The course of geriatric depression with "reversible dementia": a controlled study

OBJECTIVE: The goals of this longitudinal investigation were 1) to study the rate of development of irreversible dementia in elderly depressed patients with a dementia syndrome that subsided after improvement of depression and 2) to compare it with that of depressed, never-demented patients. METHOD: The subjects were 57 elderly patients consecutively hospitalized for major depression. At entry into the study, 23 subjects also met criteria for "reversible dementia," while 34 were without dementia. After a systematic clinical evaluation, the subjects were followed up at approximately yearly intervals for an average of 33.8 months. RESULTS: Irreversible dementia developed significantly more frequently in the depressed group with reversible dementia (43%) than in the group with depression alone (12%). Survival analysis showed that the group with reversible dementia had a 4.69-times higher chance of having developed dementia at follow-up than the patients with depression alone. No clinical characteristics at entry into the study were found to discriminate the subjects who developed irreversible dementia during the follow-up period from those who remained nondemented. CONCLUSIONS: These findings suggest that geriatric depression with reversible dementia is a clinical entity that includes a group of patients with early-stage dementing disorders. Therefore, identification of a reversible dementia syndrome is an indication for a thorough diagnostic workup and frequent follow-ups in order to identify treatable neurological disorders.     

Comparative analysis of 8-oxo-2' -deoxyguanosine in DNA by 32P- and 33P-postlabeling and electrochemical detection

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is emerging as a useful marker for oxidative DNA damage. Reported basal levels determined by 32P-postlabeling (PPL) method were 10-fold or more higher than those obtained with HPLC/electrochemical detection (ECD). This discrepancy was investigated. In commercial calf thymus DNA, levels of 4 +/- 1 and 64 +/- 14 8-oxo-dG per 10(6) 2'-deoxynucleosides (dN) were measured by the standard HPLC/ECD and PPL methods, respectively. DNA digestion by micrococcal nuclease/spleen phosphodiesterase and nuclease P1 (as used in the standard PPL method), followed by ECD analysis resulted in a level of 8 +/- 3. In calf thymus DNA spiked with chemically synthesized 8-oxo-dGp to give an increment of 9 8-oxo-dG/10(6) dN, the added standard produced a significant increase with HPLC/ECD but not PPL. After spiking the DNA with 90 8-oxo-dG/10(6) dN, the added 8-oxo-dGp was detectable also with PPL, with a labeling efficiency of 65%. In order to investigate the role of ionizing radiation from 32P for the higher 8-oxo-dG levels in PPL, incubation times and amounts of radioactivity in the phosphorylation reaction with commercial dGp were increased, and external irradiation of commercial dG with 32P was investigated. All modifications resulted in higher values of 8-oxo-dG measured, but the effect was not large enough to fully explain the discrepancy between PPL and HPLC/ECD. Using [gamma-33P]ATP instead of [gamma-32P]ATP or adding [33P]phosphate to a 32P-PPL assay resulted in even higher levels of 8-oxo-dG measured. The increase in 8-oxo-dG levels during the PPL workup is attributed to the presence and oxidation of unmodified dGp in the reaction mixture. For a determination of true basal levels, the PPL method will have to be modified, including the removal of dGp prior to the phosphorylation reaction.     

Characterization of the radical trapping activity of a novel series of cyclic nitrone spin traps

alpha-Phenyl-tert-butyl nitrone (PBN) is a nitrone spin trap, which has shown efficacy in animal models of oxidative stress, including stroke, aging, sepsis, and myocardial ischemia/reperfusion injury. We have prepared a series of novel cyclic variants of PBN and evaluated them for radical trapping activity in vitro. Specifically, their ability to inhibit iron-induced lipid peroxidation in liposomes was assessed, as well as superoxide anion (O2(-.)) and hydroxyl radical ((.)OH) trapping activity as determined biochemically and using electron spin resonance (ESR) spectroscopy. All cyclic nitrones tested were much more potent as inhibitors of lipid peroxidation than was PBN. The unsubstituted cyclic variant MDL 101,002 was approximately 8-fold more potent than PBN. An analysis of the analogs of MDL 101,002 revealed a direct correlation of activity with lipophilicity. However, lipophilicity does not solely account for the difference between MDL 101,002 and PBN, inasmuch as the calculated octanol/water partition coefficient for MDL 101,002 is 1.01 as compared to 1.23 for PBN. This indicated the cyclic nitrones are inherently more effective radical traps than PBN in a membrane system. The most active compound was a dichloro analog in the seven-membered ring series (MDL 104,342), which had an IC50 of 26 mum, which was 550-fold better than that of PBN. The cyclic nitrones were shown to trap (.)OH with MDL 101,002 being 20 25 times more active than PBN as assessed using 2-deoxyribose and p-nitrosodimethylaniline as substrates, respectively. Trapping of (.)OH by MDL 101,002 was also examined by using ESR spectroscopy. When Fenton's reagent was used, the (.)OH adduct of MDL 101,002 yielded a six-line spectrum with hyperfine coupling constants distinct from that of PBN. Importantly, the half-life of the adduct was nearly 5 min, while that of PBN is less than 1 min at physiologic pH. MDL 101,002 also trapped the O2(-.) radical to yield a six-line spectrum with coupling constants very distinct from that of the (.)OH adduct. In mice, the cyclic nitrones ameliorated the damaging effects of oxidative stress induced by ferrous iron injection into brain tissue. Similar protection was not afforded by the lipid peroxidation inhibitor U74006F, thus implicating radical trapping as a unique feature in the prevention of cell injury. Together, the in vivo activity, the stability of the nitroxide adducts, and the ability to distinguish between trapping of (.)OH and O2(-.) suggest the cyclic nitrones to be ideal reagents for the study of oxidative cell injury.     

A prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy

In a prospective, randomized study, continuous infusion of epidural fentanyl citrate (group E) was compared with patient-controlled intravenously administered morphine sulfate (group P) for analgesia in 66 men after radical retropubic prostatectomy. Although both methods provided satisfactory analgesia, the mean comfort level scores were lower (that is, greater comfort) in group E than in group P at all observation times. The difference in mean resting comfort level scores between groups E and P was statistically significant (P < or = 0.05) at 9 of the 11 observation times. In addition, significant differences in comfort level scores were noted at 8 of the 11 observation times during deep breathing, 5 of 11 during coughing, and 3 of 9 during ambulation. Maximal and minimal comfort level scores recorded by each patient during the course of the study were significantly lower (that is, less pain) in group E than in group P for all four categories of activity. The percentage of patients who reported no pain was significantly higher in group E than in group P at 9 of 11 observation times during resting and 5 of 11 observation times during deep breathing. No significant differences were noted in side effect profiles or duration of hospital stay. In summary, when two effective methods of analgesia used after radical retropubic prostatectomy were compared prospectively, patients who received epidural infusion of fentanyl were more comfortable than those with patient-controlled intravenous administration of morphine, as evidenced by lower mean, maximal, and minimal comfort level scores and a greater proportion of patients with complete relief of pain.     

A role for herpesvirus saimiri orf14 in transformation and persistent infection

The product of open reading frame 14 (orf14) of herpesvirus saimiri (HVS) exhibits significant homology with mouse mammary tumor virus superantigen. orf14 encodes a 50-kDa secreted glycoprotein, as shown previously (Z. Yao, E. Maraskovsky, M. K. Spriggs, J. I. Cohen, R. J. Armitage, and M. R. Alderson, J. Immunol. 156:3260-3266, 1996). orf14 expressed from recombinant baculovirus powerfully induces proliferation of CD4-positive cells originating from several different species. To study the role of orf14 in transformation, a mutant form of HVS (HVS Deltaorf14) was constructed with a deletion in the orf14 gene. The transforming potential of HVS Deltaorf14 was tested in cell culture and in common marmosets. Parental HVS subgroup C strain 488 immortalized common marmoset T lymphocytes in vitro to interleukin-2-independent growth, while the HVS Deltaorf14 mutant did not produce such a growth transformation. In addition, HVS Deltaorf14 was nononcogenic in common marmosets. In contrast to other nononcogenic HVS mutant viruses which were repeatedly isolated from peripheral blood mononuclear cells of infected marmosets for more than 5 months, HVS Deltaorf14 did not persist at a high level in vivo. These results demonstrate that orf14 of HVS is not required for replication but is required for transformation and for high-level persistence in vivo.     

Bupropion and desipramine increase dopamine transporter mRNA expression in the ventral tegmental area/substantia nigra of rat brain

The homeobox gene Otx2 is a mouse cognate of the Drosophila orthodenticle gene, which is required for development of the brain, rostral to rhombomere three. We have investigated the mechanisms involved in this neural function and specifically the requirement for Otx2 in the visceral endoderm and the neuroectoderm using chimeric analysis in mice and explant recombination assay. Analyses of chimeric embryos composed of more than 90% of Otx2-/- ES cells identified an essential function for Otx2 in the visceral endoderm for induction of the forebrain and midbrain. The chimeric studies also demonstrated that an anterior neural plate can form without expressing Otx2. However, in the absence of Otx2, expression of important regulatory genes, such as Hesx1/Rpx, Six3, Pax2, Wnt1 and En, fail to be initiated or maintained in the neural plate. Using explant-recombination assay, we could further demonstrate that Otx2 is required in the neuroectodem for expression of En. Altogether, these results demonstrate that Otx2 is first required in the visceral endoderm for the induction, and subsequently in the neuroectoderm for the specification of forebrain and midbrain territories.     

Positron emission tomography [15O]water studies with short interscan interval for single-subject and group analysis: influence of background subtraction

Ethanol at concentration of 200 mM induces anesthesia in experimental animals and depresses neurotransmission in isolated spinal cords. To determine whether actions on primary afferent nerve terminals contribute to ethanol's depressant effects on spinal cord, a study was undertaken to test whether ethanol blocks sodium currents (I(Na)) in dorsal root ganglion neurons (DRGn). Whole-cell patch clamp was used to examine I(Na) in DRGn isolated from 1- to 15-day-old rats. At a holding potential of -80 mV ethanol (200 mM) decreased peak tetrodotoxin-resistant (TTX-R) and tetrodotoxin-sensitive (TTX-S) I(Na) by 19.0% +/- 2.7 (mean +/- SEM) and 8.5% +/- 2.2, respectively. Maximal available I(Na) was reduced to 82 +/- 4% (TTX-R) and 93 +/- 1% (TTX-S) of control. Steady-state inactivation curves were shifted in the hyperpolarizing direction by 2.1 +/- 0.2 mV (TTX-R) and 1.1 +/- 0.1 mV (TTX-S). At prepulse potentials of -30 mV (TTX-R) and -70 mV (TTX-S), these shifts contributed an additional 17 +/- 1% (TTX-R) and 7 +/- 1% (TTX-S) reduction in available I(Na). Ethanol thus selectively induced both voltage-independent and voltage-dependent block of TTX-R I(Na) in DRGn. Because DRGn TTX-R sodium channels are associated with small-diameter primary afferent fibers, these results are consistent with a role for ethanol actions on sodium channels in depression of nociceptive-related neurotransmission in spinal cord.