Lethal graft-versus-host reaction against non-H-2 antigens. I. Prevention of GVH-associated immunodeficiency by preimmunizing the donor against host-specific non-H-2 antigens

Injection of B10.D2 cells into irradiated H-2d compatible (DBA/2xB10.D2)F1 recipients provokes a lethal GVH that can be abrogated by donor preimmunization against host-specific DBA/2 non-H-2 antigens. To study the possible relationship between the observed protection and restoration of immune responsiveness, we compared spleen cellularity, selected T and B cell functions, and NK activity in GVH and protected mice during the 1st month after grafting. Normal and isografted mice served as controls. GVH was found to be characterized by an early stimulation phase associated with splenomegaly and increased percentages (but not numbers) of Lyt-2+ and L3T4+ cells, followed by profound aplasia and abrogation of IL-2 production. Response to a B cell mitogen (LPS) is depressed, and cells from GVH mice exert a strong suppressive effect on the LPS and PHA responsiveness of normal cells. Suppression appears to be mediated by a radioresistant, nylon nonadherent, asialo GM1 negative cell expressing a low level of Thy-1 antigen. In contrast, protection correlates with progressive restoration of spleen cellularity and LPS responsiveness, with decreased but clearly detectable IL-2 production, and transient nonspecific suppressor activity. The immune status of protected mice resembles that of isografted controls. No correlation was found between mortality (or protection) and either PHA responsiveness, which remained depressed in all grafted mice throughout the observation period, or NK activity, which was strongly depressed in both GVH and protected mice. In conclusion, protection correlates with the disappearance of nonspecific suppressor cells and the restoration of cellularity and certain nonspecific immune functions. Donor immunization against host-specific non-H-2 antigens, which protects against mortality, also protects against GVH-associated immune deficiency.     

PET/CT using 18F-FDG in suspected lung cancer recurrence: diagnostic value and impact on patient management.

The goal of this study was to assess the value of hybrid imaging using a combined PET/CT device with 18F-FDG in the diagnosis and clinical management of suspected recurrent lung cancer. METHODS: Forty-two patients with non-small cell lung cancer (NSCLC) with suspected recurrence due to new clinical, biochemical, and radiologic findings were prospectively evaluated. PET/CT results were compared with PET interpreted with side-by-side CT data. A final diagnosis of recurrence was confirmed by histologic tissue sampling during surgery or biopsy or by further clinical and radiologic work-up. The impact of PET/CT on patient management was assessed. RESULTS: Twenty-four of 27 positive PET/CT studies (89%) were proven to have recurrent disease. Fourteen of 15 negative PET/CT studies (93%) had no evidence of disease. The sensitivity, specificity, and positive and negative predictive values of PET/CT for diagnosis of recurrence were 96%, 82%, 89%, and 93% compared with 96%, 53%, 75%, and 90%, respectively, for PET. PET/CT changed the PET lesion classification in 22 patients (52%), by determining the precise localization of sites of increased 18F-FDG uptake. PET/CT changed the management of 12 patients (29%) by eliminating previously planned diagnostic procedures (5 patients), by initiating a previously unplanned treatment option (4 patients), or by inducing a change in the planned therapeutic approach (3 patients). CONCLUSION: In patients with a suspected recurrence of NSCLC, PET/CT provides a better anatomic localization of suspicious lesions compared with PET interpreted with side-by-side CT data. This improved diagnostic performance of PET/CT has a further impact on the clinical management and treatment planning of the patients.     

Hyperlocomotion induced by dopamine or cholecystokinin + dopamine in the nucleus accumbens is not modified by chronic lithium treatment

1. Peptides such as cholecystokinin have been reported to modulate the effects of dopaminergic agonists on locomotion in rats. 2. The present experiments tested the possibility that lithium interacts with dopaminergic function through the same mechanism by which cholecystokinin potentiates dopaminergic function. 3. The results suggest that dietary lithium has no effect on the ability of either dopamine alone, or the combination of dopamine plus cholecystokinin, microinjected directly into the nucleus accumbens, to stimulate hyperlocomotion.     

Antibacterial properties of human amniotic membranes.

Amniotic membranes are widely used in a multitude of surgical applications and have been shown to reduce bacterial counts and promote healing in infected wounds. Antibacterial properties of amniotic fluid are well documented and the presence of many potentially antibacterial factors has been demonstrated. No such factors have yet been found in amniotic membranes. We have applied a direct disc-diffusion susceptibility test to try to establish the possible existence of such a factor. Amniotic membranes did not inhibit five bacterial species when tested at 3 X 10(6) and 3 X 10(8) colony forming units/ml. However, complete growth inhibition of all organisms was seen immediately under the amniotic membrane discs. These results support the hypothesis that the antimicrobial effect of amniotic membranes in vitro is due to their close adherence to the wound surface.     

The flavin-containing monooxygenase of mouse kidney. A comparison with the liver enzyme

Flavin-containing monooxygenase (FMO; EC 1.14.13.8) was purified from mouse kidney microsomes and compared to that isolated from mouse liver microsomes. The purified enzymes from kidney and liver appeared as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with an apparent molecular weight of 58,000 daltons. On wide range (pH 3.5 to 9.0) isoelectric focusing, FMOs from kidney and liver resolved as a single band with an isoelectric point of 8.2. The enzymes from both kidney and liver have a pH optimum of 9.2. Thiobenzamide-S-oxidation catalyzed by both enzymes was sensitive to inhibition by the competitive inhibitors thiourea and methimazole. At an n-octylamine concentration of 3 mM, thiobenzamide-S-oxidation by the kidney FMO was increased by 122% and that by the liver FMO by 148%. Km and Vmax values were determined and compared between the two tissue enzymes for xenobiotic substrates containing nucleophilic nitrogen, sulfur or phosphorus atoms. In general, for most FMO substrates, Km and Vmax values were similar between kidney and liver FMO with only a few exceptions. The Km and Vmax values for fenthion for kidney were only half of those observed for liver FMO. Fonofos was unusual in having a low Km as well as a low Vmax for both tissue enzymes. Anti-sera developed to the FMO purified from kidney and liver showed cross-reactivity with each purified enzyme as well as with a protein with the same molecular weight as the purified FMO present in both kidney and liver microsomes. These bands showed equal intensity based on an equivalent amount of protein. Analysis of kidney and liver FMO by proteolytic digestion followed by visualization of peptides by silver staining or immunoblotting showed only minor differences between the enzymes of the two tissues. The amino acid composition of both mouse kidney and liver FMO was low in methionine and histidine and rich in aspartate/asparagine, glutamate/glutamine, leucine, valine and glycine. Edman degradation of the purified mouse kidney and liver FMO provided a single amino acid sequence of the NH2-terminus. This sequence matched exactly with the cDNA-deduced sequence reported for the pig and rabbit liver beginning with the fifth amino acid and contained the highly conserved FAD-binding domain Gly-X-Gly-X-X-Gly, commonly found in a number of other FAD-binding proteins. These studies indicate that the renal and hepatic forms of FMO from mouse are similar enzymes that are immunologically related and show only a few minor differences.     

Oral contraceptives and the risk of endometrial cancer

The relationship between the use of combbination oral contraceptives (OCs) and the risk of endometrial cancer was assessed in a case-control study conducted in the Swiss Canton of Vaud between 1 January 1988 and 31 July 1990. Subjects included 122 women aged 75 or less with histologically confirmed endometrial cancer, and 309 control women in hospital for acute conditions unrelated to OC use. Overall, 14 percent of cases and 27 percent of controls had ever used OCs, corresponding to a multivariate relative risk (RR) of 0.5 (95 percent confidence interval [CI]: 0.3. 0.8). The risk of endometrial cancer was found to be related inversely to duration of OC use: RR=1.0 for less than two years of OC use; 0.5 for two to five years; and 0.3 (95 percent CI: 0.1, 0.7) for more than five years. The protection appeared greater within 20 years since last use, and the RR rose to 0.8 after 20 or more years since last use; numbers are too small, however, for reliable inference from these subanalyses. No significant interaction or modifying effect was observed with other major factors related to endometrial cancer, including parity, body mass index, estrogen replacement therapy, and cigarette smoking. While this study provides further evidence for the protective effect of OCs against risk of endometrial cancer, the relationship requires continued evaluation to assess the long-term implications and public health impact of OC use.This work was supported in part by the Swiss National Science Foundation Grant No. 3.866-0.88.     

Spatial and velocity tuning of processes underlying induced motion

A nulling procedure was used to quantify the velocity and spatial frequency tuning of induced motion for sinusoidal gratings. For each spatial frequency of test and inducing gratings, there was a range of low velocities which resulted in strong induction, with a gain of close to 1. For low spatial frequencies induction occurred at higher velocities than was the case for high spatial frequencies. Induced motion shows bandpass spatial frequency tuning, with a bandwidth of about two octaves at half-height. Induced motion appears to be mediated by spatial channels with a low pass temporal characteristic. To a first approximation, induced motion appears to be a product of velocity and spatial frequency.     

Kainic acid stimulates GABA release from a subpopulation of cerebellar astrocytes

The effect of acute exposure to micromolar concentrations of kainic acid was studied in rat cerebellar astroglial cultures consisting of two antigenically and functionally distinct subpopulations of astrocytes. Kainate (20-100 microM) released [3H]GABA preaccumulated by A2B5-positive stellate astrocytes in a concentration-, Na+- and Ca2+-dependent way, and did not interfere with [3H]GABA transport. We hypothesize that kainate depolarizes this class of cells by activating cationic channels and that this results in an imbalance of GABAergic transmission.     

Neonatal auditory brain-stem response threshold and latency: 1 hour to 5 months.

Auditory brain-stem evoked responses were recorded in normal neonates and infants ranging in age from less than 1 h to 5.5 months. The average threshold in neonates 0-5 h old was 29 dB greater than that in adults, reaching the adult threshold range within 2 weeks. The latency of wave I in 0-5 h neonates was 1.81 msec and reached the adult range within 2 weeks. The V-I interpeak latency in 0-5 h neonates was 5.3 msec and did not reach adult values within the period of this study.     

Treatment duration of obsessive compulsive disorder

The first breakthrough in the treatment of obsessive-compulsive disorder (OCD) came in 1967, when Fernandez and Lopez-Ibor reported on the efficacy of clomipramine (CMI) in the treatment of 16 patients with OCD (Fernandez and Lopez-Ibor, 1967). However, controlled studies with CMI were not published until 1980 (Montgomery, 1980; Thoren et al, 1980), and only in the last 5 years have large well-controlled studies been published (Clomipramine Collaborative Study, 1991). Several studies demonstrated that among the tricyclics (TCA), only CMI is effective in OCD, while effective antidepressants with a noradrenergic profile, such as desipramine (DMI), appear to be totally ineffective (Zohar and Insel, 1987; Goodman et al, 1990; Leonard et al, 1989). This selective response to TCA with a serotonergic profile led to the formulation of the serotonergic hypothesis of OCD and to the development and use of other serotonergic agents in the treatment of this disorder. Several drugs, possessing a serotonergic profile are currently being studied worldwide, among them CMI, fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram. Currently, as the knowledge regarding the pharmacological approach to OCD is only beginning to accumulate, very little is known regarding treatment duration in OCD. In this review we shall attempt to examine the existing data regarding treatment duration in OCD.