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1.
Clin Nephrol ; 61(1): 63-7, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14964460

ABSTRACT

Few cases of pamidronate (bisphosphonate class of drugs) nephrotoxicity in humans have been previously reported in the literature. In 7 patients, the pamidronate-related nephrotoxicity was attributed to focal collapsing glomerulosclerosis [Markowitz et al. 2001], and in 1 patient was related to tubulo-interstitial inflammatory nephritis [Van Doom et al. 2001]. We report herein on a 65-year-old Caucasian female patient who presented with acute chronic renal failure due to pamidronate-induced toxic proximal tubular necrosis without immunologic or inflammatory tubulo-interstitial involvement. The acute pattern of renal failure resolved following cessation of pamidronate administration in this patient for osteoporosis; the patient also had a monoclonal gammopathy of unspecific origin (MGUS).


Subject(s)
Anti-Inflammatory Agents/adverse effects , Diphosphonates/adverse effects , Kidney Tubular Necrosis, Acute/chemically induced , Aged , Female , Humans , Pamidronate
2.
Proc Natl Acad Sci U S A ; 98(17): 9617-23, 2001 Aug 14.
Article in English | MEDLINE | ID: mdl-11493701

ABSTRACT

Upon depolarization positive charges contained in the transmembrane segment S4 of voltage-dependent channels are displaced from the cytoplasmic to the external milieu. This charge movement leads to channel opening. In Shaker K+ channels four positively charged arginines in the S4 domain are transferred from the internal to the external side of the channel during activation. The distance traveled by the S4 segment during activation is unknown, but large movements should be constrained by the S3-S4 linker. Constructing deletion mutants, we show that the activation time constant and the midpoint of the voltage activation curve of the Shaker K+ channel macroscopic currents becomes a periodic function of the S3-S4 linker length for linkers shorter than 7 aa residues. The periodicity is that typical of alpha-helices. Moreover, a linker containing only 3 aa is enough to recover the wild-type phenotype. The deletion method revealed the importance of the S3-S4 linker in determining the channel gating kinetics and indicated that the alpha-helical nature of S4 extends toward its N terminus. These results support the notion that a small displacement of the S4 segment suffices to displace the four gating charges involved in channel opening.


Subject(s)
Ion Channel Gating , Potassium Channels/metabolism , Potassium/metabolism , Animals , Arginine/chemistry , Female , Ion Transport , Models, Molecular , Oocytes/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Potassium Channels/chemistry , Potassium Channels/genetics , Protein Conformation , Protein Structure, Tertiary , RNA, Complementary/genetics , Sequence Deletion , Shaker Superfamily of Potassium Channels , Structure-Activity Relationship , Xenopus laevis
3.
J Gen Physiol ; 115(2): 193-208, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10653896

ABSTRACT

In Shaker K(+) channels depolarization displaces outwardly the positively charged residues of the S4 segment. The amount of this displacement is unknown, but large movements of the S4 segment should be constrained by the length and flexibility of the S3-S4 linker. To investigate the role of the S3-S4 linker in the ShakerH4Delta(6-46) (ShakerDelta) K(+) channel activation, we constructed S3-S4 linker deletion mutants. Using macropatches of Xenopus oocytes, we tested three constructs: a deletion mutant with no linker (0 aa linker), a mutant containing a linker 5 amino acids in length, and a 10 amino acid linker mutant. Each of the three mutants tested yielded robust K(+) currents. The half-activation voltage was shifted to the right along the voltage axis, and the shift was +45 mV in the case of the 0 aa linker channel. In the 0 aa linker, mutant deactivation kinetics were sixfold slower than in ShakerDelta. The apparent number of gating charges was 12.6+/-0.6 e(o) in ShakerDelta, 12.7+/-0.5 in 10 aa linker, and 12.3+/-0.9 in 5 aa linker channels, but it was only 5.6+/-0.3 e(o) in the 0 aa linker mutant channel. The maximum probability of opening (P(o)(max)) as measured using noise analysis was not altered by the linker deletions. Activation kinetics were most affected by linker deletions; at 0 mV, the 5 and 0 aa linker channels' activation time constants were 89x and 45x slower than that of the ShakerDelta K(+) channel, respectively. The initial lag of ionic currents when the prepulse was varied from -130 to -60 mV was 0.5, 14, and 2 ms for the 10, 5, and 0 aa linker mutant channels, respectively. These results suggest that: (a) the S4 segment moves only a short distance during activation since an S3-S4 linker consisting of only 5 amino acid residues allows for the total charge displacement to occur, and (b) the length of the S3-S4 linker plays an important role in setting ShakerDelta channel activation and deactivation kinetics.


Subject(s)
Ion Channel Gating/physiology , Oligopeptides/metabolism , Potassium Channels/physiology , Amino Acids/metabolism , Animals , Kinetics , Membrane Potentials/physiology , Mutation , Oocytes/cytology , Xenopus
4.
J Gen Physiol ; 115(2): 209-22, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10653897

ABSTRACT

When attached outside the voltage-sensing S4 segment of the Shaker potassium channel, the fluorescent probe tetramethylrhodamine (TMRM) undergoes voltage-dependent fluorescence changes (DeltaF) due to differential interaction with a pH-titratable external protein-lined vestibule (Cha, A., and F. Bezanilla. 1998. J. Gen. Physiol. 112:391-408.). We attached TMRM at the same sites [corresponding to M356C and A359C in the wild-type (wt) channel] in a deletion mutant of Shaker where all but the five amino acids closest to S4 had been removed from the S3-S4 linker. In the deletion mutant, the maximal DeltaF/F seen was diminished 10-fold, and the DeltaF at M356C became pH independent, suggesting that the protein-lined vestibule is made up in large part by the S3-S4 linker. The residual DeltaF showed that the probe still interacted with two putative quenching groups near the S4 segment. One group was detected by M356C-TMRM (located outside of S3 in the deletion mutant) and reported on deactivation gating charge movement when applying hyperpolarizing voltage steps from a holding potential of 0 mV. During activating voltage steps from a holding potential of -90 mV, the fluorescence lagged considerably behind the movement of gating charge over a range of potentials. Another putative quenching group was seen by probes attached closer to the S4 and caused a DeltaF at extreme hyperpolarizations (more negative than -90 mV) only. A signal from the interaction with this group in the wt S3-S4 linker channel (at L361C) correlated with gating charge moving in the hyperpolarized part of the Q-V curve. Probe attached at A359C in the deletion mutant and at L361C in wt channel showed a biphasic DeltaF as the probe oscillated between the two groups, revealing that there is a transient state of the voltage sensor in between, where the probe has maximal fluorescence. We conclude that the voltage sensor undergoes two distinct conformational changes as seen from probes attached outside the S4 segment.


Subject(s)
Ion Channel Gating/physiology , Potassium Channels/physiology , Animals , Electrophysiology , Fluorescence , Fluorescent Dyes/metabolism , Hydrogen-Ion Concentration , Membrane Potentials/physiology , Mutagenesis, Site-Directed , Oocytes/cytology , Patch-Clamp Techniques , Protein Conformation , Rhodamines/metabolism , Xenopus
7.
J Pediatr ; 123(2): 275-8, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8345427

ABSTRACT

Hyperammonemia and encephalopathy developed in an 11-year-old girl with chronic interstitial lung disease and cholesterol casts in her lung biopsy specimen. She had decreased plasma levels of ornithine, lysine, and arginine and excessive urinary excretion of lysine and arginine, consistent with the diagnosis of lysinuric protein intolerance. Analysis of plasma and urinary amino acids should be considered in the diagnostic evaluation of patients with interstitial lung disease of uncertain origin.


Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Cholesterol , Granuloma, Foreign-Body/diagnosis , Lung Diseases/diagnosis , Pulmonary Fibrosis/diagnosis , Amino Acid Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/metabolism , Child , Female , Granuloma, Foreign-Body/complications , Humans , Lung Diseases/complications , Lysine/metabolism , Pulmonary Fibrosis/complications
8.
Am J Med ; 83(4): 666-72, 1987 Oct.
Article in English | MEDLINE | ID: mdl-3314492

ABSTRACT

Epidemiologic data, family history, clinical data, HLA typing, neutrophilic chemotaxis, and immunofluorescence of clinically normal non-sun-exposed skin were studied in 46 Israeli non-Ashkenazi Jewish and Arab patients with Behçet's syndrome. HLA-B51 was present in 71 percent of the patient group as compared with 13 percent of the control group (relative risk = 17.1). In four of 30 families in the B51-positive group, there was a close relative of the proband with Behçet's syndrome who was carrying the HLA-B51 antigen. Neutrophilic chemotaxis in this group was enhanced in 80 percent of the patients, and in most patients no deposition of immunoglobulin in the dermo-epidermal junction was observed, whereas C3 was present in papillary vessels. In the B51-negative group, the family history was negative for Behçet's syndrome, neutrophilic chemotaxis was enhanced in only two of eight patients, and in four of six patients, IgM deposition was detected in the dermo-epidermal junction. It is concluded that in Israeli non-Ashkenazi Jews and Arabs, there is a significant association between HLA-B51 and the risk of developing Behçet's syndrome. The B51-positive patient group has a family history of the disease, enhanced neutrophilic chemotaxis, and a lack of immunoglobulin deposition in the dermo-epidermal junction.


Subject(s)
Behcet Syndrome/genetics , HLA Antigens/genetics , HLA-B Antigens , Behcet Syndrome/immunology , Chemotaxis, Leukocyte , Female , Fluorescent Antibody Technique , Genetic Linkage , Genetic Markers , HLA-B51 Antigen , Histocompatibility Testing , Humans , Israel , Jews , Male , Neutrophils/immunology , Risk Factors , Skin/immunology
9.
Am J Nephrol ; 6(3): 220-3, 1986.
Article in English | MEDLINE | ID: mdl-3740131

ABSTRACT

A case of renal failure due to sarcoidosis with hypercalciuria and nephrocalcinosis is described. Prolonged treatment with inorganic absorbable phosphate significantly deteriorated the patient's renal function. After a sodium cellulose phosphate treatment, renal failure was completely reversed. We suggest that sodium cellulose phosphate is the treatment of choice in sarcoidotic renal failure induced by nephrocalcinosis.


Subject(s)
Cellulose/analogs & derivatives , Kidney Failure, Chronic/drug therapy , Nephrocalcinosis/complications , Sarcoidosis/complications , Calcium/urine , Cellulose/therapeutic use , Female , Humans , Hypercalcemia/complications , Kidney Failure, Chronic/etiology , Middle Aged
11.
Clin Allergy ; 12(2): 187-96, 1982 Mar.
Article in English | MEDLINE | ID: mdl-7074822

ABSTRACT

Although propylene-and-polyethylene-glycol and saline have been used in clinical studies as placebos, their possible therapeutic role as wetting agents in the treatment of perennial rhinitis was investigated. Clinical and laboratory response to these agents was measured in eighteen patients during a 2-week baseline period and with 4 weeks of active treatment in a double blind randomized study. After 2 and 4 weeks there was a significant improvement compared to baseline in nasal function (P less than 0.05) and blockage index (P less than 0.01) combining both groups, with no difference between treatments. Patients had less sneezing at 2 and 4 weeks (P less than 0.01), and less stuffiness at 4 weeks (P less than 0.01). There was a significant correlation between improvement in blockage index and nasal biopsies when both were judged independently of the other. This study has demonstrated that wetting agents offer both subjective and objective improvement in the treatment of perennial rhinitis and merit consideration prior to (or along with) other agents with known systemic side effects.


Subject(s)
Placebos/therapeutic use , Polyethylene Glycols/therapeutic use , Propylene Glycols/therapeutic use , Rhinitis, Allergic, Perennial/drug therapy , Sodium Chloride/therapeutic use , Adult , Aged , Eosinophils , Female , Humans , Immunoglobulin E/biosynthesis , Leukocyte Count , Male , Middle Aged , Nasal Mucosa/drug effects , Nasal Mucosa/metabolism , Peak Expiratory Flow Rate , Polyethylene Glycols/adverse effects , Propylene Glycol , Propylene Glycols/adverse effects , Rhinitis, Allergic, Perennial/diagnosis , Rhinitis, Allergic, Perennial/pathology , Sodium Chloride/adverse effects , Wetting Agents/therapeutic use
13.
Metabolism ; 26(1): 17-24, 1977 Jan.
Article in English | MEDLINE | ID: mdl-834140

ABSTRACT

Long-term fructose feeding to the genetically selected albino rat resulted in the development of diabetes mellitus and diffuse glomerulosclerosis. Siblings of these animals that were starch fed did not develop the metabolic impairments nor did they develop diabetic microangiopathy. These results are similar to those observed following sucrose feeding to these genetically selected animals. Hence, fructose feeding is not different than that of sucrose in producing diabetes and diabetic angiopathy.


Subject(s)
Diabetes Mellitus/chemically induced , Fructose , Animals , Blood Glucose/metabolism , Body Weight , Cholesterol/blood , Diabetes Mellitus/pathology , Dietary Carbohydrates , Disease Models, Animal , Glucose/pharmacology , Insulin/blood , Kidney Glomerulus/pathology , Rats , Rats, Inbred Strains , Triglycerides/blood
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