Context-specific adaptation of vertical vergence to correlates of eye position

Vertical phoria (vertical vergence in the absence of binocular feedback) can be trained to vary with non-visual cues such as vertical conjugate eye position, horizontal conjugate eye position and horizontal vergence. These prior studies demonstrated a low-level association or coupling between vertical vergence and several oculomotor cues. As a test of the potential independence of multiple eye-position cues for vertical vergence, context-specific adaptation experiments were conducted in three orthogonal adapting planes (midsagittal, frontoparallel, and transverse). Four vertical disparities in each of these planes were associated with various combinations of two specific components of eye position. Vertical disparities in the plane were associated with horizontal vergence and vertical conjugate eye position; vertical disparities in the frontoparallel plane were associated with horizontal and vertical conjugate eye position; and vertical disparities in the transverse plane were associated with horizontal vergence and horizontal conjugate eye position. The results demonstrate that vertical vergence can be adapted to respond to specific combinations of two different sources of eye-position information. The results are modeled with an association matrix whose inputs are two classes of eye position and whose weighted output is vertical vergence.     

Hyperlipoproteinemia enhances susceptibility to acute disseminated Candida albicans infection in low-density-lipoprotein-receptor-deficient mice

Recent studies have suggested the use of lipoproteins as an adjuvant treatment of lethal gram-negative infections. However, other important microorganisms for the etiology of sepsis, such as Candida species, grow better in lipid-rich environments. We investigated the effect of hyperlipoproteinemia on systemic candidiasis in low-density-lipoprotein-receptor-deficient (LDLR-/-) mice, in which the loss of the receptor results in a seven- to ninefold-higher plasma LDL level than that in their wild-type littermates (C57BL/6J). LDLR-/- mice died earlier, and the outgrowth of Candida albicans in the kidneys and livers of LDLR-/- mice was significantly higher compared with that of controls. After infection, circulating cytokine concentrations were significantly higher in LDLR-/- mice. In vitro, C. albicans grew better in plasma samples of LDLR-/- mice than in control plasma samples and peritoneal macrophages of LDLR-/- mice challenged with heat-killed C. albicans produced more cytokines than did those of controls. This latter phenomenon was probably due to increased binding of yeast cells to macrophages of LDLR-/- mice. These data suggest that hyperlipoproteinemia is deleterious in systemic candidiasis.     

Bat-deafness in day-flying moths (Lepidoptera, Notodontidae, Dioptinae)

Assuming that bat-detection is the primary function of moth ears, the ears of moths that are no longer exposed to bats should be deaf to echolocation call frequencies. To test this, we compared the auditory threshold curves of 7 species of Venezuelan day-flying moths (Notodontidae: Dioptinae) to those of 12 sympatric species of nocturnal moths (Notodontidae: Dudusinae, Noctuidae and Arctiidae). Whereas 2 dioptines (Josia turgida, Zunacetha annulata) revealed normal ears, 2 (J. radians, J. gopala) had reduced hearing at bat-specific frequencies (20-80 kHz) and the remaining 3 (Thirmida discinota, Polypoetes circumfumata and Xenorma cytheris) revealed pronounced to complete levels of high-frequency deafness. Although the bat-deaf ears of dioptines could function in other purposes (e.g., social communication), the poor sensitivities of these species even at their best frequencies suggest that these moths represent a state of advanced auditory degeneration brought about by their diurnal life history. The phylogeny of the Notodontidae further suggests that this deafness is a derived (apomorphic) condition and not a retention of a primitive (pleisiomorphic), insensitive state.     

Cure of malignant ascites and generation of protective immunity by monoclonal antibody-targeted activation of a glucuronide prodrug in rats

We examined the in vivo efficacy of targeting beta-glucuronidase (betaG) to activate a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard (pHAM) at hepatoma ascites in Sprague-Dawley rats. Injection i.p. of 500 microg RH1-betaG, a conjugate formed between recombinant betaG and monoclonal antibody RH1 with specificity for an antigen expressed on AS-30D rat hepatoma cells, into rats bearing AS-30D ascites resulted in the accumulation of 54 microg conjugate per 10(9) tumor cells after 2 hr. Ascites fluid and serum contained 0.53 and 0 microg/ml, respectively, RH1-betaG 2 hr after injection of the conjugate. Conjugate binding to AS-30D cells was heterogeneous and non-saturated, as determined by flow cytometry. BHAMG was less toxic than pHAM to SD rats based on measures of animal mortality, weight loss and hematological toxicity. Treatment of rats bearing established hepatoma ascites with 500 microg RH1-betaG followed 2 hr later with a single i.p. injection of 30 mg/kg BHAMG or 3 i.p. injections of 10 mg/kg BHAMG 2, 3 and 4 hr later resulted in the cure of 6/8 and 8/8 animals, respectively. Treatment with BHAMG or pHAM alone did not produce cures, whereas treatment with a control antibody-betaG conjugate and BHAMG produced significantly greater hematological toxicity compared to treatment with RH1-betaG and BHAMG. All cured rats were completely protected from rechallenge with 2 x 10(7) AS-30D cells, indicating that successful treatment of animals induced protective immunity.     

The placental transfer of sufentanil: effects of fetal pH, protein binding, and sufentanil concentration

This study investigated factors that influence the placental transfer of sufentanil using the dual-perfused, single-cotyledon human placental model. Placentas were collected from healthy women. Experiments were designed to elucidate the effects of maternal protein binding, changing maternal sufentanil concentration (1, 10, 20, and 100 ng/mL) and decreasing fetal pH (fetal acidemia 7.2, 7.0, 6.8) on the placental transfer of sufentanil. Sufentanil crossed the placenta rapidly at a rate two-thirds that of the transfer marker, antipyrine. Sufentanil transfer increased linearly with the maternal concentration (r = 0.999). Sufentanil/antipyrine maternal to fetal (M-->F) transfer ratios were significantly reduced (0.66 +/- 0.05 vs 0.40 +/- 0.04, P < 0.05) when fresh frozen plasma was added to the maternal circuit to enhance protein binding. Fetal pH and sufentanil transfer were related because sufentanil M-->F clearance increased significantly as the fetal pH decreased (r = 0.973, P < 0.05). Sufentanil appears to cross the placenta by passive diffusion but is modulated by the degree of maternal protein binding. Sufentanil M-->F transfer is enhanced by fetal acidemia.     

Adrenomedullary secretion of epinephrine is increased in mild essential hypertension

To assess whether patients with mild essential hypertension have excessive activities of the sympathoneuronal and adrenomedullary systems, we examined total body and forearm spillovers and norepinephrine and epinephrine clearances in 47 subjects with mild essential hypertension (25 men, 22 women, aged 38.1 +/- 6.7 years) and 43 normotensive subjects (19 men, 24 women, aged 36.5 +/- 5.9 years). The isotope dilution method with infusions of tritiated norepinephrine and epinephrine was used at rest and during sympathetic stimulation by lower body negative pressure at -15 and -40 mm Hg. Hypertensive subjects had a higher arterial plasma epinephrine concentration (0.20 +/- 0.01 nmol.L-1: mean +/- SE) than normotensive subjects (0.15 +/- 0.01) (P < .01). The increased arterial plasma epinephrine levels appeared to be due to a higher total body epinephrine spillover rate in the hypertensive subjects (0.23 +/- 0.02 nmol.min-1.m-2) than the normotensive subjects (0.18 +/- 0.01) (P < .05) and not to a decreased plasma clearance of epinephrine. The arterial plasma norepinephrine level, total body and forearm norepinephrine spillover rates, and plasma norepinephrine clearance were not altered in the hypertensive subjects. The responses of the catecholamine kinetic variables to lower body negative pressure were not consistently different between normotensive and hypertensive individuals. These data indicate that individuals with mild essential hypertension (1) have elevated arterial plasma epinephrine concentrations that are due to an increased total body epinephrine spillover rate, indicating an increased adrenomedullary secretion of epinephrine; (2) have no increased generalized sympathoneuronal activity and no increased forearm norepinephrine spillover; and (3) have similar responses of both the sympathoneuronal and adrenomedullary systems to sympathetic stimulation by lower body negative pressure.     

Phencyclidine (PCP) acts at sigma sites to induce c-fos gene expression

Phencyclidine (PCP) is a compound that results in abnormal human behavior and has been proposed as a chemical model for schizophrenia. It was hypothesized that PCP induction of the immediate-early gene, c-fos, should be seen in areas associated with emotional behavior, such as the cortex and limbic system. It was also proposed that PCP may induce c-fos via the sigma receptor. PCP and two sigma ligands, 1,3-di(2-tolyl)guanidine (DTG) and pentazocine, were shown to induce c-fos in similar patterns. The three compounds abundantly induced c-fos in the cingulate, parietal, and piriform cortices and the midline structures of the thalamus and hypothalamus. Neither PCP nor the sigma ligands induced c-fos in the hippocampus. This suggests that PCP binding at NMDA receptors does not result in significant c-fos induction. Rimcazole, a putative sigma2 receptor antagonist, and other sigma ligands have been shown to ameliorate PCP stereotypic behavior. Rimcazole inhibited PCP c-fos induction in the cingulate and parietal cortices and DTG c-fos induction in the cingulate cortex. DTG shows both sigma1 and sigma2 binding affinity. Rimcazole failed to inhibit pentazocine c-fos induction. Pentazocine binds only to sigma1 receptors. This suggests that PCP may produce a significant fraction of its c-fos induction via sigma2 receptors.     

A patient with a cytomegalovirus infection and multiple stomach ulcers

In a 64-year-old, previously healthy woman an upper gastrointestinal endoscopy was performed because of serious dyspeptic complaints during fourteen days. Multiple fundic gastric ulcers were found without Helicobacter pylori and the patient did not take non-steroidal anti-inflammatory drugs (NSAIDs). The diagnosis was primary cytomegalovirus infection, based on the demonstration of infected cells in the biopsy specimens, using specific monoclonal anti-cytomegalovirus antibodies.     

A prospective study of endogenous serum hormone concentrations and breast cancer risk in post-menopausal women on the island of Guernsey

The associations between serum concentrations of oestradiol, testosterone and sex hormone-binding globulin (SHBG) and risk of breast cancer in post-menopausal women were investigated in a prospective study on the island of Guernsey. Sixty-one women who developed breast cancer an average of 7.8 years after blood collection were matched for age, year of blood collection and number of years post-menopausal with 179 control subjects. Women using exogenous hormones at the time of blood collection were excluded from the study. Women who subsequently developed breast cancer had a 29% higher geometric mean oestradiol concentration than control women (P = 0.004). The odds ratio for breast cancer in the top third compared with the lowest third of the oestradiol concentration distribution was 5.03 (95% confidence interval 2.02-12.49, P for trend < 0.001). Adjusting for testosterone and SHBG concentrations did not substantially alter the odds ratio for oestradiol. Although testosterone and SHBG concentrations were associated with breast cancer risk, the concentrations of these hormones were correlated with those of oestradiol; the associations were not statistically significant after adjusting for oestradiol concentration. These data provide evidence that serum oestradiol concentrations in post-menopausal women may have a substantial effect on breast cancer risk.     

Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid

Patients with acute promyelocytic leukemia (APL) usually relapse after all-trans retinoic acid (RA) treatment because this therapy fails to eradicate the malignant clone. Our data showed that KH 1060 and other 20-epi vitamin D3 analogs alone were potent inhibitors of clonal growth of NB4 cells, an APL cell line (ED50, approximately 5 x 10(-11) M). The combination of KH 1060 and 9-cis-RA synergistically and irreversibly enhanced this effect. Neither KH 1060 nor 9-cis-RA (10(-6) M, 3 d) were strong inducers of differentiation of NB4 cells. However, 98% of the cells underwent differentiation to a mature phenotype with features of both granulocytes and monocytes after exposure to a combination of both compounds. Apoptosis only increased after incubation of NB4 cells with 9-cis-RA alone (28%) or with a combination of 9-cis-RA plus KH1060 (32%). Immunohistochemistry showed that the bcl-2 protein decreased from nearly 100% of the wild-type NB4 cells to 2% after incubation with a combination of KH 1060 and 9-cis-RA, and the bax protein increased from 50% of wild-type NB4 cells to 92% after culture with both analogs (5 x 10(-7) M, 3 d). Western blot analysis paralleled these results. Studies of APL cells from one untreated individual paralleled our results with NB4 cells. Taken together, the data demonstrated that nearly all of the NB4 cells can be irreversibly induced to differentiate terminally when exposed to the combination of KH 1060 and 9-cis-RA.