Underestimated caregiver burden by cancer patients and its association with quality of life, depression and anxiety among caregivers.

This study examined how patients with cancer estimate caregiver burden (CB) and the association between their underestimation of CB and their caregivers' self-ratings of their quality of life (CQOLC-K; Korean version of the Caregiver Quality of Life Index-Cancer), depression and anxiety (Korean version of the Hospital Anxiety and Depression Scale). Participants consisted of 990 patient-caregiver dyads recruited from a nationwide cross-sectional survey conducted in South Korea. Medical baseline data were retrieved from the hospital information systems of the participating centres. The patients with cancer who underestimated CB ranged from 18.62% (for physical CB) to 23.33% (for social CB). They had less advanced cancer, a lower income, were the caregiver's spouse, reported higher levels of family avoidance of communication about cancer, and had female caregivers. The patients' underestimation of CB was significantly related to lower CQoL and higher levels of caregiver depression and anxiety. The current study provides empirical evidence for the link between the underestimation of CB by patients with cancer and compromised caregiving experiences of cancer caregivers. Open family communication about cancer was discussed as one of several practical strategies for decreasing patients' underestimation of CB.

Clinical heterogeneity of extranodal NK/T-cell lymphoma, nasal type: a national survey of the Korean Cancer Study Group.

BACKGROUND: This national survey was undertaken to propose the classification of extranodal natural killer (NK)/T-cell lymphoma (NTCL) subtypes and to clarify a clinical heterogeneity. PATIENTS AND METHODS: Two hundred and eighty patients newly diagnosed as NTCL were enrolled from 22 Korean medical centers. Two subsets were compared: one involving the upper aerodigestive tract (UAT) and another involving the non-upper aerodigestive tract (NUAT) region, which comprises the skin, gastrointestinal tract, and liver or soft tissues. Clinical prognostic factors, survival outcomes, and independent predictors for survival were compared between each subset. RESULTS: NUAT-NTCL (59 patients) had significantly higher proportions of disseminated disease, aggressive biologic features, and unfavorable host reactions compared with UAT-NTCL (221 patients). NUAT-NTCL had shortened 5-year overall survival (OS) (22% versus 41%, P = 0.001). Ann Arbor staging, the International Prognostic Index, and the NTCL prognostic index failed to predict the OS of NUAT-NTCL, but did predict the OS in UAT-NTCL. Independent predictors for OS by multivariate analyses differed between each subset. In the NUAT subset, extranodal sites and regional nodes predicted the OS, while Ann Arbor staging, age, performance status, and lactate dehydrogenase level predicted the OS in the UAT subset. CONCLUSION: NUAT-NTCL may represent a distinctive disease entity in terms of clinical factors, independent predictors, and survival outcomes.

Macrophage nitric oxide synthesis delays progression of ultraviolet light-induced murine skin cancers.

The role of macrophages in the host immune response against cancers remains uncertain. Since nitric oxide synthesis represents a significant macrophage antitumor mechanism in vitro, we evaluated whether NO was synthesized during the immune response to growing murine skin cancers. NO synthesis was readily detectable in enzymatically dissociated tumors (RD-995 and LR-298) and was inhibited by N omega-monomethyl-L-arginine (MLA) and by macrophage depletion. Nitrosylation of iron-sulfur and heme complexes was observed in these tumors using electron paramagnetic resonance spectroscopy. NO production in the presence of increasing concentrations of MLA correlated inversely with tumor cell proliferation in vitro. To elucidate the role of NO during in vivo tumor progression, tumor-bearing mice were treated with continuous infusions of the nitric oxide synthase inhibitor MLA. MLA-treated mice demonstrated increased growth and delayed rejection of the highly antigenic UV radiation-induced regressor tumor LR-298. These experiments demonstrate that macrophage-derived NO synthesis can contribute to the antitumor immune response in vivo.

Glycosylphosphatidylinositol-anchored NAD glycohydrolase is released from peritoneal macrophages activated by interferon-gamma and lipopolysaccharide.

We have previously shown that an ectoenzyme, NAD glycohydrolase (NADase) could be solubilized by treatment with bacterial phosphatidylinositol phospholipase C (PIPLC). However, it is unknown whether endogenous PIPLC can cleave this ectoenzyme. In this study, we used mouse peritoneal exudate macrophages which have been known to have relatively high activity of NADase. The results show that release of ecto-NADase was markedly increased when mouse peritoneal macrophages were costimulated with interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS), compared to unstimulated cells. This increase was preceded by markedly enhanced activity of endogenous glycosylphosphatidylinositol phospholipase C (GPIPLC). The cross-reacting determinant (CRD) of the glycosylphosphatidylinositol anchor in released NADase from activated macrophages was detected by immunoblotting with anti-CRD antibody. Taken together, ecto-NADase is release from peritoneal exudate macrophages during IFN-gamma/LPS-induced activation and endogenous GPIPLC is involved in the NADase release from the activated macrophages.

Neuromodulatory action of dopamine in the nucleus accumbens: an in vivo intracellular study.

Intracellular recordings were made from neurons in the nucleus accumbens in situ to determine how dopamine produces the selective neuromodulatory action in the accumbens observed in previous studies. Electrical stimulation of the basolateral nucleus of the amygdala was found to produce monosynaptically evoked depolarizing and hyperpolarizing postsynaptic potential sequences in a large proportion of the accumbens neurons sampled. Dopamine applied iontophoretically or released endogenously by stimulation of the ventral tegmental area produced consistent membrane depolarization and an increase in membrane conductance but not an increase in spontaneous activity of the accumbens neurons. Stimulation of the ventral tegmental area with trains of 10 pulses at 10 Hz prior to stimulation of the amygdala produced 8-58% reduction in the amplitude of the depolarizing postsynaptic potential but no change in the late hyperpolarizing postsynaptic potential. Although attenuation of the depolarizing postsynaptic potential amplitude from ventral tegmental area stimulation was often accompanied by membrane depolarization, it appeared that the two responses were not causally related. The effect of ventral tegmental area stimulation on the evoked depolarizing postsynaptic potential and the membrane potential were blocked by haloperidol indicating the involvement of dopamine. Iontophoretically applied dopamine produced responses similar to ventral tegmental area stimulation with two exceptions: (i) iontophoretically applied dopamine produced consistently stronger maximal attenuation of the depolarizing postsynaptic potential than did ventral tegmental area stimulation; and (ii) iontophoretically applied dopamine always attenuated both the depolarizing postsynaptic potential and hyperpolarizing postsynaptic potential whereas ventral tegmental area stimulation produced selective attenuation of the depolarizing postsynaptic potential only. These electrophysiological results are complementary to those from pharmacological experiments and suggest that one of several physiological functions of dopamine in the nucleus accumbens is a neuromodulatory one involving presynaptic action on non-dopaminergic terminals.

Chemical modulation of ephaptic activation of CA3 hippocampal pyramids.

In rats under urethane anaesthesia, antidromic population spikes were evoked in CA3 pyramidal layer by fimbrial/commissural stimulation at a very low frequency (approximately 0.5 Hz). Submaximal population spikes--between 20 and 90% of maximum--were enhanced by 8-38% by applications of acetylcholine and bicuculline, or by medial septal stimulation. Noradrenaline had a less pronounced and regular facilitatory action, whereas gamma-aminobutyrate and glutamate only depressed population spikes. Maximal enhancement by acetylcholine or bicuculline was observed when the antidromic population spike was initially at 38-53% of maximum amplitude. A simple explanation of these results is that acetylcholine and bicuculline, by raising their excitability, facilitate the excitation of non-invaded pyramidal cells by antidromic field potentials. They are fully in keeping with previous intracellular observations on ephaptic interactions between CA3 neurons, and provide a further illustration, in situ, of the importance of increased excitability and disinhibition--whether caused by drugs or synaptic action--in promoting synchronized excitation by ephaptic currents.

Intrinsic membrane potential oscillations in hippocampal neurons in vitro.

Membrane potential oscillations (MPOs) of 2-10 Hz and up to 6 mV were found in almost all stable hippocampal CA1 and CA3 neurons in the in vitro slice preparation. MPOs were prominent for pyramidal cells but less pronounced in putative interneurons. MPOs were activated at threshold depolarizations that evoked a spike and the frequency of the MPOs increased with the level of depolarization. MPOs were distinct from and seemed to regulate spiking, with a spike often riding near the top of a depolarizing MPO wave. Analysis of the periodicity of the oscillations indicate that the period of MPOs did not depend on the afterhyperpolarization (AHP) following a single spike. MPOs persisted in low (0-0.1 mM) Ca2+ medium, with or without Cd2+ (0.2 mM), when synaptic transmission was blocked. Choline-substituted low-Na+ (0-26 mM) medium, 3 microM tetrodotoxin (TTX) or intracellular injection of QX-314 reduced or abolished the fast Na(+)-spike and reduced inward anomalous rectification. About 40% of CA1 neurons had no MPOs after Na+ currents were blocked, suggesting that these MPOs were Na(+)-dependent. In about 60% of the cells, a large depolarization activated Ca(2+)-dependent MPOs and slow spikes. MPOs were not critically affected by extracellular Ba2+ or Cs2+, or by 0.2 mM 4-aminopyridine, with or without 2 mM tetraethylammonium (TEA). However, in 5-10 mM TEA medium, MPOs were mostly replaced by 0.2-3 Hz spontaneous bursts of wide-duration spikes followed by large AHPs. Low Ca2+, Cd2+ medium greatly reduced the spike width but not the spike-bursts. In conclusion, each cycle of an MPO in normal medium probably consists of a depolarization phase mediated by Na+ currents, possibly mixed with Ca2+ currents activated at a higher depolarization. The repolarization/hyperpolarization phase may be mediated by Na+/Ca2+ current inactivation and partly by TEA-sensitive, possibly the delayed rectifier, K+ currents. The presence of prominent intrinsic, low-threshold MPOs in all hippocampal pyramidal neurons suggests that MPOs may play an important role in information processing in the hippocampus.

Effect of picrotoxin and nipecotic acid on inhibitory response of dopaminergic neurons in the ventral tegmental area to stimulation of the nucleus accumbens.

Electrical stimulation of nucleus accumbens inhibited the activity of neurons in the ventral tegmental area (VTA). Inhibition was potentiated by nipecotic acid, a GABA uptake inhibitor, and was attenuated by picrotoxin, a GABA antagonist. Four units inhibited by nucleus accumbens stimulation were also antidromically activated. These observations suggest that neurons in the VTA, including specifically those projecting to the nucleus accumbens, receive a descending GABAergic input from that area.

Response of nucleus accumbens neurons to amygdala stimulation and its modification by dopamine.

Extracellular single unit recordings were obtained from the nucleus accumbens of urethane anesthetized rats. It was found that electrical stimulation of the basal lateral and basal medial nuclei of the amygdala produced strong excitatory responses in neurons of the nucleus accumbens, in particular the medial region. Latencies of activation were relatively short with a mean of 10.7 ms. Dopamine applied iontophoretically had a marked attenuating effect on the excitatory response of nucleus accumbens neurons to amygdala stimulation. The spontaneous activity of all neurons recorded from the nucleus accumbens was also suppressed by dopamine, but the excitatory response was more sensitive to dopamine inhibition than the spontaneous activity. Neurons in the nucleus accumbens showed a variety of responses to single-pulse electrical stimulation of the ventral tegmental area (VTA). Some units in the nucleus accumbens received convergent inputs from both the amygdala and the VTA. Stimulation of the VTA also attenuated the response of nucleus accumbens neurons to excitatory inputs from the amygdala. A train of 10 pulses (0.15 ms, 200--600 microA) at 10 Hz delivered to the VTA at 100 ms before stimulation of the amygdala caused attenuation of the original excitatory response. The attenuating effect could be observed irrespective of whether individual single-pulse stimulation of the VTA elicited a response in that particular accumbens neuron or not. 6-Hydroxydopamine injected into the VTA 2 days prior to the recording experiment, or haloperidol injected intraperitoneally 1 h before the recording session, abolished this attenuating effect. However, responses to single-pulse stimulations of the VTA were not abolished. The results suggest that the attenuation of the excitatory response to amygdala stimulation was due to the release of dopamine from mesolimbic dopaminergic neurons. Responses to single-pulse stimulations of the VTA were probably due to activation of non-dopaminergic neurons projecting from the same area. It is suggested as a working hypothesis that this inhibitory effect of dopamine may be an important function of the mesolimbic dopamine pathway in modulating the extent to which limbic structures can exert an influence on the motor system through the accumbens.

Electrophysiological studies of neurons in the ventral tegmental area of Tsai.

Extracellular recordings were obtained from single neurons in the ventral tegmental area of rats anesthetized with urethane. It was found that the area appeared to contain two groups of neurons with distinctly different spike durations, firing rates and firing patterns. One group (group A) had properties similar to those of nigral dopaminergic neurons: slow random firing rates, unusually long spike durations and slow conduction velocities. The discharge rate of the majority of these neurons was reduced by iontophoretically applied dopamine. It was concluded that neurons of this group were probably A10 dopaminergic neurons. The other group (group B) had relatively faster and rhythmical firing rates, short spike durations and faster conduction velocities and were considered to be non-dopaminergic. Forty-nine units in the ventral tegmental area were antidromically activated by electrical stimulation of the nucleus accumbens. Units antidromically activated included neurons of group A and group B, suggesting that the nucleus accumbens received dural projections of dopaminergic and non-dopaminergic fibres from the ventral tegmental area. The discharge rate of 141 out of 142 neurons tested in the ventral tegmental area (group A: 66/66, group B: 75/76) was found to be reduced by GABA. The inhibition was blocked by the simultaneous application of picrotoxin. Picrotoxin alone activated 47.7% of 155 units tested. These results provide further evidence of a GABAergic input to dopaminergic and non-dopaminergic neurons projecting to the limbic forebrain structures.

Low doses of accumbens dopamine modulate amygdala suppression of spontaneous exploratory activity in rats.

The effect of pharmacological stimulation of the amygdala on spontaneous locomotor activity in the rat and its modulation by accumbens dopamine were investigated. Bilateral injection of N-methyl-D-aspartic acid into the basolateral nucleus of the amygdala produced a dose-dependent suppression of spontaneous locomotor activity in the rat. The suppression of locomotor activity was reversed completely by injection of L-glutamic acid diethyl ester, a putative glutamatergic antagonist, into the nucleus accumbens but partially enhanced by injection of nipecotic acid, a GABA uptake inhibitor, into the ventral pallidum. Furthermore, low doses of dopamine injected into the accumbens, which by itself did not elicit hyperactivity in the animals, completely reversed the suppression of locomotor activity following amygdala stimulation. These results show that the projection from the amygdala to nucleus accumbens has an inhibitory effect on spontaneous locomotor activity in rats and that dopamine in the accumbens attenuated this suppression effect possibly due to its neuromodulatory action as demonstrated in previous electrophysiological experiments.

Intracellular records of theta rhythm in hippocampal CA1 cells of the rat.

In the urethane-anesthetized rat, intracellular recordings from hippocampal CA1 cells, some of them identified as projection (probably pyramidal) cells, showed oscillations of the resting membrane potential in the theta frequency range ('intracellular theta rhythm') which is phase-locked to the extracellularly recorded theta rhythm. Current injection or acetate ion diffusion, which reversed an inhibitory postsynaptic potential (IPSP) evoked by alvear stimulation, inverted the phase relationship between intracellular and extracellular theta rhythms. A high correlation was also found between amplitudes of the intracellular theta and the evoked IPSP at different membrane potentials. These results indicate that hippocampal theta rhythm in the urethane-anesthetized rat is predominantly caused by a rhythmic modulation of impinging IPSPs on pyramidal cells.

Mesolimbic dopamine projection modulates amygdala-evoked EPSP in nucleus accumbens neurons: an in vivo study.

In urethane anesthetized rats, excitatory postsynaptic potential (EPSP) recorded intracellularly from nucleus accumbens neurons following stimulation of the amygdala was attenuated by repetitive stimulation of the ventral tegmental area (VTA). VTA stimulation also depolarized the resting membrane potential of accumbens neurons. Attenuation of the EPSP and membrane depolarization were frequently dissociated but both were blocked by haloperidol, a dopamine antagonist.

Excitatory input from sensory motor cortex to neostriatum and its modification by conditioning stimulation of the substantia nigra.

Extracellular single unit responses were recorded from 381 neurons in the neostriatum of urethane-anesthetized rats. Single pulse stimulation of the sensory motor cortex produced strong excitatory responses in neostriatal neurons with a mean onset latency of 7.9 ms. A train of 10 pulses (0.15 ms, 300-600 microA) at 10 Hz delivered to the substantia nigra 100 ms before cortical stimulation attenuated the original excitatory response of 22 of 53 striatal neurons tested and enhanced the excitatory response of 12 of these neurons. These attenuating and enhancing effects were reduced or abolished by the systemic administration of haloperidol, a dopamine antagonist. Single pulse nigral stimulation 100 ms before the cortical stimulation had little or no effect on the excitatory response of neostriatal neurons. The iontophoretic application of dopamine also had attenuation and enhancement effects on the excitatory response of striatal neurons to cortical stimulation. The results suggest that the attenuation and enhancement of the excitatory responses of striatal neurons to cortical stimulation which resulted from nigral conditioning stimulation is mediated by nigrostriatal dopaminergic neurons.

The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder.

BACKGROUND: Persistent impairment in cognitive function has been described in euthymic individuals with bipolar disorder. Collective work indicates that obesity is associated with reduced cognitive function in otherwise healthy individuals. This sub-group post-hoc analysis preliminarily explores and examines the association between overweight/obesity and cognitive function in euthymic individuals with bipolar disorder. METHODS: Euthymic adults with DSM-IV-TR-defined bipolar I or II disorder were enrolled. Subjects included in this post-hoc analysis (n=67) were divided into two groups (normal weight, body mass index [BMI] of 18.5-24.9 kg/m2; overweight/obese, BMI ≥ 25.0 kg/m2). Demographic and clinical information were obtained at screening. At baseline, study participants completed a comprehensive cognitive battery to assess premorbid IQ, verbal learning and memory, attention and psychomotor processing speed, executive function, general intellectual abilities, recollection and habit memory, as well as self-perceptions of cognitive failures. RESULTS: BMI was negatively correlated with attention and psychomotor processing speed as measured by the Digit Symbol Substitution Test (P<0.01). Overweight and obese bipolar individuals had a significantly lower score on the verbal fluency test when compared to normal weight subjects (P<0.05). For all other measures of cognitive function, non-significant trends suggesting a negative association with BMI were observed, with the exception of measures of executive function (i.e., trail making test B) and recollection memory (i.e., process-dissociation task). CONCLUSION: Notwithstanding the post-hoc methodology and relatively small sample size, the results of this study suggest a possible negative effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder. Taken together, these data provide the impetus for more rigorous evaluation of the mediational role of overweight/obesity (and other medical co-morbidity) on cognitive function in psychiatric populations.