Reversible hypocalcemic heart failure with T wave alternans and increased QTc dispersion in a patient with chronic renal failure after parathyroidectomy.

Despite the crucial role of calcium in myocardial contractility, hypocalcemia has very rarely been reported as a reversible cause of heart failure. In this article, we describe a case of a 51-year-old woman with advanced stages of chronic renal failure after parathyroidectomy who exhibited congestive heart failure, severe hypocalcemia, hypomagnesemia and hypokalemia. Severe hypocalcemia resulted from discontinuation of taking calcium supplements after parathyroidectomy and from reduced 1.25(OH)2D3 synthesis by damaged kidneys. The patient presented with reduced left ventricular ejection fraction (EF) and ECG abnormalities (T wave alternans and increased QTc dispersion), both of which improved after correction of serum calcium levels. Her serum levels of total calcium corrected for serum albumin, but not serum levels of magnesium or potassium, positively and negatively correlated with EF and QTc dispersion, respectively. In the present case, both heart failure and the ECG abnormalities are directly associated with hypocalcemia.

Effects of hyperosmolality on Na, K-ATPase gene expression in vascular smooth muscle cells.

Cultured vascular smooth muscle cells (VSMC) from rat thoracic aortas were exposed to hyperosmotic media to determine the effects on Na, K-ATPase alpha1- and beta1-mRNA expression. Hyperosmotic media (500 mOsm/kgH2O) supplemented with glucose or mannitol increased alpha1-mRNA levels threefold at 24 hr and beta1-mRNA levels sevenfold at 12 hr. In sharp contrast, hyperosmotic urea medium had no effect at any time. Both the protein synthesis inhibitor cycloheximide and the RNA transcription inhibitor actinomycin D reduced alpha1- and beta1-mRNA upregulation induced by hyperosmotic glucose or mannitol media. Protein kinase C (PKC) inhibitors (staurosporine A or calphostin C) or tyrosine kinase (TK) inhibitors (genistein or herbimycin A) had no effect on the alpha1-mRNA upregulation induced by hyperosmotic glucose or mannitol media. Hyperosmotic glucose or mannitol media (500 mOsm/kgH2O) significantly increased alpha1- and beta1-subunit protein levels and Na, K-ATPase activity, whereas hyperosmotic urea medium had no effect. Transfection experiments with the 5'-flanking sequences of the alpha1- or beta1-subunit genes linked to the luciferase reporter gene revealed that hyperosmolar glucose medium increased luciferase activity 2.9- and 3.7-fold, respectively. Similarly, hyperosmotic mannitol medium increased such activity 2.7- and 3.4-fold, respectively. These results demonstrate that: (i) hyperosmolality induced by the poorly permeating solutes (glucose and mannitol) stimulates alpha1- and beta1-mRNA accumulation, alpha1- and beta1-subunit protein accumulation, and Na, K-ATPase activity, whereas the rapidly permeating solute (urea) has no effect; (ii) the upregulation of alpha1- and beta1-mRNA in response to hyperosmotic glucose or mannitol media requires, at least in part, de novo synthesis of intermediate regulatory proteins; (iii) the hyperosmolality-induced alpha1-mRNA upregulation occurs through PKC- and TK-independent mechanisms, whereas the hyperosmolality-induced beta1-mRNA upregulation occurs through activation of PKC and TK; and (iv) hyperosmolality induced by glucose or mannitol increases promoter activities of the alpha1- and beta1-subunit genes.

Growth inhibition of leukemic cells by (-)-epigallocatechin gallate, the main constituent of green tea.

In this report, we presented the results that EGCG, the main constituent of the polyphenols present in Japanese green tea inhibited growth of leukemic cell lines of both human and mice. The proliferation of human leukemic cell lines and mouse NFS60 cell line was inhibited by EGCG. Sensitivity of each line to EGCG was different, and more than 50% of DNA synthesis was reduced in all the cell lines in the presence of 50 microM EGCG. On the other hand, normal hematopoietic progenitor cells retained their natural function of supplying mature cells of various lineages in the presence of less than 10 microM EGCG in vitro. Even in the presence of 100 microM EGCG, half the colonies containing all the lineages of cells were developed. All the dead cells of each line showed characteristics of apoptosis, which might be due to inhibition by EGCG of growth factors' signaling. Besides anticarcinogenic activity, EGCG is expected to have a new function for leukemia therapy without side effects.

Relationship between a low toxicity of the mutant A subunit of enterotoxigenic Escherichia coli enterotoxin and its strong adjuvant action.

In the work described here it was determined if and how unnicking in the A subunit of Escherichia coli enterotoxin at Arg192 or nearby residues affected biological activities of the toxin. The mutant toxin was constructed to lack the nick site in the A subunit by deleting the tripeptide Arg192-Thr193-Ile194, which is essential for toxicity. The mutant toxin did not exhibit agmatine ADP-ribosyltransferase activity in the presence or absence of the ADP-ribosylation factor and had less diarrhoeal activity and lower induction of cyclic AMP than did LT. The mutant toxin exhibited a much stronger adjuvant action on antibody responses to measles virus, keyhole limpt haemocyanin, bovine immunoglobulin and ovalbumin compared with LT. The altered toxicity of the mutant toxin might be closely related to the potent adjuvant action on antibody responses to antigens. The relationship between two activities is discussed.

Effect of (-)-epigallocatechin gallate on leukemic blast cells from patients with acute myeloblastic leukemia.

Information on the anti-carcinogenic effect of EGCG, the main constituent of the polyphenols present in Japanese green tea leaves, has recently been accumulating. In this report, we evaluate the effect of EGCG on leukemic blast cells from AML patients. The results showed that EGCG inhibited the proliferation of AML cells in all cases examined. Since AML cells might proliferate by autocrine or paracrine growth mechanisms, we also examined the effect of EGCG on the production of GM-CSF from AML cells. Although EGCG did not directly inhibit the production of GM-CSF, it did inhibit the effect of TNF-alpha or TPA, both of which stimulated AML cells to produce GM-CSF. On the other hand, the modulation of receptors for growth factors might play a role in the proliferation or carcinogenesis of AML cells. We also found that EGCG inhibited the modulation of c-kit, a receptor for stem cell factor, on leukemic cells. These findings suggested that EGCG might be available as a new therapeutic tool for AML patients.

Hyperosmolality stimulates Na-K-ATPase gene expression in inner medullary collecting duct cells.

Primary cultures of inner medullary collecting duct (IMCD) cells of rats were incubated in hyperosmotic media to determine the effects on Na-K-ATPase alpha 1- and beta 1-subunit mRNA expression. Osmolality of the incubation media was raised from 300 up to 500 mosmol/kgH2O by adding NaCl, mannitol, raffinose, or urea. Hyperosmotic media supplemented with NaCl, mannitol, or raffinose caused two- to fourfold increases in the alpha 1-subunit mRNA accumulation and five- to eightfold increases in the beta 1-subunit mRNA accumulation, with peak elevations of both subunits at 12 h after addition. In sharp contrast, hyperosmolar urea medium had no effect at any time. When NaCl or mannitol was added to the media in amounts ranging from 300 to 600 mosmol/kgH2O, the maximal effects on both alpha 1- and beta 1-subunit mRNA accumulation occurred at 500 mosmol/kgH2O. In urea-supplemented medium, however, there was no significant change at any level of osmolality. The upregulation of alpha 1- and beta 1-subunit mRNA induced by hyperosmotic mannitol- or raffinose-supplemented media was markedly inhibited by removal of Na from the culture medium. Furthermore, pretreatment with a protein synthesis inhibitor cycloheximide partially inhibited the upregulation of alpha 1- and beta 1-subunit mRNA in IMCD cells exposed to hyperosmotic media treated with NaCl or mannitol. When IMCD cells were incubated with hyperosmotic media (500 mosmol/kgH2O) supplemented with NaCl or mannitol for 24 h, Na-K-ATPase activity increased by 78.6 and 82.8%, respectively. In contrast, hyperosmolar urea medium had no significant effect on Na-K-ATPase activity. These results demonstrate that 1) hyperosmolality induced by the poorly permeating solutes (NaCl, mannitol, and raffinose) but not the rapidly permeating solute (urea) stimulates both alpha 1- and beta 1-subunit mRNA accumulations in IMCD cells in a time- and an osmolality-dependent manner, 2) the hyperosmolality-induced upregulation of alpha 1- and beta 1-subunit mRNA leads to an increase in Na- K -ATPase activity; and 3) the above upregulation of alpha1- and beta 1-subunit mRNA in response to hyperosmotic media requires, at least in part, the presence of Na in the extracellular medium and the de novo synthesis of intermediate proteins.

Two distinct quinoprotein amine oxidases are induced by n-butylamine in the mycelia of Aspergillus niger AKU 3302. Purification, characterization, cDNA cloning and sequencing.

Two distinct quinoprotein amine oxidases were found in Aspergillus niger mycelia grown on n-butylamine medium and purified using chromatographic techniques. The respective enzymes were termed AO-I, which had already been isolated, and AO-II, a new enzyme found in this study. HPLC indicated that their molecular masses are 150 kDa and 80 kDa, respectively. On SDS/PAGE, the enzymes gave a similar but distinct mobility, which corresponds to 75 kDa for the subunit dimeric AO-I and 80 kDa for monomeric AO-II. The absorption spectra of both enzymes were different from each other; the absorption maxima in the visible region were at 490 nm for AO-I and 420 nm for AO-II. The enzymes showed positive quinone staining, comparable substrate specificity, and sensitivity to inhibitors typical for copper/topa quinone-containing amine oxidases, but they had different copper contents and also differed in their N-terminal sequences. Their peptide maps showed almost identical patterns, with the exception of two additional bands for AO-II. Among the peptides obtained from digestion of AO-II, peptides with sequences corresponding to the N-terminal part of AO-I were detected. Polyclonal antibodies raised against AO-I and AO-II recognized both enzymes, but with different specificities. Using precipitation with AO-I, the antibody prepared against AO-II was purified and was shown to be specific only for AO-II. The cDNA of AO-I was cloned and sequenced. A highly conserved tetrapeptide sequence, Asn-Tyr-Glu-Tyr, was identified in which the first tyrosine residue (Tyr404) that could be converted to topa quinone was present in the 670-residue deduced amino acid sequence. Northern blot analysis indicated that AO-I was highly expressed in A. niger grown on n-butylamine as a single nitrogen source. Genomic Southern blot analysis confirmed that both enzymes are likely to be encoded by the same gene.

IL-3 augments TCR-mediated responses of type 2 CD4 T cells.

A subset of type 2, but not type 1, CD4 T cell clones expresses IL-3R and can be stimulated by IL-3. Expression of IL-3R on these type 2 T cell clones is induced by TCR stimulation, and subsequent stimulation by IL-3 augmented the proliferation of and IL-4 production by these cells. This augmented response is inhibited by anti-IL-4 mAb, suggesting the involvement of IL-4 in this response. In place of TCR stimulation, treatment of these type 2 CD4 T cell clones with PMA rendered them responsive to further stimulation of proliferation by IL-3, indicating the cooperation between the IL-3R-elicited signals and PKC-mediated signals in stimulating proliferation. Although the augmentation of the TCR-mediated proliferative response by IL-3 was mainly due to the increased production of IL-4, we also demonstrated the presence of IL-4-independent mechanism mediating the response to IL-3. In situ, we found that splenic T cells could be induced to respond to Il-3 by TCR stimulation. Thus, IL-3 can stimulate a specific population of T cells and influence the immune response.

Urinary excretion of thiobarbituric acid reactive substances of healthy subjects supplemented with a high dose of d-alpha-tocopherol.

The level of urinary thiobarbituric acid reactive substances (TBARS) consisting of bound forms of malonaldehyde and, to a lesser extent, other aldehydes is one of the indices of lipid peroxidation status. Levels of urinary TBARS in healthy subjects before and after supplementation with a high dose of d-alpha-tocopherol were measured using high performance liquid chromatography. Four healthy Japanese were given a supplement of 300 mg d-alpha-tocopherol/d, about 40-fold higher than the normal intake recommended, for a period of 50 d. Levels of urinary TBARS (nmol/kg body weight.h) within-day, before and after supplementation with d-alpha-tocopherol, exhibited similar behavior and levels of daily urinary TBARS (nmol/kg body weight.d) were unchanged by d-alpha-tocopherol supplementation. These results indicate that supplementation with a high dose of d-alpha-tocopherol does not affect the level of urinary TBARS.

Activation and cytotoxicity of 2-alpha-aminoacyl prodrugs of methotrexate.

In an effort to improve the selectivity of the anticancer drug methotrexate (MTX), a series of potential prodrugs in which the 2-amino group was acylated with various alpha-amino acids (as well as L-pyroglutamic acid) was synthesized. Such derivatives are anticipated to be hydrolysed to MTX by appropriate aminopeptidases localized (over-expressed naturally or targeted as anti-tumor antibody conjugates) in the vicinity of the tumor. The L-leucyl, L-valyl, L-isoleucyl, D-alanyl and L-pyroglutamyl derivatives were assessed as to their suitability as prodrugs. Except for the L-pyroglutamyl compound, all derivatives decomposed slowly when incubated in phosphate buffer, pH 7.3; the formation of MTX was minimal. No major differences were observed when serum was included in the incubation medium, except for the L-leucyl compound, which was hydrolysed to MTX. The L-leucyl, L-valyl and L-isoleucyl derivatives were hydrolysed readily to MTX by aminopeptidase M (EC 3.4.11.2), while the L-pyroglutamyl and D-alanyl compounds were activated by pyroglutamate aminopeptidase (EC 3.4.19.3) (from Bacillus amyloliquefaciens) and D-aminopeptidase (from Ochrobactrum anthropi), respectively. When tested for inhibition of the target enzyme dihydrofolate reductase (DHFR; EC 1.5.1.3), 2-L-valyl-MTX showed inhibition two orders of magnitude poorer than that given by MTX, in agreement with the expectation that acylation of the 2-amino group reduces binding to DHFR. After treatment of this derivative with aminopeptidase M, the extent of inhibition correlated with the amount of MTX formed. MTX derivatives alone or in combination with the complementary peptidase were tested for cytotoxicity on murine L1210 cells in culture. The above-listed derivatives were considerably less cytotoxic than MTX, except for the L-leucyl derivative which showed considerable cytotoxicity. When the appropriate exogenous peptidase was included, the cytotoxicity of the activated prodrugs approached that of MTX. These results indicate that 2-L-leucyl-MTX is unsuitable as a prodrug since it is activated prematurely by serum enzymes. Although the L-valyl and L-isoleucyl derivatives do not hydrolyse to MTX in serum and are readily activated, they are not ideal prodrugs since they decompose under physiological conditions; the properties of the decomposition product will have a bearing on the ultimate suitability of these compounds. 2-L-Pyroglutamyl-MTX is the best candidate prodrug, showing stability and ready activation by the appropriate aminopeptidase.

Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder.

Phototherapy was administered to 24 depressed patients with seasonal affective disorder (SAD), of which 62%, 24%, and 14%, respectively, showed improvements of greater than or equal to 50%, 25-50%, and less than 25% based on the Hamilton rating scale for depression for SAD (HAMSAD). No patients showed aggravation or side effects. Although the improvement rate in HAMSAD correlated significantly with the pretreatment severity of atypical symptoms of depression, it did not correlate with that of typical symptoms. This suggests that phototherapy is a useful treatment in SAD and that responsiveness to phototherapy in SAD can possibly be predicted by the atypical depressive symptoms before treatment.

Multi-center study of seasonal affective disorders in Japan. A preliminary report.

A multi-center study on seasonal affective disorder (SAD) was conducted from the autumn of 1988 to the spring of 1989 with the cooperation of 16 facilities in Japan. Forty-six SAD patients were identified among 1104 respondents to our advertisements in mass media, or patients seen at the outpatient clinics. Essentially similar findings to other previous reports were obtained in terms of onset age of the first episode, duration of episode, high proportion of depression in first-degree relatives and atypical vegetative symptoms. However, a nearly equal sex ratio, together with a high proportion of unipolar depression, is characteristic of the present study. Increased appetite and carbohydrate craving were predominant only in female patients, whereas hypersomnia was prominent in both sexes. Effective response to light therapy was found in 17 SAD patients. However, a controlled study on a large number of patients is required to allow final conclusions on the efficacy of light therapy in Japanese SAD patients.

Hyponatremia and hyperreninemic hypoaldosteronism in a critically ill patient: combination of insensitivity to angiotensin II and tubular unresponsiveness to mineralocorticoid.

A 62-year-old man with pneumonia and left flank pain had a clinical syndrome of hyponatremia, hypotension, dehydration, and high urinary sodium excretion in the presence of a normal glomerular filtration rate. The plasma level of antidiuretic hormone was relatively high despite decreased serum osmolality. Thyroid function and excretion of glucocorticoid and sex steroids were normal. The serum aldosterone level was very low despite elevated plasma renin activity. Angiotensin II failed to stimulate any secretion of aldosterone, despite the occurrence of a progressive rise in blood pressure. On the other hand, rapid ACTH administration increased both serum aldosterone and cortisol. The patient showed no effective response to increased salt intake, but large doses of mineralocorticoid resulted in a normal serum sodium level without dehydration. Subsequently, he suffered cardiac arrest secondary to ventricular tachycardia. Postmortem examination showed well differentiated adenocarcinoma in the left pleura and an intact, histologically normal adrenal zona glomerulosa and kidney. This is the first reported case of a critically ill patient with hyponatremia caused by hyperreninemic hypoaldosteronism possibly due to angiotensin II insensitivity and tubular unresponsiveness to mineralocorticoid.

[A case of syphilitic meningitis presenting the seventh nerve and the eighth nerve palsies].

Here we described a case of syphilitic meningitis presenting the seventh nerve and the eighth nerve palsies. A 56-year-old man was admitted because of left facial palsy and hearing loss of bilateral ears. He had a penile chancre five months before admission. Cerebrospinal fluid examination showed high pressure, pleocytosis predominantly with mononuclear cells and high protein content. STS and TPHA of serum and CSF were positive. High dose penicillin G was effective, and he was discharged with only mild hearing loss in the left. Considering the penetration of penicillin G into the CSF and the minimum fully treponemicidal concentration of penicillin, the administration of large doses of aqueous penicillin G intravenously or intramuscularly was effective in such a case to prevent permanent deafness, though CDC recommends relatively low dose.

The role of endogenous dopamine in congestive heart failure.

Although the effects of epinephrine and norepinephrine in congestive heart failure have been extensively studied, and exogenous dopamine, another of the catecholamines, has been widely used for the treatment of congestive heart failure, little attention has been paid to the physiological significance of endogenous dopamine in this condition. The present study was therefore designed to assess the physiological significance of endogenous dopamine in congestive heart failure. Nineteen patients with congestive heart failure caused by such conditions as acute myocardial infarction, valvular disease and dilated cardiomyopathy were examined before and after treatment with diuretics, digitalis and vasodilators. Electrolyte, creatinine and catecholamine concentrations in plasma and urine were analyzed. Urinary dopamine levels were increased in 13 out of 19 cases before treatment and returned to the normal range after treatment, falling from 2448 +/- 950.7 to 528.8 +/- 56.3 micrograms/day (normal level, less than 700 micrograms/day). Urinary dopamine excretion was markedly elevated within 24 hours after the onset of symptoms of heart failure, such as chest pain, palpitations and dyspnea. The relationship between urinary dopamine excretion and time after the onset of symptoms showed a strong statistical correlation (r = 0.55, p less than 0.001). Urinary dopamine excretion was also well correlated with plasma dopamine concentration, urinary norepinephrine excretion and venous pressure. From these results, it is concluded that endogenous dopamine seems to play an important role during the acute phase of congestive heart failure.

Cardiac arrhythmias in hemodialysis patients. A study of incidence and contributory factors.

Cardiac arrhythmias were evaluated in 100 patients undergoing regular maintenance hemodialysis for chronic renal failure by Holter ECG monitoring a 72-hour period beginning on the day of hemodialysis. Clinically significant ventricular arrhythmias (more than 700 beats/24 h) were found in 18 patients (the frequent group) in whom premature ventricular contractions (PVCs) were recorded frequently during and for 4 h after hemodialysis. In the frequent group, the values of the serum calcium concentration times those of phosphorus were significantly higher than those of patients without PVCs (the no arrhythmia group) or those with fewer PVCs (less than 700 beats/day; sporadic group) (54.9 +/- 3.5 vs. 43.8 +/- 3.2, 43.0 +/- 1.8, respectively; p less than 0.005). Also, in the frequent group, the percent fractional shortening of the left ventricle, as measured by two-dimensional echocardiography, was significantly lower than those in the no arrhythmia and sporadic groups (30.7 +/- 1.8% vs. 40.7 +/- 1.9%, 37.7 +/- 1.1%, respectively; p less than 0.01). On the other hand, in those with frequent premature atrial contractions, the left atrial end-diastolic dimension was significantly enlarged (42.1 +/- 1.2 mm vs. 36.5 +/- 1.1 mm, 38.1 +/- 0.9 mm, respectively; p less than 0.01). From these results, we conclude that impaired cardiac performance and a high calcium phosphate product predialysis may be correlated with an increased incidence of ventricular arrhythmias in uremic patients.

Laser trabeculoplasty and cataract surgery.

We have compared long-term intraocular pressure control in patients with open angle glaucoma, cupping and atrophy of the optic nerve head and visual field loss as well as cataract after: trabeculectomy posterior to the scleral spur and cataract extraction without implantation in 108 patients. guarded posterior lip sclerectomy, cataract extraction and Mark VIII or Mark IX anterior chamber implantation in 28 patients. argon laser trabeculoplasty followed by lens extraction and implantation in 27 patients. Approximately 75 per cent of patients achieve intraocular pressures of 18 mm Hg or less without medication after (a), and approximately 40 per cent of patients achieve similar control without medication after (b). Approximately 25 per cent of these glaucoma patients have intraocular pressure levels of less than or equal to 18 mm Hg on topical medication three months after ALT, and none achieve this control without medication. Cataract surgery with anterior or posterior chamber implantation caused loss of topical control in four of the seven patients benefiting from ALT. These data imply that combined surgery with or without implantation produces better and more significant intraocular pressure control than the presently utilized techniques of ALT subsequently followed by lens extraction and implantation.

Acute and chronic hypotensive effects of nifedipine and niludipine in hypertensive patients with chronic renal failure.

The present study was aimed to evaluate the acute and chronic hypotensive effects of nifedipine (Bay a 1040, Adalat) and niludipine (Bay a 7168) in hypertensive patients with chronic renal failure. 1. The decrease of blood pressure lasted for at least 3 h and maximum decrement was achieved in 60 min (26% decrement, p less than 0.05) after oral administration of nifedipine (10 mg). On the other hand, niludipine (20 mg) caused decrease of blood pressure for at least 4 h and attained maximum decrement in 90 min (13% decrement, p less than 0.05) after oral administration. 2. In chronic studies of both drugs, the maximum decrease of blood pressure (p less than 0.05) was attained after one week and lasted at least 4 weeks. There were no significant changes of pulse rate, body weight and urine volume in both nifedipine and niludipine groups. 3. Nifedipine caused great diurnal or day-to-day fluctuations of blood pressures after chronic administrations. On the other hand niludipine did not cause any significant fluctuations. Any serious complications could not be seen during these studies. In conclusion, these results provide clinical evidence that niludipine could be usefused great diurnal or day-to-day fluctuations of blood pressures after chronic administrations. On the other hand niludipine did not cause any significant fluctuations. Any serious complications could not be seen during these studies. In conclusion, these results provide clinical evidence that niludipine could be useful for treatment of hypertension associated with chronic renal failure. Results also suggest that the optimal efficacy of nifedipine and niludipine in part depends on the specific clinical situation at hand. For example, nifedipine seems to be the drug of choice in hypertensive emergencies when there is a need for rapid lowering of blood pressure.