene-1,2-dione group and the connecting carbon chain of IT-066 are crucial for determining the irreversibility of H2-receptor blocking action, though the connecting carbon chain is replaceable with another chain with appropriate length and configuration.

Up-regulation of telomerase in primary cultured rat hepatocytes.

Telomerase is a unique reverse transcriptase involved in the maintenance of telomeric DNA, which is generally undetectable in normal human somatic cells. However, it has been found in organs of normal adult rodents including the liver. In order to elucidate relevant control mechanisms operating in normal somatic cells, we examined telomerase activity in primary cultured rat hepatocytes. During culture under serum-free conditions, rat hepatocytes rapidly lose the ability of organ-specific expression of serum albumin, apolipoprotein A-I, and hepatocyte nuclear factor 4, and the capacity for cytochrome P-450 induction by xenobiotics. The telomerase activity was found to be concomitantly increased about 2. 5-fold at 48 h and 3-fold at 72 h. Northern blot and RT-PCR analyses with primary cultured hepatocytes revealed the associated accumulation of rat telomerase RNA subunits (TR), and the mRNAs for a telomerase reverse transcriptase (TERT) and a telomerase-associated protein (TEP1). The activity of hepatocyte telomerase, which was elevated during the primary culture, increased further when the cells were stimulated with hepatocyte growth factor. In this case, however, the levels of TR, TERT, and TEP1 mRNA did not show any detectable changes.

Usefulness of metyrapone treatment to suppress cancer metastasis facilitated by surgical stress.

BACKGROUND: One causative factor of tumor metastasis enhanced by surgical stress is thought to be hypersecretion of endogenous glucocorticoids. This study evaluated the effectiveness of metyrapone treatment and adrenalectomy in preventing the harmful effects of glucocorticoids in the enhancement of tumor metastasis resulting from surgical stress. METHODS: The effect of dexamethasone on pulmonary metastasis of MRMT-1 cells and on the number of peripheral lymphocytes was evaluated in rats. To evaluate the suppressive effect of adrenalectomy and metyrapone treatment on operation-induced enhancement of metastasis, several parameters such as induction of pulmonary metastasis, serum corticosterone levels, and the number of blood lymphocytes and apoptotic thymocytes were determined. RESULTS: With dexamethasone treatment, the number of peripheral lymphocytes rapidly decreased; in contrast, pulmonary metastasis increased. The serum corticosterone level was doubled at 1 hour, apoptotic thymocyte numbers were increased about sevenfold at 3 hours and about fourfold at 6 hours, and blood lymphocyte numbers were decreased at 3 hours after laparotomy, which facilitated about a 10-fold increase in the pulmonary metastasis. These changes were almost completely suppressed by preoperative adrenalectomy and metyrapone treatment. CONCLUSIONS: Preoperative metyrapone treatment, which suppresses hypersecretion of endogenous glucocorticoids as a result of operation, modulates the enhancement of cancer metastases and may be an effective treatment.

Femoro-internal carotid artery bypass for cerebral ischemia in takayasu's arteritis.

In two patients with Takayasu's arteritis, severe cerebral ischemia was successfully treated by femoral to internal carotid artery bypass using a polytetrafluoroethylene (PTFE) graft through a subcutaneous tunnel. All of the arch branches were critically stenotic or occluded in both patients. The entire thoracic aorta was affected by the active inflammation process in one patient and there was marked calcification in the other patient. In these situations we hesitate to use the thoracic aorta as the donor site of bypass. Considering that Takayasu's arteritis affects the thoracic aorta and the proximal portions of its branches, the femoro-internal carotid artery bypass can be constructed without involving severely diseased vessels and can be expected to result in good cerebral revascularization.

AVP rhythm in the suprachiasmatic nucleus in relation to locomotor activity under constant light.

To examine the roles of Arg-vasopressin (AVP)- and vasoactive intestinal peptide (VIP)-containing neurons in the suprachiasmatic nucleus (SCN) in production of circadian rhythmicity of locomotor activity, variations in the contents of AVP and VIP in punched-out SCN tissue and locomotor activity were measured under a light-dark cycle as well as under conditions of constant light for up to 3 weeks. Under the light-dark cycle, contents of AVP and VIP, and locomotor activity showed marked circadian rhythmicity. Under constant light, AVP content showed circadian rhythmicity until 3 weeks, while VIP rhythm disappeared from the first week with decreases in its content. Locomotor activity showed a free-running circadian rhythm for more than 3 weeks under constant light conditions in most cases. These results suggest that AVP but not VIP in the SCN may be involved in the generation of locomotor activity rhythm under conditions of constant light.

GABAergic control of Arg-vasopressin release from suprachiasmatic nucleus slice culture.

gamma-Aminobutyric acid (GABA) is contained in many neurons in the suprachiasmatic nucleus (SCN), and is considered to be a circadian entraining factor. Arg-vasopressin (AVP)-containing neurons represent one of the output paths from the SCN to other brain areas. We examined the effects of GABA, muscimol (GABA-A agonist), bicuculline (GABA-A antagonist), baclofen (GABA-B agonist) and phaclofen (GABA-B antagonist) on AVP release using SCN slice preparations in culture. SCN slices were prepared from coronally sliced brain tissue and cultured in organic tissue culture dishes with DMEM/N2 medium in a CO2 (5%) incubator. The culture medium was changed at 3-h intervals until 9 h after 3 h application of each drug. Concentrations of AVP in 1 ml aspirates of the medium were analyzed by EIA. Muscimol (1, 10 microM) increased and bicuculline (1, 10, 100 microM) decreased the AVP release 3-6 h after application. However, baclofen and phaclofen had no apparent effects on AVP release. Riluzole (0.1 mM) and nipecotic acid (1 mM), GABA uptake inhibitors, increased AVP release 3-6 h after application. These results indicate that GABA promotes AVP release mediated by GABA-A receptors in the SCN.

Circadian rhythm of Arg-vasopressin contents in the suprachiasmatic nucleus in relation to corticosterone.

Circadian rhythms of locomotor activity and adrenal glucocorticoid are controlled by the suprachiasmatic nucleus (SCN), the center of a biological clock, in mammals. Arg-vasopressin (AVP) contents in the SCN play a role in endogenous circadian rhythm during the absence of time cues. The AVP-containing neurons in the SCN are considered to transmit a circadian signal to the other parts of the brain. The circadian rhythms of AVP in the SCN in relation to the plasma corticosterone and locomotor activity were investigated. Under the light-dark cycle, plasma corticosterone levels were reciprocally correlated with the AVP content in the SCN. Under free-running conditions with constant dim light, AVP rhythms were reciprocally synchronized with the locomotor activity. The correlation of AVP with plasma corticosterone is different at different times of the day both under the LD cycle and constant dim light. Dexamethasone (i. p., 0.1 mg/100) increased the AVP contents, and this tendency was significantly greater during the dark period. These results indicate that corticosterone in the blood may regulate the circadian rhythm through AVP variation in the SCN.

Circadian rhythm of drinking and running-wheel activity in rats with 6-hydroxydopamine lesions of the ventral tegmental area.

Circadian rhythms in drinking and running-wheel (locomotor) activity of rats with 6-hydroxydopamine (6-OHDA, 4 microg/2 microl per rat)-induced lesions in the ventral tegmental area (VTA) were examined under a light-dark (LD) cycle and constant dim light (5 lux). Under the LD cycle, the length of the locomotor activity period was decreased during the dark, and increased during the light period in the lesioned rats. Under the constant dim light conditions, the free-running circadian period (tau) of drinking and activity rhythm was longer in lesioned rats than in sham-operated controls. The elongation of the circadian period was accompanied by decrements in activity. These observations suggest that the mesolimbic dopaminergic system modulates rhythms in circadian drinking and locomotor activity.