Shared Individual Formulation Therapy (SIFT): an open-label trial of a new therapy accommodating patient heterogeneity in functional neurological disorder.

BACKGROUND: Functional Neurological Disorder (FND) is a complex neuropsychiatric condition with a multifactorial aetiology. The heterogeneity of patients with FND is rarely considered in psychotherapy trials, which may contribute to variable outcomes. Shared Individual Formulation Therapy (SIFT) is a new, brief (four session) psychotherapy that aims to accommodate heterogeneity by providing a personalised, trans-theoretical formulation of the person's difficulties and accompanying management plan. METHODS: An open-label, prospective trial of outpatient SIFT for adults with FND was conducted, using health-related quality of life (SF-12) as the principal outcome measure, with secondary measures of mental health, dissociation, health care use and attitude to the FND diagnosis. Measures were collected at baseline, end of treatment and 6- and 12-month follow-ups. RESULTS: Twenty-nine participants with various FND symptoms enrolled. Twenty-four completed all four sessions and 25 completed follow-up measures at 12 months. SF-12 scores improved significantly at end of treatment and were sustained throughout follow-up with moderate effect sizes (0.39-0.47; all p < 0.001). Most secondary outcomes also improved significantly at all time points. The intervention was highly acceptable and tolerable to patients and perceived as beneficial. CONCLUSION: This trial provides preliminary evidence for initial and sustained benefit from SIFT for adults with FND. Further study is needed to validate these findings.

Compact steady-state and high-flux Falcon ion source for tests of plasma-facing materials.

This paper describes the design and operation of the Falcon ion source. It is based on conventional design of anode layer thrusters. This ion source is a versatile, compact, affordable, and highly functional in the research field of the fusion materials. The reversed magnetic field configuration of the source allows precise focusing of the ion beam into small spot of ≈3 mm and also provides the limited capabilities for impurity mass-separation. As the result, the source generates steady-state ion beam, which irradiates surface with high heat (0.3 - 21 MW m(-2)) and particle fluxes (4 × 10(21) - 3 × 10(23) m(-2)s(-1)), which approaches the upper limit for the flux range expected in ITER.

Electron-impact ionization of silicon tetrachloride (SiCl4).

We measured absolute partial cross sections for the formation of various singly charged and doubly charged positive ions produced by electron impact on silicon tetrachloride (SiCl4) using two different experimental techniques, a time-of-flight mass spectrometer (TOF-MS) and a fast-neutral-beam apparatus. The energy range covered was from the threshold to 900 eV in the TOF-MS and to 200 eV in the fast-neutral-beam apparatus. The results obtained by the two different experimental techniques were found to agree very well (better than their combined margins of error). The SiCl3(+) fragment ion has the largest partial ionization cross section with a maximum value of slightly above 6x10(-20) m2 at about 100 eV. The cross sections for the formation of SiCl4(+), SiCl+, and Cl+ have maximum values around 4x10(-20) m2. Some of the cross-section curves exhibit an unusual energy dependence with a pronounced low-energy maximum at an energy around 30 eV followed by a broad second maximum at around 100 eV. This is similar to what has been observed by us earlier for another Cl-containing molecule, TiCl4 [R. Basner, M. Schmidt, V. Tamovsky, H. Deutsch, and K. Becker, Thin Solid Films 374 291 (2000)]. The maximum cross-section values for the formation of the doubly charged ions, with the exception of SiCl3(++), are 0.05x10(-20) m2 or less. The experimentally determined total single ionization cross section of SiCl4 is compared with the results of semiempirical calculations.

Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

Blood pressure inversely correlates with thrombin-evoked calcium rise in platelets.

Earlier investigations showed a positive correlation between basal cytosolic free calcium in human platelets and blood pressure; however, recent studies have failed to show this relation. We undertook the present work to examine which platelet cytosolic calcium parameters (namely, cytosolic calcium in resting or stimulated states in calcium-containing and calcium-free media) present the least variability and best correlation with blood pressure. We studied 17 healthy white men on three different occasions separated by 1- and 4-week intervals. Their manual and ambulatory automated 24-hour blood pressure measurements were correlated with cytosolic calcium in resting and stimulated (thrombin-treated) fura 2-loaded platelets. The following cytosolic calcium parameters were measured in 1 mmol/L calcium and calcium-free media: basal cytosolic calcium, peak thrombin-evoked cytosolic calcium, and post-transient cytosolic calcium 5 minutes after thrombin treatment. The highest and lowest coefficients of variation were respectively shown by the basal cytosolic calcium (22.8%) and peak thrombin-evoked cytosolic calcium (10.1%) in calcium medium. Basal cytosolic calcium did not correlate with any of the blood pressure parameters. Of the cytosolic calcium parameters, peak thrombin-evoked cytosolic calcium in calcium medium demonstrated consistent (negative) correlations with blood pressure, with better correlations shown with diastolic than systolic blood pressure of both automated and manual blood pressure readings. Peak thrombin-evoked cytosolic calcium in calcium medium showed similar correlations with nighttime and daytime automated blood pressure measurements. There were no correlations between peak thrombin-evoked cytosolic calcium in calcium-free medium and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism is characterized by unusual sensitivity of aldosterone secretion to ACTH. Suppressibility by glucocorticoid and continued stimulability by exogenous ACTH has provided the basis for diagnosis and treatment of the disorder. A qualitative biochemical abnormality consisting of marked overproduction of the products of the cortisol C-18 oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, has been examined in 10 patients with the disorder and compared to the normal C-18 oxidation products of corticosterone, aldosterone, and 18-hydroxycorticosterone. The technique, based on stable isotope dilution mass fragmentography, measured the tetrahydro urinary metabolites of aldosterone, 18-hydroxycorticosterone, and 18-oxocortisol and unmetabolized 18-hydroxycortisol. All 4 C-18 oxygenated corticosteroids were markedly elevated in the untreated state and showed rapid parallel suppression with low doses of glucocorticoid. The proportional changes in C-18 oxygenated cortisols together with aldosterone and 18-hydroxycorticosterone suggested the mechanism of a common catalytic site of a cytochrome P450 methyl oxidase serving both cortisol and corticosterone substrates. The ACTH-dependent secretion of the C-18 oxidation products of both corticosterone and cortisol in the disorder is attributed to the acquisition of methyl oxidase activity by the fasciculata zone, where there are abundant pools of these precursors.

Variations in the apparent pH set point for activation of platelet Na-H antiport.

To explore the role of the Na-H antiport in essential hypertension, we studied the kinetics of cytosolic pH and external sodium activation of this transport system in platelets from 65 normotensive and essential hypertensive subjects on and off antihypertensive medications. Subjects included both blacks and whites, as well as men and women. The fluorescent dye 2'7-bis(carboxyethyl)-5,6-carboxyfluorescein was used to monitor the cytosolic pH in these cells. Platelets from black (hypertensive and normotensive) men and hypertensive white men demonstrated a highly significant alkaline shift in the apparent cytosolic pH set point for activation of the Na-H antiport. For the hypertensive subgroups, the cytosolic pH set point values (mean +/- SEM) were: white men, 7.45 +/- 0.052; white women, 7.04 +/- 0.089; black men, 7.66 +/- 0.148; and black women, 7.20 +/- 0.082. For the normotensive subgroups, the cytosolic pH set point values were: white men, 7.13 +/- 0.034; white women, 7.05 +/- 0.036; black men, 7.50 +/- 0.110; and black women, 7.20 +/- 0.176 (p = 0.0016 for race and p = 0.0001 for gender, using a three-way analysis of variance by race, gender, and hypertension). There were no race-, gender-, or blood pressure-related differences among the various cohorts in the kinetics of sodium activation of the Na-H antiport, the cellular buffering power, and basal pH. These results suggest that at basal pH the Na-H antiport is quiescent in platelets from both black and white women and normotensive white men.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of Ca2(+)-ATPase activation in platelet membranes of essential hypertensives and normotensives.

To explore the etiology of altered Ca metabolism in essential hypertension, we studied parameters, i.e., maximal initial reaction velocity (Vmax) and Michaelis constant (Km), of Ca activation kinetics of Ca2(+)-ATPase in membrane fractions (isolated by a sucrose gradient) from platelets of blacks and whites, 27 of whom were essential hypertensives, 17 of whom were normotensives with a family history of essential hypertension, and 10 of whom were normotensives without a family history of the disease. The Vmax of hypertensives was significantly lower than in normotensives without a family history of essential hypertension (hypertensives, 14.99 +/- 1.71 nmol Pi.mg protein-1.min-1; normotensives, positive family history, 22.67 +/- 3.17 nmol Pi.mg protein-1.min-1; normotensives, negative family history, 27.54 +/- 4.37 nmol Pi.mg protein-1.min-1; overall, P = 0.0078). The Km was lower in both hypertensives and normotensives with a positive family history of essential hypertension as compared with normotensives with a negative family history of the disease (hypertensives, 1.70 +/- 0.23 microM; normotensives, positive family history, 1.38 +/- 0.2 microM; normotensives, negative family history, 2.79 +/- 0.58 microM; overall, P = 0.0251). Furthermore, the Km in whites was inversely related to plasma renin activity (r = 0.50; P less than 0.005). We propose that a lower Vmax for Ca2(+)-ATPase may play a role in the higher level of free Ca in platelets of essential hypertensives and that a higher affinity of the enzyme to Ca may reflect a process compensating for the lower Vmax. We also suggest that a higher Km for Ca2(+)-ATPase in juxtaglomerular cells of whites would result in blunting the release of renin.

Colonic involvement in angioimmunoblastic lymphadenopathy resembling inflammatory bowel disease.

A woman 68 years of age had fever, malaise, diffuse lymphadenopathy, splenomegaly followed by abdominal pain, and diarrhea. A lymph node biopsy specimen showed nonspecific follicular hyperplasia. Symptoms were responsive initially to prednisone. Recurrent symptoms warranted colonic biopsy, which was consistent with Crohn's disease, and were responsive partially to prednisone and azulfidine. Because of progressive deterioration, a repeat lymph node biopsy was performed and showed the characteristic histologic feature of angioimmunoblastic lymphadenopathy (AILD). The evolution of the histopathologic features of the case is discussed, and gastrointestinal (GI) manifestations of AILD are reviewed. Although the GI tract is an unusual site for extra nodal AILD, colonic involvement can imitate the clinical and histologic features of inflammatory bowel disease.

Bordetella bronchiseptica peritonitis associated with continuous ambulatory peritoneal dialysis.

Bordetella bronchiseptica has rarely been reported as an opportunistic pathogen in humans. This is the first documented report of peritonitis due to B. bronchiseptica. The organism was seen on a Gram strain of peritoneal fluid and was isolated from a culture of the fluid. It was thought that the source of infection was related to the close contact of the patient with his dog. The patient was successfully treated with chloramphenicol administered intraperitoneally and intravenously.

Plasma prolactin in essential and renovascular hypertension.

Plasma prolactin response to postural change and variation in dietary sodium was evaluated in five normal volunteers and 15 patients with essential hypertension. Values at 0800 hours (11.9 +/- 3.5 ng/ml, mean +/- 1 S.D.) were uninfluenced by the duration of recumbency (10 or 34 hr) and were significantly higher than those obtained at noon (6.9 +/- 3.5 ng/ml, mean +/- 1 S.D., p less than 0.001). The latter were uninfluenced by postural change. There was no correlation between sodium intake and plasma prolactin, nor was there any apparent correlation between prolactin and plasma renin activity. There was no significant difference in prolactin concentrations between normotensive and hypertensive subjects. In 10 additional patients with unilateral renal disease, renal vein prolactin concentrations did not differ significantly from simultaneously obtained peripheral concentrations. Renal vein prolactin was uninfluenced by the presence of renal disease and did not correlate with renal blood flow. It is concluded that there is no evidence of feedback between sodium intake and prolactin in man. Human kidneys do not seem to clear significant amounts of prolactin. It appears unlikely that alterations in prolactin concentration, at least as assessed by daytime values, participate in the maintenance of either essential or renovascular hypertension. Since values at 0800 hours are frequently elevated as a reflection of preceding sleep-related peaks, sampling at 1200 hours may be preferable when search is undertaken for hypothalamic-pituitary disease.

Synergistic effects of hydralazine and alpha- or beta-adrenergic blockers: the role of plasma renin activity.

Intravenous hydralazine, 0.15, 0.30 or 0.60 mg/kg, was administered to 11 supine hypertensives on two occasions: once after pretreatment with intravenous propranolol, 0.1 mg/kg, and once after pretreatment with intravenous placebo. The average fall in mean arterial pressure for each dosage of hydralazine was no different with or without propranolol, even though propranolol inhibited rises in plasma renin activity and pulse due to hydralazine. However, in each of four patients who had high supine baseline plasma renin activity, propranolol enhanced the fall in blood pressure caused by hydralazine. A second group of patients was given an infusion of 0.01 or 0.02 mg/kg per minute phentolamine, which did not change baseline blood pressure. Subsequent administration of intravenous hydralazine, 0.15 mg/kg, resulted in a fall in blood pressure which was larger than previously observed with intravenous hydralazine alone, regardless of supine baseline plasma renin activity. These data are consistent with the hypothesis that reflex catecholamine release interferes with the hypotensive effect of intravenous hydralazine. Pretreating with propranolol weakens homeostatic defenses against hydralazine such as rises in pulse rate and plasma renin activity. However, propranolol appears to enhance the alpha-adrenergic effect of released catecholamines, and the antihypertensive response to hydralazine is unaltered. In patients with high supine plasma renin activity, propranolol potentiates the fall in blood pressure induced by hydralazine, perhaps because the hypertension in such patients is renin dependent.

Individual renal clearances determined at renal vein catheterization.

Renal para-aminohippurate (PAH) clearances were predicted in 16 kidneys of eight hypertensive patients with renal artery stenosis, pyelonephritis, or obstructive nephropathy, without individual ureteral catheterization. Predictions of left or right kidney clearance (CL or CR) were based on roentgenographic renal frontal areas (A), on total PAH clearances (CT), and on individual PAH extractions (E) measured at renal vein catheterization according to the formula (formula: see text). When these patients underwent ureteral catheterization for diagnostic reasons, individual PAH clearances were measured and ranged from 22 to 286 cm3/min. After correction for differences in total PAH clearance on the two occasions, predicted and individually measured values corresponded closely along a line of identity. The 95% confidence limit (+/- 2 SEM) for predictions of individual PAH clearance was approximately +/- 38 cm3/min and for percet of total PAH clearance distributed to left or right kidney, +/- 6%. Individual renal PAH clearances can therefore be predicted at renal vein catheterization with acceptable error. Thus, the substantially invasive procedure of ureteral catheterization is not required to ascertain left and right kidney PAH clearance in patients already at risk from renal disease.

The circadian rhythm of renin.

The circadian rhythm of plasma renin activity during continuous recumbency was determined fifty-one times in thirty subjects who either slept at night or remained awake for 24 h. Both groups had maximum values between 2400 and 0800 h, despite absence of the expected early morning fall in blood pressure, pulse, and glomerular filtration rate in the awake subjects. Infusion of normal saline between 2300 and 0300 h initially suppressed renin, but did not prevent its subsequent rise regardless of the amount of sodium appearing in the urine. Of thirteen patients tested two to five times, twelve had recurrence of the zenith within a single 4 h period on retesting, despite differences in sodium intake, basal blood pressure, and mean plasma renin activity. Peaks of lesser magnitude were also frequently noted, most commonly at 1000 h and 1800-2000 h. Minimum PRA values were not restricted to a particular time of day and did not generally recur at the same time upon retesting. The mean ratio of maximum to minimum PRA in each study was 246% +/- 18.3% (+/- 1 SEM). The circadian rhythm of renin appears to be independent of known renal mechanisms responsible for regulating renin release. It is possible that this rhythm is controlled by the central nervous system.

Circadian rhythm of plasma renin activity in primary hyperaldosteronism.

The circadian periodicity of plasma renin activity (PRA) during continuous recumbency was determined five times in a patient with primary hyperaldosteronism. All curves were parallel with one another. There were significant elevations of PRA at 1600-2000 h, falls at 2400 h, and peaks at 0200-0800 h. This periodicity was uninfluenced by changes in baseline PRA, serum potassium concentration, salt intake, plasma volume, blood pressure, or mineralocorticoid effect. It persisted despite inability of the patient to sleep on two nights. It is suggested that the observed periodicity of renin is a true endogenous diurnal rhythm of possible central nervous system origin.

Normal plasma renin activity in low renin hypertension.

Plasma renin activity (PRA) was measured every 4 h during a 24-h period of continuous recumbency in 10 patients with essential hypertension. All had maximum values at 12 midnight, 4 AM or 8 AM. Analysis of our date and that of others indicates that in some patients with "low renin" hypertension (LRH) these noctural peaks are of normal magnitude, occasionally exceeding values obtained after four hours of erect posture. Sleep-induced renin release in these patients is not suppressed despite blunted responses to other stimuli. This suggests that the ability to synthesize and release renin may be normal in these patients. Such peaks were not obserived in all LRH subjects, however. The area enclosed by the recumbent PRA curve was also normal in some, but not all patients with LRH. Low renin hypertension may not be a homogeneous disorder.