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Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, nongenomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal hippocampus (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERβ agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Further, while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect appeared independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5 min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via nongenomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS-, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS- pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l-741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Background: COVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel., Methods: The MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular., Recommendations: Each subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred., Conclusion: These guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability., (© 2020 Wiley Periodicals, Inc.)

This study tracked a radiology department's conversion from utilization of a Kodak Amber analog system to a Kodak DirectView DR 5100 digital system. Through the use of ProModel Optimization Suite, a workflow simulation software package, significant quantitative information was derived from workflow process data measured before and after the change to a digital system. Once the digital room was fully operational and the radiology staff comfortable with the new system, average patient examination time was reduced from 9.24 to 5.28 min, indicating that a higher patient throughput could be achieved. Compared to the analog system, chest examination time for modality specific activities was reduced by 43%. The percentage of repeat examinations experienced with the digital system also decreased to 8% vs. the level of 9.5% experienced with the analog system. The study indicated that it is possible to quantitatively study clinical workflow and productivity by using commercially available software.

The effect of intermittent glucose administration on the circadian rhythm of body temperature was studied in rats to provide evidence of sugar addiction, withdrawal and relapse. Metabolic and behavioral phenomena were also observed. Biotelemetry transmitters recorded body temperature for the duration of the 4-week experiment. Rats were divided into an experimental and a control group, which were maintained on the same habituation conditions for the duration of the experiment, with the exception of weeks 2 and 4, when the experimental group was presented with a 25% glucose solution. Experimental animals displayed a precipitous drop in body temperature and behavioral changes associated with withdrawal during week 3, when sugar was removed. There was an increase in kilocalories (kcal) consumed during weeks 2 and 4 by experimental animals and, by the end of the experiment, these animals showed a greater percent increase in body weight. Elevated blood glucose levels were found in experimental animals. The study demonstrates that the effects of sugar addiction, withdrawal and relapse are similar to those of drugs of abuse. Implications of the rewarding and addicting effects of sugar are related to weight gain, obesity and Type II diabetes. Furthermore, pitfalls related to dieting are elucidated.

Cell survival in the hypertonic environment of the renal medulla is dependent on the intracellular accumulation of protective organic solutes through the induction of genes whose transcriptional regulation is mediated in part by interaction between osmotic response elements and the transcription nuclear factor of activated T lymphocyte 5. It is shown that cyclosporine A (CsA) prevents the nuclear translocation of the transcription nuclear factor of activated T lymphocyte 5 and inhibits osmotic response element-mediated reporter gene expression. The expression of mRNA for hypertonicity-induced genes (aldose reductase, betaine/gamma-amino-n-butyric acid transporter 1, and heat shock protein 70) is also decreased in the medulla of CsA-treated rats. CsA inhibits the increase of betaine/gamma-amino-n-butyric acid transporter 1 and heat shock protein 70 mRNA in osmotically stressed MDCK cells, blocks cell proliferation under isotonic conditions, and augments hypertonicity-induced apoptosis. Histologic examination of the kidneys of CsA-treated rats shows a marked increase in apoptosis in the renal medulla where hypertonicity normally prevails. The data are consistent with calcineurin-mediated induction of hypertonic stress-response genes, and they suggest that CsA nephrotoxicity may in part result from inhibition of the adaptive responses to hypertonicity occurring during the urinary concentrating mechanism.

We evaluated the relation between venous thrombosis and plasma fibrinogen levels, the HaeIII and BcI polymorphisms of the beta fibrinogen gene, and the MspI polymorphisms of the factor VII gene in a case-control study of African-Americans. The study included 91 venous thrombosis cases and 185 control subjects obtained from a hospital in Atlanta, Georgia. High plasma fibrinogen was associated with increased risk of venous thrombosis, but the finding was not statistically significant. There was little association between the HaeIII polymorphisms and the BclI polymorphisms and the risk of venous thrombosis. The prevalence of the M2/M2 genotype of the factor VII gene was higher among cases than controls, but the difference was not statistically significant. The prevalence of the HaeIII H2 allele and the BclI B2 allele of the beta fibrinogen gene, both of which have been associated with slightly higher levels of plasma fibrinogen in most studies, is considerably lower among African-Americans in this study than it is among Whites in the United States and among Northern Europeans. The study is limited by its small size. However, despite this limitation, it supports the belief that increased plasma fibrinogen levels are associated with increased venous thrombosis risk. The study also indicated that the HaeIII and the BclI polymorphisms of the beta fibrinogen gene and the MspI polymorphisms of the factor VII gene are not strong determinants of venous thrombosis.

Vasopressin-containing Long-Evans and vasopressin-deficient Brattleboro rats were maintained in individual cages while telemetered activity (AC) and body temperature (BT) data were collected. Rats were initially exposed to a 12 h/12-h light/dark cycle (photic zeitgeber) and were allowed ad-libitum access to food and water. Daily feeding, care, and handling (nonphotic zeitgebers) occurred at the beginning of the second hour of the dark cycle. After a 14-day habituation period, rats were subjected to continuous light (LL) or dark (DD) and nonphotic cues were presented irregularly. During the habituation period, both strains exhibited clear 24-h circadian rhythms of AC and BT. In LL or DD, photic cues were removed and nonphotic cues were presented irregularly. There was a shift in the rhythm for Long-Evans animals to 26 h for both AC and BT in LL and 24.6 h in DD. Feeding, care, and handling were seen as minor artifact. In Brattleboro rats, although there were robust 26-h and 24.6-h circadian rhythms of AC in the LL and DD, respectively, BT data were inconsistent and showed sporadic fluctuations. In the BT rhythm of Brattleboro animals, strong peaks were associated with feeding, care, and handling times and trough periods were characterized by a dramatic drop in temperature. This experiment demonstrates that AC and BT are controlled by separate oscillators. In addition, the importance of vasopressinergic fibers in the control of circadian rhythms of BT is evidenced by the loss of circadian rhythms in animals lacking these functional fibers when exposed to free-running paradigms where there is no entrainment of photic or nonphotic oscillators.

In the developing spinal cord, axons project in both the transverse plane, perpendicular to the floor plate, and in the longitudinal plane, parallel to the floor plate. For many axons, the floor plate is a source of long- and short-range guidance cues that govern growth along both dimensions. We show here that B-class transmembrane ephrins and their receptors are reciprocally expressed on floor plate cells and longitudinally projecting axons in the mouse spinal cord. During the period of commissural axon pathfinding, B-class ephrin protein is expressed at the lateral floor plate boundaries, at the interface between the floor plate and the ventral funiculus. In contrast, B-class Eph receptors are expressed on decussated commissural axon segments projecting within the ventral funiculus, and on ipsilaterally projecting axons constituting the lateral funiculus. Soluble forms of all three B-class ephrins bind to, and induce the collapse of, commissural growth cones in vitro. The collapse-inducing activity associated with B-class ephrins is likely to be mediated by EphB1. Taken together, these data support a possible role for repulsive B-class Eph receptor/ligand interactions in constraining the orientation of longitudinal axon projections at the ventral midline.

The Auger electron emitting agent 5-[125I]iodo-2'-deoxyuridine (i.e. [125I]IUdR) holds promise for the treatment of residual glioma after surgery because this thymidine analogue kills only proliferating cells. However, malignant cells which are not synthesizing DNA during exposure to the radiopharmaceutical will be spared. To determine whether tumour incorporation of [125I]IUdR could be enhanced by protracted administration, we used a C6 cell line, growing in the brains of Wistar rats, as a glioma model and compared three methods of intracerebral delivery of [125I]IUdR. Twenty-four hours after administration of drug, autoradiography of brain sections demonstrated nuclear uptake of the radiopharmaceutical in cells throughout tumour while normal brain cells remained free of radioactivity. The [125I]IUdR labelling indices (% +/- s.e.m.) achieved were 6.2 (0.4) by single injection, 22.5 (4.1) using a sustained release polymer implant (poly(lactide-co-glycolide)) and 34.3 (2.0) by mini-osmotic pump. These results emphasize the need for a sustained delivery system as a prerequisite for effective treatment. These findings are also encouraging for the development of a sustained release system for radiolabelled IUdR for use in the treatment of intracranial tumours, particularly in the immediate postoperative setting.

A variety of molecules expressed at the midline of the developing central nervous system (CNS) control multiple aspects of pattern formation and axon guidance. We recently identified monoclonal antibody (mAb) CARO 2 as a novel marker of the ventral midline in the developing rat CNS, and the corresponding antigen as a membrane-associated 28-kDa protein. We report here the isolation of cDNA clones encoding the mAb CARO 2 antigen, which we rename VEMA, for ventral midline antigen. The deduced amino acid sequence of VEMA contains a single transmembrane domain near its N-terminus and several tyrosine-based internalization motifs. These structural features are consistent with the association of VEMA to intracellular membranes. In situ hybridization analyses demonstrate that VEMA mRNA is predominantly expressed at the ventral midline. The restricted distribution of VEMA, as well as several characteristics of its primary structure, suggest a role for this protein in regulating axon guidance in the mammalian CNS.

Previous research has demonstrated that vasopressin-containing rats are capable of adapting to the stress of food restriction; whereas, vasopressin-deficient rats cannot adapt to this stressor. In the present study, the value of using a low-calorie (Splenda) or no-calorie (Equal) artificial sweetener to reverse the deleterious effects of food restriction in vasopressin-deficient rats was examined. In association with this effect, the role of vasopressin in long-term preferences for the two artificial sweeteners was studied. Vasopressin-deficient, Brattleboro (DI) rats and vasopressin-containing, Long-Evans (LE) rats underwent an habituation phase during which they had ad-libitum access to food. This was followed by an experimental phase during which the rats were divided into four groups. (1) DI rats continued with ad-libitum feeding, (2) LE rats continued with ad-libitum feeding, (3) DI rats subjected to 23 h of food restriction, and (4) LE rats subjected to 23 h of food restriction. All rats had ad-libitum access to an 8% Splenda solution, a 1% Equal solution, and water throughout both phases of the experiment. The deleterious effects of food restriction were completely reversed in DI rats, including survival, no stomach pathology, and normal plasma levels of glucose and urea nitrogen.

Telemetered body temperature (BT), heart rate (HR), and motor activity (AC) data were collected in vasopressin-containing, Long-Evans (LE) and vasopressin-deficient, Brattleboro (DI) rats. In Experiment 1, the rats were initially exposed to a 12 h/12 h light/dark cycle under ad-libitum feeding and were then subjected to either a phase-advance or phase-delay shift of 6 h. After the phase-advance shift, neither strain adapted; however, after the phase-delay shift, both strains adapted rapidly. In Experiment 2, the animals were subjected to either a nocturnal or a diurnal restricted-feeding paradigm and were then exposed to either a phase-advance or phase-delay shift with synchronized feeding. In the nocturnal restricted-feeding paradigms, both strains rapidly adapted to both shifts. Concerning diurnal restricted-feeding, DI animals readily entrained to the presentation of food in both shifts; whereas, LE animals exhibited a confused rhythmicity. In Experiment 3, animals were subjected to a phase-advance shift, while the time of feeding was held constant. Following the shift, LE animals responded to the onset of the dark at the new time; yet, were still influenced by the presentation of food. The DI animals maintained the preshift circadian pattern and continued to be dominated by the presentation of food. These experiments indicate that circadian rhythms of LE animals are dominated by the light entrainable oscillator (LEO) in ad-libitum feeding and by both the LEO and food entrainable oscillator (FEO) in restricted-feeding. On the other hand, the circadian rhythms of DI animals are dominated by the FEO unless food is provided ad-libitum. The demonstrated role of vasopressin in synchronizing circadian rhythms to the LEO may be of significance in understanding human circadian rhythm disturbances, such as jet lag.

Vasopressin-deficient (DI) and vasopressin-containing (LE) rats were given continuous access to 32% sucrose and 32% polycose solutions under ad-libitum and food-restricted conditions in a long-term preference test. Although all animals preferred Polycose to sucrose in both conditions, food restriction introduced a stress that significantly increased the consumption of Polycose in DI rats. Considering total caloric intake, Polycose was preferred by both strains only under food restriction and the effect was greatly exacerbated in DI animals compared to LE animals. The differences observed between DI and LE animals in response to ad-libitum feeding and food-restriction stress indicate that vasopressin, directly and/or indirectly, influences the physical and metabolic functions and processes of the animals, which, in turn, affect their intake of Polycose.

The function of the compound eye is dependent upon a developmental program that specifies different cell fates and directs the expression of spectrally distinct opsins in different photoreceptor cells. Rh5 is a novel Drosophila opsin gene that encodes a biologically active visual pigment that is expressed in a subset of R8 photoreceptor cells. Rh5 expression in the R8 cell of an individual ommatidium is strictly coordinated with the expression of Rh3, in the overlying R7 cell. In sevenless mutant files, which lack R7 photoreceptor cells, the expression of the Rh5 protein in R8 cells is disrupted, providing evidence for a specific developmental signal between the R7 and R8 cells that is responsible for the paired expression of opsin genes.

Telemetered body temperature (BT), heart rate (HR), and activity (AC) data were collected in vasopressin-containing Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. The rats were exposed to a 12/12 h light/dark cycle under three conditions: 1) ad lib feeding throughout the 24-h cycle, 2) two scheduled-feeding periods during the diurnal component of the light/dark cycle, and 3) two scheduled-feeding periods during the nocturnal component of the light/dark cycle. With ad lib feeding, natural nocturnal cycles of BT, HR, and AC were maintained in both strains. Marked changes were observed under the condition of scheduled feeding during the diurnal component of the light/dark cycle. In DI animals the influence of the photic oscillator was lost and BT, HR, and AC shifted from nocturnal to diurnal patterns. Circadian rhythms in DI animals were now synchronized by the nonphotic zeitgeber of scheduled food presentation. On the other hand, LE animals lost a well-defined circadian rhythmicity resulting from adherence to the photic oscillator, while at the same time being influenced by the nonphotic oscillator. Under the condition of scheduled feeding during the nocturnal component of the light/dark cycle, the circadian rhythms were similar in DI and LE rats. Results show that vasopressin has a significant interaction with the photic oscillator, which is obvious only when the photic and nonphotic oscillators are uncoupled. In addition, the results demonstrate that the strength of the photic oscillator is decreased or that the effect of this oscillator is masked or lost in DI rats compared to LE rats.

To investigate the role of the hormone vasopressin (VP) in mediating the response of an organism to food restriction stress-induced analgesia, tail flick latencies and scored qualitative behavioral responses were recorded in VP-containing (LE) rats and VP-deficient (DI) rats. These variables were measured under nonstressed (ad lib) and stressed (food restriction) conditions. In the ad lib condition, DI and LE rats had a similar tail flick latency and scored qualitative behavioral response to the stimulus eliciting the tail flick. During the food restriction condition, however, LE animals developed significant food restriction stress-induced analgesia, as measured by tail flick latency. On the other hand, DI animals did not develop significant analgesia. In addition, DI animals exhibited a significantly greater scored qualitative behavioral response to the stimulus eliciting the tail flick than LE animals. These results demonstrate that VP plays an important role in the regulation of food restriction stress-induced analgesia, as well as the scored qualitative behavioral response elicited by the tail flick stimulus.

To investigate the role of the hormone vasopressin (VP) in mediating the response of the body to stress, corticosterone levels of VP-containing (LE) rats and VP-deficient (DI) rats were compared following administration of the dexamethasone suppression test (DST) under stressed and nonstressed conditions. The stressor utilized was immobilization, an acute physical stressor. Dexamethasone (DEX), a synthetic glucocorticoid, was injected subcutaneously at a dose of 0.025 mg/kg. This dose of DEX was found to significantly suppress plasma corticosterone in the nonstressed animals (both DI and LE) via feedback inhibition of the hypothalamic-pituitary-adrenocortical (HPA) axis. In the stressed situation, however, LE animals exhibited "escape" from DEX suppression, whereas DI animals did not. Escape indicates a resistance of the HPA axis to the suppressive action of DEX. Thus, in the absence of corticotropin-releasing factor, which is inhibited by DEX, VP alone appears to be sufficient to elicit significant corticosterone release. These results support the hypothesis that VP plays an important role in the regulation of glucocorticoid release in acute stress via the HPA axis.

The performance of a passive avoidance task (measured for two trials based upon number of complete step-downs and latency to respond) and blood glucose levels were examined in five groups of animals. The groups included vasopressin-deficient (DI) and vasopressin-containing (LE) rats under ad lib (AL) and food-restricted (FR) conditions, as well as DI-FR animals provided with access to an 8% sucrose solution (SUC). In the AL condition, no significant differences were found between DI and LE animals in either step-down occurrences or blood glucose levels. However, the DI animals were significantly slower in latency to respond in trial 1. With FR, the LE animals resembled the LE-AL animals in both passive avoidance behavior and blood glucose levels. The DI-FR animals that were not provided with SUC showed an impairment in passive avoidance behavior and low blood glucose levels, whereas DI-FR animals provided with SUC showed an amelioration of passive avoidance deficiencies and had blood glucose levels comparable to AL animals and LE-FR animals. On trial 2, a significant negative correlation was found between number of step-down occurrences and blood glucose levels, and a significant positive correlation was found between latency to respond and blood glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin-containing, Long-Evans (LE) rats and vasopressin-deficient, Brattleboro (DI) rats were monitored for activity and core body temperature via telemetry. Rats were exposed to a 12-12 light-dark cycle and allowed to habituate with ad lib access to food and water. The habituation period was followed by an experimental period of 23 h of food-restriction stress in which a 1-h feeding period was provided during the light cycle. Although both strains of animals showed nocturnal activity and temperature rhythms during the habituation period, DI rats were more active than LE rats. The DI rats also had a lower body temperature in the dark. During the experimental period, both strains exhibited a phase shift of activity and body temperature correlating with the presentation of food. The DI rats developed a diurnal shift more rapidly than LE rats. The DI animals showed a dramatic increase in activity during the light phase and a marked decrease in body temperature during the dark phase. The LE animals showed a significant attenuation of activity, but maintained both nocturnal and diurnal temperature peaks throughout the food-restricted condition.

A defect involving poor anticoagulant response to activated protein C (APC), an anticoagulant serine protease known to inactivate factors Va and VIIIa in plasma, was recently reported and the existence of a novel APC cofactor was suggested. To define the frequency of this defect among 25 venous thrombophilic patients with no identifiable laboratory test abnormality and among 22 patients previously identified with heterozygous protein C or protein S deficiency, the APC-induced prolongation of the activated partial thromboplastin time assay for these patients was compared with results for 35 normal subjects. The results show that this new defect in anticoagulant response to APC is surprisingly present in 52% to 64% of the 25 patients, ie, in the majority of previously undiagnosed thrombophilia cases, but is not present in 20 of 22 heterozygous protein C or protein S deficient patients, suggesting that the new factor is a risk factor independent of protein C or protein S deficiency. The results demonstrate that abnormalities in the anticoagulant protein C pathway are present in the majority of thrombophilic patients.

Decreases in protein S levels have recently been reported in some human immunodeficiency virus (HIV)-infected patients. To examine predisposing factors, 25 men randomly selected from a long-term study of HIV-infected patients were studied. The minimum mean duration of HIV seropositivity in this group was 106.6 months (range 15 to 143 months). No patients were anticoagulated at the time of the study. Three of the 25 randomly selected patients gave a history of thrombosis, in each instance occurring after the onset of HIV positivity. Two of the 3 patients with thrombosis had more than one episode. Coagulation studies showed that 3 of 3 (100%) of the patients with thrombosis and 16 of 22 (72.7%) of those without previous thrombosis had decreased free protein S. Mean-free and total protein S levels were statistically lower for HIV-infected patients with and without previous thrombosis compared with healthy male controls. C4b-binding protein was not increased in study patients with decreased protein S levels. Decreases in protein S levels did not correlate with CD4+ cell levels, CDC class, p24 antigen positivity, zidovudine (AZT) use, or Pneumocystis carinii prophylaxis. The duration of disease statistically correlated with decreases in protein S levels (r = .37, P < .05). A linear correlation existed between increasing IgG anticardiolipin antibody levels and decreasing free protein S antigen (r = .67, P < .005). This study shows that protein S deficiency is common in long-term HIV-infected patients and is caused by a decrease in the free protein, rather than by changes in the bound complex. The data suggest that protein S deficiency is not correlated with HIV disease severity but may predispose patients to thromboembolic complications.

Plasma levels of glucose and urea nitrogen were compared in vasopressin-containing (LE) and vasopressin-deficient (DI) rats under ad lib and food-restricted conditions. In the ad lib situation, DI and LE rats had similar levels of glucose and urea nitrogen. Variations in this pattern were observed under food-restricted conditions. The DI animals exhibited lower levels of glucose and higher levels of urea nitrogen than their LE counterparts. During food restriction, the glucose levels of LE animals were not different from that observed under ad lib conditions. A significant decrease, however, was observed in the glucose levels in DI animals during food restriction. Urea nitrogen levels in LE animals decreased during food restriction as compared to the ad lib situation, whereas urea nitrogen levels of DI animals increased during food restriction. These observations indicate that vasopressin has a modulatory role on glucose and protein metabolism during the stress of food restriction.

Corticosterone levels and ulcers were compared in vasopressin-containing (LE) and vasopressin-deficient (DI) rats under ad lib and food-restricted conditions. In the ad lib situation, DI and LE rats had similar corticosterone levels and no ulcers. After 1 day of food restriction, the corticosterone levels were elevated in DI and LE rats, with a significantly higher level in LE rats. No ulcers were present in either strain. After 2 days of food restriction, the corticosterone levels were similar in DI and LE rats. The level in DI rats was comparable to that of the preceding day, but the level in LE animals dropped significantly from the previous day. Significant ulceration was evident in DI rats, but absent in LE rats. Following 3 days of food restriction, the corticosterone level in LE rats had returned to the ad lib level, whereas, for DI rats, an elevated level was maintained. There were no ulcers in LE rats, but they were present in DI rats. Thus LE and DI rats responded differently to the stress of food restriction. The mechanism underlying the response is most likely related to changes in the hypothalamic-pituitary-adrenocortical axis and its reaction to stress.

This study examined patterns of consummatory behavior in normal and vasopressin-deficient rats under ad lib and food-restricted conditions. Differing patterns of intake of food, water, sucrose, and saccharin were found in the two groups. During the ad lib period, the normal rats gained more weight and ate significantly more food than vasopressin-deficient rats. The vasopressin-deficient animals consumed significantly more sucrose than normal animals during this period. No significant differences in body weight, food intake, sucrose intake, or saccharin intake were noted during the food-restricted period between the two groups. During the food-restricted condition the normal animals showed a cyclic pattern of food, sucrose, and saccharin intake. This cyclic pattern of intake was absent in vasopressin-deficient animals. A vasopressin-serotonin interaction is hypothesized as a possible mechanism producing the differences in the two strains of animals. In addition, the data support the position that food consumption is regulated primarily by caloric and/or nutritional factors.

The effects of subcutaneous injections of vasopressin in vasopressin-deficient (Brattleboro or DI) rats were observed during nonstress (habituation) and stress (food-restriction) conditions as compared to other rats. Four groups of animals were employed: 1) Long-Evans (LE) rats that were food restricted with no injections (normal control animals), 2) DI rats that were food restricted with no injections, 3) DI rats injected with vasopressin, and 4) DI rats injected with peanut oil (vehicle). The parameters studied were: body weight, food intake, water intake, and gastric ulcer formation. With respect to body weight, water intake, and ulcer formation, two sets of animals emerged. The vasopressin-injected DI rats resembled the LE control rats, whereas the peanut oil-injected DI rats were similar to the DI rats with no injections. The former set of animals showed a higher body weight, reduced water intake, and fewer gastric ulcers than the latter set of animals. Thus the vasopressin-injected DI rats and the LE control rats could cope with the stress of food restriction, but the peanut oil-injected DI rats and the DI rats with no injections could not.

Inherited deficiencies of protein S, an inhibitor of the coagulation system, are now recognized as occurring at least twice as frequently as antithrombin III deficiency in patients with venous thrombosis. Protein S is present in plasma in a complexed form, which is inactive, and in a free or functional form. Free protein S combines with activated protein C to inhibit factors V and VIII. This report describes the evaluation of a family with recurrent deep venous thrombosis and superficial thrombophlebitis. Levels of antithrombin III and protein C as well as plasminogen were normal. The levels of total protein S, which includes the value for the free and complexed forms of protein S, were also normal. However, the free protein S levels were greatly reduced in all symptomatic members who were studied. This report illustrates the importance of obtaining measurement of free protein S levels in patients who are suspected of having inherited venous thrombotic disorders.

In order to assess the impact of demographic factors on serum levels of cyclosporine (CsA) estimated by radioimmunoassay (RIA) in renal allograft recipients, 493 pharmacokinetic studies were performed in 212 patients. Neither the presence of diabetes mellitus nor the CsA dosing frequency affected the measured pharmacokinetic parameters. Age over 45 years led to slower CsA clearance with resultant increase in maximum serum concentration (Cmax) per administered milligram, and increased volume of distribution. Female patients showed more rapid drug clearance, but greater volume of distribution. Concomitant hepatic impairment reduced drug clearance, increasing the area under the curve (AUC) per administered milligram of drug, and the Cmax. Patients treated with a rapid steroid taper showed a shorter half-life and lower Cmax than those receiving a slow steroid taper. Nephrotoxicity was associated with increased AUC per administered mg, while patients with acute tubular necrosis requiring dialysis showed poorer drug absorption, lower Cmax, and longer time to peak. The only effect of cimetidine administration was a slightly shortened time to peak. Serial analyses posttransplant in 17 patients suggested a tendency toward improved drug absorption with no effect on other parameters. These studies demonstrating the significant impact of demographic factors thus afford a basis on which to predict the trend of anticipated CsA levels as measured by RIA in renal allograft recipients.

The first experiment was conducted in an attempt to ascertain the effects of hippocampal lesions on plasma levels of total T4, total T3, free T4, and TSH. Animals with hippocampal lesions had significantly lower levels of total T4, free T4 and TSH than cortical control and normal animals. There were no significant differences in total T3 among the three groups. Since these results indicated that animals with hippocampal lesions manifested a dysfunction in the hypothalamic-pituitary-thyroid axis, a second experiment was undertaken to determine the site of mediation. A TRH injection test demonstrated that the dysfunction occurs at the level of the hypothalamus. It is hypothesized that in the normal animal the hippocampus exerts a facilitating effect on the hypothalamic-pituitary-thyroid axis.

A family with a history of recurring thrombosis was studied to determine if a plasma protein deficiency could account for the observed disease. Protein C levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his father, and his paternal uncle, who are severely affected, had 38-49% of normal levels of protein C antigen, whereas unaffected family members had normal levels. There was no familial deficiency of antithrombin III and plasminogen. Because activated protein C is a potent in vitro anticoagulant enzyme and an in vivo profibrinolytic agent, it is suggested that the recurrent thrombotic disease in this family is due to an inherited deficiency in protein C.

The results of cadaveric retransplantation in 55 recipients immunosuppressed with cyclosporine and prednisone were compared to 156 recipients of primary renal allografts. By 3 yr posttransplant, there is no significant difference in patient survival, but the yearly graft survival for primary (79%, 72%, 72%) as compared to retransplant (69%, 58%, 58%) recipients was significantly (p less than 0.05) better. There was no significant difference in rejection episodes or mean +/- SD serum creatinine (mg/dl) at 2 yr between primary (32%, 2.14 +/- 1.1) and retransplant (33%, 2.08 +/- 1.4) patients, respectively. Donor source, third kidneys, human leukocyte antigen AB and Dr matching, percent reactive antibody levels, and cause of first graft loss do not have significant impact on cyclosporine-treated retransplant outcome. However, retransplant patients who have lost a previous graft in less than 3 months continue to be at high risk for subsequent early graft loss. These results suggest that the combination of cyclosporine and prednisone is the preferred regimen for cadaveric retransplantation.

Antithrombin III (AT III) is the most potent physiologic inactivator of thrombin and other serine proteases in the blood clotting mechanism. Hereditary deficiency of this protein is associated with recurrent deep-vein thrombosis that begins in late adolescence. Untreated, this disease may lead to early death from recurrent and massive pulmonary emboli. Attempts to identify groups of patients who are the most likely to develop thromboembolic disease because of an acquired deficiency of AT III have been frustrated by the lack of standardization of the assays and the inability to compare results of the different AT III assays. The functional assays and immunoelectrophoretic determinations do not measure the same component. In order to compare the ability of current AT III procedures to determine levels of AT III in various disease states, we used immunoelectrophoretic, chromogenic, and clottable assays to measure the AT III of patients with congenital AT III deficiency and of patients with possible acquired AT III deficiency.

A multivariate analysis dissected the impact of donor procurement variables, immunologic risk factors, and alternate cyclosporine and prednisone induction immunosuppressive regimens on the early and eventual function of 303 consecutive cadaveric renal allografts. Primarily warm, but to a slight extent cold, ischemia time had an adverse impact on allograft function, as did the requirement for vasopressor or diuretic therapy. The occurrence of initial graft non-function adversely affected the probability of three-month graft survival, but did not alter either the longevity of organs, which subsequently recovered function, or patient mortality rate. The major immunologic risk factor was a second or multiple transplant, which was associated with an increased incidence of early graft failure, and impaired renal function in successful transplants. Correlations with HLA-B and DR matching were reflected in the quality of renal function, but not in graft survival rates. Cyclosporine (CsA) administration by continuous intravenous infusion, in order to avert initial elevated mean three-day, serum radioimmunoassay drug levels reduced the incidence of initial graft non-function. High levels were also associated with impaired early and eventual renal function. Rapid posttransplant taper of corticosteroids to 30 mg prednisone by day six was associated with a greater incidence of rejection episodes and early graft failure than a taper that achieved 30 mg prednisone at 60 days. Both the serum creatinine value and the degree of hypertension observed at one month afforded good prognostic indices of eventual graft survival. Therefore, renal allografts in CsA-treated patients were sensitive not only to adverse donor and immunologic risk factors, but also to excessive CsA drug levels in the early postoperative period. These findings suggest an induction immunosuppressive strategy utilizing slightly higher initial doses of steroids for CsA-sparing during the first three days, followed by increased, but judicious, administration of CsA to achieve steroid-sparing by virtue of effective rejection prophylaxis.

CsA has improved the outcome of renal allotransplantation with CAD and LRD kidneys. CsA mitigates risk factors heretofore presenting substantial obstacles to CAD transplantation: HLA matching, pretransplant splenectomy, extensive numbers of conditioning blood transfusions, and old age. In LRD transplantation, CsA obviates the need for donor-specific transfusions in the haploidentical situation, and for prednisone in the HLA-identical setting. The incidence of drug-induced nephrotoxicity beyond six months is 30% with the degree of dysfunction proportionate to the degree of histo-incompatibility, suggesting that subclinical allograft rejection due to overzealous dose reduction may compromise allograft function. At present, total conversion from CsA to Aza appears ill-advised; even patients who never suffered allograft rejection under CsA therapy frequently lose their allograft when the inferior level of Aza suppression is substituted. Drug-induced hypertension, a modestly significant factor, diminishes further by two years posttransplant. The benefit of CsA therapy is a reduced incidence of 19% initial and 10% recurrent rejection episodes. Of great importance is the observation that 17% of rejection episodes followed patient noncompliance. Further, the incidence of bacterial infections was greatly reduced, and viral infections modestly lessened. Only the occurrence of pneumocystis carinii was increased, but 92% of patients survived in spite of serious pulmonary infection. Development of a consistent CsA regimen has reduced the median initial hospitalization to 12.5 days for LRD and 14 days for CAD, a level well within the range stipulated for the Disease-Related Guidelines of the Medicare Program. Furthermore, readmission is less frequent; one-third of patients never reenter the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors report a case of arteriovenous malformations (AVMs) of the small intestine in a young patient with protein S deficiency. These disorders have not been previously reported to occur together. Protein S deficiency may cause thromboses in unusual sites, including the mesenteric veins. Several mechanisms linking protein S deficiency to the occurrence of AVMs in this patient are offered.

The use of cyclosporine, a fungal endecapeptide immunosuppressive agent, has greatly improved the outcome of haploidentical transplantation in adults, but less impressively improved the result of parent to child transplantation. The incidence of allograft loss and treated rejection episodes was much greater in pediatric than in adult recipients, and the evidences of nephrotoxicity lessened. Although resistance of the child's immune system to the effects of the drug cannot be excluded, it appears more likely that this relates to the rapid clearance of the agent in the pediatric age group (39.6 mL/min/kg) versus in adults (12.3 mL/min/kg), thereby reducing the area under the serum concentration curve from 765 +/- 593 to 386 +/- 277 ng/mL/hr per mg/kg (mean +/- SD). This effect caused trough serum levels measured by radioimmunoassay to be below the putative threshold. These findings demonstrate the need for higher cyclosporine doses and frequency in pediatric compared with adult patients.

The cause of the thrombotic tendency in nephrotic patients is unknown. Recent reports of thrombotic complications in patients with deficiencies of protein C or protein S (natural inhibitors of coagulation) have raised the possibility that decreased levels of these proteins may play a role in the hypercoagulable state of nephrotic patients. We measured the levels of protein C, total protein S, and free protein S antigens in 42 patients (21 nephrotic and 21 non-nephrotic) with one of four types of glomerular pathology: diabetic nephropathy (DM), focal glomerular sclerosis (FGS), membranous glomerulonephritis (MGN), and chronic renal failure due to hypertension (CRF). Protein C and total protein S antigen levels were significantly higher in FGS and MGN than they were in DM or CRF. Free protein S levels were lower in DM than they were in MGN. Protein C, total protein S, and free protein S levels did not significantly correlate with either serum albumin or degree of proteinuria. The mean levels of the three proteins did not differ between nephrotic and non-nephrotic patients. Free protein S and protein C were, however, significantly correlated (P less than .005 and P less than .002, respectively) with the type of glomerular pathology, independent of differences in age, sex, serum albumin, or degree of proteinuria. These data suggest that abnormalities of free protein S and protein C are related to the nature of the underlying renal disease, rather than to the degree of proteinuria.