Successful mirtazapine treatment of an 81-year-old patient with syndrome of inappropriate antidiuretic hormone secretion.

Elderly patients are at a higher risk for inappropriate antidiuretic hormone secretion when treated with antidepressants. In response to severe depressive symptoms, we initiated treatment with citalopram of an 81-year-old female patient with slightly reduced sodium and chloride levels. The sodium and chloride levels decreased continuously during treatment with citalopram; six days after the citalopram was discontinued, sodium and chloride levels returned to normal. We then switched treatment to mirtazapine. Close monitoring revealed that the patient's sodium and chloride levels never decreased and the patient did not relapse for more than two months. This case study indicates that treatment with citalopram may worsen preexisting hyponatremia. Mirtazapine appears to be safe for use in high-risk, elderly patients.

Quetiapine in combination with citalopram in patients with unipolar psychotic depression.

This 6-week, open-label, multicenter study evaluated the efficacy and safety of quetiapine in combination with citalopram in adult patients (n=25) with ICD-10/DSM-IV unipolar psychotic depression. The primary endpoint was change from baseline to Week 6 in the Hamilton Depression Rating Scale (HAM-D-21) score. Secondary endpoints were change from baseline to Week 6 in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores. Spontaneously reported adverse events (AEs), the Simpson Angus Scale (SAS), and the Udvalg for Kliniske Undersogelser (UKU) side effects rating scale scores were recorded. Patients' average age was 51.4 years and baseline weight was 72.6 kg. Quetiapine (50-750 mg/day, mean dose+/-SD: 303+/-118 mg/day), in combination with citalopram (20-60 mg/day, mean dose+/-SD: 34+/-12 mg/day), provided significant improvements in depression. Mean (+/- SD) HAM-D-21 was reduced to 13.25+/-10.87 at Week 6 from a baseline value of 31.21+/-5.18. Significant improvement of psychotic symptoms (mean+/-SD) was indicated by the decrease from baseline (59.25+/-6.60) to Week 6 (35.25+/-15.60) in BPRS scores. No serious AEs occurred. The mean change in weight was +2.1 kg. Mean (+/- SD) weight at visit 1 was 72.72 (+/-16.34) kg and mean (SD) weight at visit 4 was 74.79 (+/-18.69) kg. Quetiapine in combination with citalopram appears to be effective and is well tolerated in the treatment of unipolar psychotic depression. Further studies of larger, double-blind, parallel-group design are warranted to confirm these findings.

Efficacy and tolerability of quetiapine in patients with schizophrenia switched from other antipsychotics.

OBJECTIVE The Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication (SPECTRUM) study assessed the efficacy and tolerability of quetiapine (Seroquel™) in patients with schizophrenia switched from treatments providing suboptimal outcomes. METHODS This was an international, open-label, non-comparative study, designed with titration to 400 mg/day quetiapine over 7 days, then flexible dosing (300-750 mg/day) for 11 weeks. Efficacy was assessed with the Positive and Negative Syndrome Scale (PANSS); Clinical Global Impression (CGI) Severity of Illness and Global Improvement scores; and the Calgary Depression Scale for Schizophrenia (CDSS). Clinical benefit and tolerability were also assessed. RESULTS The mean modal dose of quetiapine was 505 mg/day; 509 patients switched to quetiapine from olanzapine (13%), risperidone (11%), conventional antipsychotics (37%) and combinations of antipsychotics (28%), amongst others. Significant decreases in CGI Severity of Illness and PANSS scores and a significant improvement in CDSS score resulted from the switch (all P<0.001 versus baseline). There were significant reductions in extrapyramidal symptoms (EPS) on the Simpson-Angus Scale (SAS) and Barnes Akathisia Scale (BAS) (both P<0.001 versus baseline) and a low incidence of EPS-related adverse events (4.7%). CONCLUSION Results indicate that switching to quetiapine was clinically beneficial for patients with poor efficacy or intolerable side effects on their previous antipsychotic medication.

Selectivity of the renal collecting duct water channel aquaporin-3.

Aquaporin-3 (AQP3) is a water channel found in the basolateral cell membrane of principal cells of the renal collecting tubule as well as in other epithelia. To examine the selectivity of AQP3, the permeability to water (Pf), urea (Pur), and glycerol (Pgly) of Xenopus oocytes injected with cRNA encoding AQP3 was measured. Oocytes injected with cRNA encoding either human or rat aquaporin-1 (AQP1) were used as controls. Although both aquaporins permit water flow across the cell membrane, only AQP3 was permeable to glycerol and urea (Pgly > Pur). The uptake of glycerol into oocytes expressing AQP3 was linear up to 165 mM. For AQP3 the Arrhenius energy of activation for Pf was 3 kcal/mol, whereas for Pgly and Pur it was >12 kcal/mol. The sulfhydryl reagent p-chloromercuriphenylsulfonate (1 mM) abolished Pf of AQP3, whereas it did not affect Pgly. In addition, phloretin (0.1 mM) inhibited Pf of AQP3 by 35%, whereas it did not alter Pgly or Pur. We conclude that water does not share the same pathway with glycerol or urea in AQP3 and that this aquaporin, therefore, forms a water-selective channel.

Feedback regulation of Na channels in rat CCT. IV. Mediation by activation of protein kinase C.

The hypothesis that feedback inhibition of the apical Na+ channels in the cortical collecting tubule (CCT) is mediated by activation of a Ca(2+)-dependent protein kinase was tested using the patch-clamp technique. Na+ channel activity was monitored in cell-attached patches in principal cells of split-open rat tubules. Mean number of open channels (NPo) and single-channel current (i) were measured at 37 degrees C during continuous tubule superfusion. Phorbol 12-myristate 13-acetate (PMA; 50 nM), an activator of protein kinase C (PKC), decreased NPo to 33% of the control value. Staurosporine (200 nM), an inhibitor of PKC and of Ca(2+)-calmodulin kinase II, practically abolished the effect of PMA. Ouabain (1 mM), reduced NPo to 29% of control values and decreased i. Ouabain did not downregulate the channels in tubules exposed to staurosporine, although it still reduced i. Incubation of the tubules with 10 microM KN-62, a specific cell membrane-permeable inhibitor of Ca(2+)-calmodulin kinase II, did not interfere with the ouabain-dependent downregulation of the channels. The results support the view that the downregulation caused by ouabain involves the Ca(2+)-dependent phosphorylation of the channel itself or of proteins regulating the channel.

Serum dehydroepiandrosterone and cortisol measurements in Huntington's chorea.

Serum levels of dehydroepiandrosterone sulfate (DHEAS), known to antagonize metabolic effects of glucocorticoids in animals, and cortisol (CRT), already shown to be related to cognitive dysfunction in man and animals, were measured in 11 drug-free male subjects with definite Huntington's chorea (HC) and in 25 age-matched male normal controls. Statistical difference was found between DHEAS serum levels (p < 0.05), CRT levels (p < 0.05) and the DHEAS/CRT ratio (p < 0.01) of HC subjects and normal individuals. These findings may indicate a dysfunction of the hypothalamic-pituitary-adrenal axis (HPAA) and possibly suggest a role of DHEAS as an antiglucocorticoid in HC.

Feedback regulation of Na channels in rat CCT. III. Response to cAMP.

The effects of exogenous adenosine 3',5'-cyclic monophosphate (cAMP) on apical Na channels in the rat cortical collecting tubule were studied using the patch-clamp technique and fura 2 fluorescence measurements of intracellular Ca2+ (Ca2+i). When the permeant analogue, 8-(4-chlorophenylthio)-cAMP (CPT-cAMP, 200 microM), was added to the superfusate during recording from cell-attached patches, both the mean number of open channels (NPo) and the single-channel current (i) decreased within 3 min. When the superfusate also contained amiloride (10 microM), there was no effect of CPT-cAMP on either NPo or i. When CPT-cAMP was added to the bath before formation of the patch, the density of conducting channels was increased from 10 +/- 2 to 37 +/- 6 per patch, as estimated by analysis of channel-induced noise. This suggests that cAMP increases open-channel density in the regions of the apical membrane outside the patch but not within the patch. Channels already active in the patch before stimulation with the nucleotide are subject to feedback inhibition secondary to increased Na entry into the cell. CPT-cAMP increased Ca2+i from 104 to 198 nM. This increase in Ca2+i was abolished by benzamil (0.5 microM) or by low extracellular Ca2+. The cAMP-dependent reduction in NPo was still observed in Ca(2+)-free medium, indicating that a rise in Ca2+i was not essential for the feedback response. The decrease in NPo was attenuated, however, when cAMP was added in the absence of Ca2+ and in the presence of ouabain (1 mM) in the superfusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Cloning and expression of AQP3, a water channel from the medullary collecting duct of rat kidney.

The terminal part of the inner medullary collecting duct exhibits a high degree of water permeability that is independent of increased intracellular cAMP and not accounted for by the activity of the known renal epithelial water channels CHIP28 (28-kDa channel-forming integral protein) and WCH-CD (collecting duct water channel protein). Starting with rat kidney papilla mRNA, reverse transcription PCR was performed with degenerate primers assuming that the putative channel would be a member of the major intrinsic protein (MIP) family of proteins. A cDNA fragment was identified and used to screen a rat kidney cDNA library. A 1.9-kb cDNA clone was isolated. The open reading frame of 876 bp coded for a protein of 292 amino acids (M(r), 31,431). Aquaporin 3 (AQP3; 31.4-kDa water channel protein) is a newly discovered member of the MIP family. Northern blot analysis showed a single transcript for AQP3 of approximately 1.9 kb present in the renal medulla, predominantly in the inner medulla. With in situ hybridization, abundant message was found in the cells of the medullary collecting ducts. Injection of the complementary RNA of AQP3 into Xenopus oocytes markedly increased the osmotic water permeability. This permeability had an energy of activation of 3.0 kcal/mol (1 cal = 4.184 J), it was fully blocked by 1 mM p-chloromercuriphenylsulfonate, and this inhibition was reversed by 5 mM dithiothreitol. cAMP did not increase this water permeability. AQP3 did not permit passage of monovalent ions (Na, K, Cl); however, it is slightly permeable to urea. The present study demonstrates the existence of an additional water channel, AQP3, in epithelial cells of the medullary collecting duct.

Expression of multiple water channel activities in Xenopus oocytes injected with mRNA from rat kidney.

To test the hypothesis that renal tissue contains multiple distinct water channels, mRNA prepared from either cortex, medulla, or papilla of rat kidney was injected into Xenopus oocytes. The osmotic water permeability (Pf) of oocytes injected with either 50 nl of water or 50 nl of renal mRNA (1 microgram/microliter) was measured 4 d after the injection. Pf was calculated from the rate of volume increase on exposure to hyposmotic medium. Injection of each renal mRNA preparation increased the oocyte Pf. This expressed water permeability was inhibited by p-chloromercuriphenylsulfonate and had a low energy of activation, consistent with the expression of water channels. The coinjection of an antisense oligonucleotide for CHIP28 protein, at an assumed > 100-fold molar excess, with either cortex, medulla, or papilla mRNA reduced the expression of the water permeability by approximately 70, 100, and 30%, respectively. Exposure of the oocyte to cAMP for 1 h resulted in a further increase in Pf only in oocytes injected with medulla mRNA. This cAMP activation was not altered by the CHIP28 antisense oligonucleotide. These results suggest that multiple distinct water channels were expressed in oocytes injected with mRNA obtained from sections of rat kidney: (a) CHIP28 water channels in cortex and medulla, (b) cAMP-activated water channels in medulla, and (c) cAMP-insensitive water channels in papilla.

[Psychotic manifestation of hypothyroidism. A case report]. / Psychotische Manifestation einer Hypothyreose. Ein Fallbericht.

The case of a young woman is reported, who was treated one and a half years with psychopharmacologic agents and psychotherapy until hypothyroidism was diagnosed. Initially the psychopathology with prominent though disorders led to a tentative diagnosis of schizophrenia. Under administration of thyroid hormone the patient was free of psychiatric and somatic symptoms within 3 months. Problems of diagnosis, therapy and prognosis are discussed in relation of the literature.

Feedback regulation of Na channels in rat CCT. I. Effects of inhibition of Na pump.

Na channels in the apical membrane of the rat renal cortical collecting tubule were studied using the patch-clamp technique. Channel activity was monitored in cell-attached patches on tubules that were split open to expose the luminal surface. Channel number (N), open probability (Po), and currents (i) were measured at 37 degrees C during continuous superfusion of the tubule. Addition of ouabain (1 mM) to the superfusate to increase cell Na resulted in a decrease in the mean number of open channels (NPo) to less than 20% of control values within 2 min. This effect was not reversible within 5 min after removal of ouabain. There was, in addition, a parallel decrease in i. The mechanism of inhibiton appeared to involve increased intracellular Ca (Cai). Cai was measured using the fluorescence of the Ca indicator fura-2 in principal cells of split tubules under conditions identical to those used for electrical measurements. Cai increased from a basal level (153 +/- 36 nM) to a peak level (588 +/- 53 nM) approximately 3 min after the addition of ouabain. When a Ca-free superfusate was used, ouabain did not increase Cai or decrease NPo, although the decrease in i was similar to that observed in Ca-containing solutions. Similar increases in Cai were elicited by the Ca ionophore ionomycin (5 microM) in the presence of 0.1 mM extracellular Ca. This maneuver also resulted in a decrease in NPo which was similar to that observed in the presence of ouabain. Ouabain had no observable effect on cell pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Feedback regulation of Na channels in rat CCT. II. Effects of inhibition of Na entry.

Na channels in the apical membrane of the rat renal cortical collecting tubule were studied using the patch-clamp technique. Channel activity was monitored in cell-attached patches on tubules that were split open to expose the luminal surface. Channel number (N), open probability (Po), and single-channel currents (i) were measured at 37 degrees C during continuous superfusion of the tubule. Addition of amiloride (10 microM) or benzamil (0.5 microM) to the superfusate resulted in a twofold increase in the mean number of open channels (NPo) after 2 min. The effect closely paralleled an increase in i, presumably reflecting membrane hyperpolarization. The effects on both i and NPo reversed within 3 min after removal of amiloride. The increase in NPo was accounted for, at least in part, by an increase in Po. Several cellular events may contribute to this phenomenon. Channels could be activated directly by membrane hyperpolarization and by cell shrinkage, both of which are known to occur during acute administration of amiloride. In addition, benzamil elicited a 30% decrease in intracellular Ca compared with control levels as measured by fura-2 fluorescence. A comparable decrease observed after reducing extracellular Ca did not increase NPo. No changes in cell pH, measured with 2',7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein fluorescence, were observed. The modulation of channel Po by the rate of Na entry into the cell will act as a feedback mechanism to maintain cellular ion homeostasis, and this may also serve to distribute Na reabsorption more evenly along the nephron.

Age and sex differences of dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels in normal controls and Alzheimer's disease (AD).

In 50 healthy subjects (23 female, 27 male, aged 18-81) and 24 patients with Alzheimer's disease (AD) (11 female, 13 male, aged 58-88) DHEAS and CRT plasma levels were studied. In normal subjects there was a clear negative correlation of DHEAS to age, while no significant age correlated decrease of CRT plasma levels was found. There was a significant decrease in the DHEAS/CRT ratio in elderly controls (aged > 60) as compared to young individuals (aged < 45). Overall there was a trend to lower DHEAS/CRT ratios in AD patients compared to age matched controls out of the total group of normals (P < 0.1), there was a significant decrease of this ratio in female AD patients (P < 0.05), compared to age matched female controls, but there was none in male Alzheimers; furthermore there was a significant difference in CRT plasma levels between female AD patients and age matched female controls (P < 0.01) and between female and male AD patients (P < 0.05). Considering the antiglucocorticoid effects of DHEAS, this ratio may account for its protective effect against hippocampal degeneration caused by glucocorticoids and possibly for the higher rate of AD in females.

Expression of renal Na(+)-Ca2+ exchange activity in Xenopus laevis oocytes.

The expression of a renal Na(+)-Ca2+ exchanger by Xenopus oocytes has been investigated. Each oocyte was injected with 50 ng of poly(A)+ RNA from either rat or rabbit kidney or with an equivalent volume of water. Na(+)-Ca2+ exchange was determined 3 days after injection, by measuring Ca2+ uptake by oocytes in the presence or absence of an outwardly directed Na+ concentration gradient. To manipulate Na+ concentration gradients, oocytes were first loaded with Na+ in Ca(2+)-free medium containing 90 mM Na+ and nystatin. They were then exposed to medium containing 45Ca and either 90 mM or 0 Na+. Na(+)-free media contained (in mM) either 90 K+, 90 choline or 85 choline plus 5 K+. Oocytes injected with rat kidney poly(A)+ RNA showed a Na+ gradient-dependent Ca2+ uptake of 6.6 +/- 0.8 (SE, n = 5) pmol.oocyte-1.30 min-1. This is significantly higher than the value of 3.4 +/- 0.5 (SE, n = 5) pmol.oocyte-1.30 min-1 obtained in water-injected oocytes (P less than 0.001). Similar results were obtained using poly(A)+ RNA from rabbit kidney cortex. Neither 10 microM nifedipine nor 0.5 mM D 600 significantly affected this Ca2+ uptake. However, 90% of the Ca2+ uptake was inhibited in the presence of 0.1 mM La3+. The poly(A)+ RNA-induced Na(+)-Ca2+ exchange activity was stimulated by the presence of 5 mM K+ in the extracellular choline solution compared with choline alone. Fractionation experiments indicate that the rat kidney Na(+)-Ca2+ exchanger was encoded by poly(A)+ RNA of 3-4 kb.

Clinical and electrodiagnostic findings, nerve biopsy and blood group markers in a family with hereditary neuropathy with liability to pressure palsies.

Clinical, electrophysiologic and biopsy findings as well as studies of blood group markers in a family with hereditary neuropathy with liability to pressure palsies (HNPP) are reported. There was an autosomal dominant trait without genetic linkage between the HNPP gene and blood group markers controlled by chromosome 1. Reduced motor and sensory nerve conduction velocity was found in clinically affected and unaffected nerves. Characteristic morphological changes in sural nerve biopsy including tomaculous swelling were present.

Long latency EMG responses in early diagnosis of Huntington's chorea.

In healthy subjects, 2 EMG responses of the thenar muscles can be distinguished, elicited by electrical stimulation of the median nerve during an isometric contraction: an early spinal response (M1) and a long latency response (LLR) (M2); earlier studies have shown that in patients with Huntington's chorea (HC) this late EMG response is missing. LLR were studied in the nine subjects at risk out of three families with definite HC. In 6 of them, LLR was clearly asymmetrical or absent on one or both sides, while normal LLRs were seen in the rest of the subjects studied; LLR abnormalities found in clinically free members of HC families may assist in early diagnosis of individuals who may later develop symptoms and may help in genetic counselling.