Dimensional depression severity in women with major depression and post-traumatic stress disorder correlates with fronto-amygdalar hypoconnectivty.

Depressive symptoms are common in multiple psychiatric disorders and are frequent sequelae of trauma. A dimensional conceptualization of depression suggests that symptoms should be associated with a continuum of deficits in specific neural circuits. However, most prior investigations of abnormalities in functional connectivity have typically focused on a single diagnostic category using hypothesis-driven seed-based analyses. Here, using a sample of 105 adult female participants from three diagnostic groups (healthy controls, n=17; major depression, n=38; and post-traumatic stress disorder, n=50), we examine the dimensional relationship between resting-state functional dysconnectivity and severity of depressive symptoms across diagnostic categories using a data-driven analysis (multivariate distance-based matrix regression). This connectome-wide analysis identified foci of dysconnectivity associated with depression severity in the bilateral amygdala. Follow-up seed analyses using subject-specific amygdala segmentations revealed that depression severity was associated with amygdalo-frontal hypo-connectivity in a network of regions including bilateral dorsolateral prefrontal cortex, anterior cingulate and anterior insula. In contrast, anxiety was associated with elevated connectivity between the amygdala and the ventromedial prefrontal cortex. Taken together, these results emphasize the centrality of the amygdala in the pathophysiology of depressive symptoms, and suggest that dissociable patterns of amygdalo-frontal dysconnectivity are a critical neurobiological feature across clinical diagnostic categories.

Ground water development--the time to full capture problem.

Ground water systems can be categorized with respect to quantity into two groups: (1) those that will ultimately reach a new equilibrium state where pumping can be continued indefinitely and (2) those in which the stress is so large that a new equilibrium is impossible; hence, the system has a finite life. Large ground water systems, where a new equilibrium can be reached and in which the pumping is a long distance from boundaries where capture can occur, take long times to reach a new equilibrium. Some systems are so large that the new equilibrium will take a millennium or more to reach a new steady-state condition. These large systems pose a challenge to the water manager, especially when the water manager is committed to attempting to reach a new equilibrium state in which water levels will stabilize and the system can be maintained indefinitely.

Time-resolved characterization of diesel particulate emissions. 2. Instruments for elemental and organic carbon measurements.

The measurement of elemental carbon (EC) and organic carbon (OC) mass for particles emitted by diesel vehicles is currently accomplished using particle collection on filters, followed by analysis using the thermal/optical reflectance carbon analysis method (TOR) or one of its variations. Such filter methods limit time resolution to a minimum of several minutes, making it impossible to study emissions during transient operating conditions. Testing of five different measurement methods has demonstrated that fast response measurement of diesel exhaust particulate EC and OC concentrations, consistent with TOR filter measurements, is feasible using existing technology. EC mass concentrations are best measured through determination of particulate light absorption with a photoacoustic instrument or determination of light extinction with a smoke meter. The photoacoustic instrument has the better dynamic range and sensitivity, whereas the smoke meter is a simpler instrument. Fast response OC measurements cannot be made with any single instrument tested. However, a combination of real time weighing as implemented in the tapered element oscillating microbalance with the photoacoustic instrument has been shown to be capable of determining OC concentrations with good time response. The addition of a nephelometer to the OC measurement could potentially improve time resolution, freedom from interferences, and sensitivity.

Time resolved characterization of diesel particulate emissions. 1. Instruments for particle mass measurements.

The measurement of diesel vehicle exhaust particulate mass is currently accomplished using filter collection methods according to the Code of Federal Regulations (CFR). Such filter methods limit time resolution to a minimum of several minutes, making it impossible to study emissions during transient operating conditions. Extensive testing of five different measurement methods has demonstrated that fast response measurements of diesel exhaust particulate mass concentrations, consistent with CFR filter measurements, are feasible using existing technology. The measurement principles of choice are the real time weighing of exhaust samples as implemented in the tapered element oscillating microbalance (TEOM) and the measurement of light scattering from exhaust particles as implemented in the DustTrak nephelometer. Each of these two instruments has distinctive strengths. The TEOM excels in the area of constant calibration, independent of vehicle. For the DustTrak, this calibration varies by vehicle. On the other hand, the DustTrak has an excellent signal-to-noise ratio, freedom from interference due to other exhaust sample properties, good time resolution, and simplicity. The strengths of the two measurement methods are complimentary, so an obvious suggestion is to integrate them. The nephelometer would obtain a fast response signal, with near real time calibration provided by the microbalance.

Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention.

BACKGROUND: Polyamines (e.g., putrescine, spermidine, and spermine) are required for optimal cell growth. Inhibition of polyamine synthesis suppresses carcinogen-induced epithelial cancers, including colon cancer, in animal models. In a short-term phase IIa trial, we determined that low doses of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (an enzyme involved in polyamine synthesis), reduced the polyamine content of normal-appearing rectal mucosa of subjects with a prior history of resected colon polyps. In a follow-up study, we have attempted to determine the lowest dose of DFMO that can suppress the polyamine content of rectal mucosa over a course of 1 year with no or minimal side effects. METHODS: Participants were randomly assigned to daily oral treatment with a placebo or one of three doses (0.075, 0.20, or 0.40 g/m2) of DFMO. Baseline and serial determinations of polyamine levels in rectal mucosa and extensive symptom monitoring (including audiometric measurements, since DFMO causes some reversible hearing loss at higher doses) were performed over a 15-month period. RESULTS: DFMO treatment reduced putrescine levels in a dose-dependent manner. Following 6 months of treatment, doses of 0.20 and 0.40 g/m2 per day reduced putrescine levels to approximately 34% and 10%, respectively, of those observed in the placebo group. Smaller decreases were seen in spermidine levels and spermidine:spermine ratios. Polyamine levels increased toward baseline values after discontinuation of DFMO. Although there were no statistically significant differences among the dose groups with respect to clinically important shifts in audiometric thresholds and nonaudiologic side effects, statistically significant higher dropout and discontinuation rates were observed in the highest dose group. CONCLUSIONS: Polyamine levels in rectal mucosa can be continuously suppressed by daily oral doses of DFMO that produce few or no side effects. A dose of 0.20 g/m2 can be used safely in combination phase IIb or single-agent phase III chemoprevention trials.

The clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma.

BACKGROUND: Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) of pancreatic lesions is being increasingly used. Our aim was to determine the safety, accuracy, and clinical utility of EUS-guided FNA in both the diagnosis and staging of pancreatic cancer. METHODS: Forty-four patients (24 men/20 women) had EUS-guided FNA of pancreatic lesions (39 head/neck, 5 body, 3 tail) and/or associated lymph nodes. The mean age was 61 (range, 28 to 88 years). The indication for EUS-guided FNA was a pancreatic lesion seen initially on CT (39%), ERCP (43%), or EUS (18%). Follow-up data were collected on all patients for mean of 14.5 months (range 1 to 33 months). RESULTS: CT detected only 15 of 61 (25%) focal lesions seen by EUS, Adequate specimens were obtained by EUS-guided FNA in 44 of 47 (94%) pancreatic lesions and 14 of 14 (100%) associated lymph nodes (overall adequacy was 95%). Of the 46 lesions in which specimens were adequate and a final diagnosis was available (32 malignant, 14 benign), EUS-guided FNA had a sensitivity of 92%, specificity of 100%, and diagnostic accuracy of 95% for pancreatic lesions and 83%, 100%, and 88% for lymph nodes, respectively. Six percent of pancreatic cases had inadequate specimens and, if included, lowered the sensitivity to 83%, specificity to 80%, and diagnostic accuracy to 88% for pancreatic lesions. In 3 patients with enlarged celiac nodes on EUS, EUS-guided FNA was able to make a tissue diagnosis of metastasis, which changed the preoperative staging and precluded surgery. EUS in combination with EUS-guided FNA precluded surgery in 12 of 44 (27%) and may have precluded surgery in an additional 6 of 44 (14%). EUS-guided FNA avoided the need for further diagnostic tests, thus expediting therapy in a total of 25 (57%) patients and influenced clinical decisions in 30 of 44 (68%) patients. The estimated cost savings based on surgeries avoided was approximately $3300 per patient. There was only one complication (2%), a post-FNA fever. CONCLUSION: EUS-guided FNA of the pancreas appears to be a safe and effective method that increases both the diagnostic and staging capability of EUS in pancreatic cancer. The clinical impact of EUS-guided FNA includes avoiding surgery and additional imaging studies with a substantial cost savings.

Endoscopic ultrasound-guided fine-needle aspiration.

Thirty-eight consecutive patients underwent endoscopic ultrasound-guided fine-needle aspiration. Of 46 lesions, 34 were extraluminal (12 pancreatic masses, 8 periesophageal nodes, 6 celiac nodes, 2 pericolonic masses, 1 mediastinal mass, 1 perigastric mass, 1 liver, 1 periduodenal node, 1 perirectal mass, 1 perirectal node) and 12 were submucosal (8 gastric, 3 duodenal, 1 esophageal). One hundred sixty-three passes were made, with an average of 3.5 passes per lesion and 4.3 passes per patient (range, 1 to 8). Adequate specimens were obtained from 91% of targeted lesions. The overall diagnostic accuracy was 87%. In patients with malignant lesions, sensitivity was 91% and specificity 100%. Celiac nodes were successfully sampled and diagnostic in 5 of 6 (83%) patients. No complications occurred. Using this technique, an initial tissue diagnosis of malignancy was made in 66% of cancer patients without a previous diagnosis and the preoperative stage was changed in 44% of cancer patients. The additional information gained by this modality directly influenced the decision not to perform surgery in 26% of patients with a primary malignancy. Endoscopic ultrasound-guided fine-needle aspiration is feasible and can be safely used to evaluate submucosal and extraluminal lesions in both the upper and lower gastrointestinal tract with a high degree of diagnostic accuracy.

Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats.

Expression of epidermal growth factor receptor (EGFR) was studied immunohistochemically in rat gastric mucosa during healing of acetic acid-induced ulcers. In normal control gastric oxyntic mucosa, EGFR was expressed in proliferative zone cells and in some parietal cells. In mucosa of the ulcer margin, at 3, 7, and 16 days after ulcer induction, there was a 75-fold increase (over controls) in the number of cells expressing EGFR. Seventy percent of ulcers healed by the 16th day, and all were healed by the 25th day. The mucosal scar that replaced the ulcer was composed of dilated glands lined with poorly or aberrantly differentiated cells showing persistence of increased EGFR expression. An increased EGFR expression indicates an important role of EGF in ulcer healing and scar formation.

Calcium channel blockers and prostaglandin generation by gastric surface epithelial cells.

We investigated the effects of calcium channel blockers on generation of prostaglandin (PG) E2 and 6-keto PGF1 alpha by gastric mucosal surface epithelium. Surface epithelial cells (SEC) isolated from rat gastric mucosa were incubated with either verapamil (1 or 10 micrograms/ml), diltiazem (2.5 or 25 micrograms/ml) or nifedipine (2.5 or 25 micrograms/ml) for 30 min at 37 degrees C in calcium containing or calcium-free medium. Verapamil (both doses) significantly increased PGE2 and 6-keto PGF1 alpha generation by the surface epithelial cells but only in calcium containing medium. Diltiazem did not affect PG generation in calcium containing nor calcium-free medium. Nifedipine 25 micrograms/ml decreased PGE2 but increased 6-keto PGF1 alpha generation. The inhibitory effect of nifedipine on PGE2 generation was abolished in calcium-free medium, while the calmodulin antagonist did not affect verapamil-induced increase in PG generation.

Expression of epidermal growth factor receptor in rat gastric oxyntic mucosa.

Epidermal growth factor (EGF) is a mitogenic polypeptide that inhibits gastric acid secretion, protects the gastric mucosa against acute injury, and accelerates ulcer healing. In the present study we demonstrated immunohistochemically, using two different techniques, localization of EGF receptors in normal rat gastric oxyntic mucosa: in proliferative zone cells and in some parietal cells. It is likely that these cells represent the major targets for the EGF [and transforming growth factor alpha (TGF-alpha) which shares a common receptor with EGF] actions, stimulating cell proliferation and inhibiting acid secretion.

Clonidine and lidamidine (WHR-1142) stimulate sodium and chloride absorption in the rabbit intestine.

The effects of clonidine and lidamidine on ion transport in the intestine of the rabbit were determined. In the ileum both clonidine (10(-6) M) and lidamidine (10(-3) M) (a) decreased the short circuit current (-1.9 +/- 0.3 and -2.0 +/- 0.4 muEq/h . cm2, respectively) and potential difference; (b) increased net sodium absorption (2.0 +/- 0.6 and 1.8 +/- 0.4 muEq/h . cm2) and chloride absorption (3.4 +/- 0.5 and 3.4 +/- 0.6 muEq/h . cm2); and (c) increased tissue conductance (8.7 +/- 1.7 and 10.0 +/- 1.6 mmho/cm2). The increase in net sodium and chloride absorption was primarily due to an increase in mucosal-to-serosal movement of the ions and a decrease in serosal-to-mucosal movement of chloride. The action of clonidine on the short circuit current was quantitatively similar to the action of epinephrine. Both were readily reversed by yohimbine, a specific alpha 2-adrenergic antagonist. Further, methoxamine, an alpha 1-adrenergic agonist has no effect on the short circuit current up to the concentration of 10(-5) M; and prazosin, an alpha 1-adrenergic antagonist, did not affect the change of the short circuit current induced by epinephrine. The results indicate the presence of alpha 2-adrenergic receptors on the intestine and suggest that alpha 2-adrenergic stimulation may account for the effect of epinephrine on ion transport. Lidamidine was studied because it is structurally related to clonidine and has many similar actions. Yohimbine transiently reversed the effect of lidamidine. alpha 1-Adrenergic or dopaminergic antagonists did not reverse the effect of lidamidine, suggesting that it may affect alpha 2-adrenergic receptors. The results indicate that both clonidine and lidamidine stimulate electrolyte absorption and may be clinically useful.

Clonidine and lidamidine to inhibit watery diarrhea in a patient with lung cancer.

A patient with watery diarrhea syndrome secondary to bronchogenic carcinoma responded to treatment with clonidine and lidamidine. Stool weight decreased to 43% and 53% of control on two separate trials of clonidine. Stool weight decreased to 35% of control during a trial of lidamidine. Both clonidine and lidamidine increased sodium and chloride absorption in vitro in human intestine. Clonidine, lidamidine, or drugs that are structurally similar may become therapeutic choices for secretory diarrhea.