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Recessively inherited disorders can most often be considered loss of function: the patient has only defective copies of the defective gene (homozygous or hemizygous), with little or no functional protein products produced. Dominantly inherited disorders can most often be considered change of function: the patient has both mutant and normal copies of the gene (heterozygous); however, the mutant gene produces an abnormal protein product that causes dysfunction of the cell. Categorization of inherited disorders simply by their inheritance pattern thus affords some predictions concerning the underlying biochemical defect. To illustrate these generalizations, the molecular data on two important human inherited neurologic disorders will be described. X-linked recessive Duchenne/Becker muscular dystrophy has been shown to caused by loss of function of the dystrophin product. Dominantly inherited hyperkalemic periodic paralysis and paramyotonia congenita have been shown to be the result of single amino acid changes of the skeletal muscle voltage-sensitive sodium channel that alter the channel's function in response to environmental or physiologic stimuli (change of function).
RPM2 is a Saccharomyces cerevisiae nuclear gene required for normal cell growth yet the only known function of Rpm2p is as a protein subunit of yeast mitochondrial RNase P, an enzyme responsible for the 5' maturation of mitochondrial tRNAs. Since mitochondrial protein synthesis in S. cerevisiae is not essential for viability, RPM2 must provide another function in addition to its known role as a mitochondrial tRNA processing enzyme. During a search for RPM2 homologues from Kluyveromyces lactis, we recovered a K. lactis gene that compensates for the essential function but not the RNase P function of RPM2. We have named this gene SEF1 (Suppressor of the Essential Function), DNA sequence analysis of SEF1 reveals it contains a Zn(2)-Cys(6) binuclear cluster motif found in a growing number of yeast transcription factors. The SEF1 homologue of S. cerevisiae also compensates for the essential function of RPM2. The two proteins share 49% identity and 72% amino acid sequence similarity.
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there are conflicting views on whether NSAIDs are associated with adverse renal effects. OBJECTIVES: The primary objective of this review was to determine the effects of NSAIDs on postoperative renal function in adults with normal preoperative renal function. SEARCH STRATEGY: Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Handsearching of conference abstracts published in major anaesthetic journals was also performed. (Search date: 7 February 2003) SELECTION CRITERIA: The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of postoperative pain, with relevant postoperative renal outcome measures, in adult surgical patients with normal renal function. DATA COLLECTION AND ANALYSIS: The data was extracted independently by two reviewers. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium, need for dialysis and need for diuretic or dopamine treatment for renal insufficiency. Weighted mean differences for continuous outcomes and relative risk for dichotomous outcomes were estimated. MAIN RESULTS: Nineteen trials ( n = 1204) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 ml/min (95%CI 5 to 28) and potassium output by 38 mmol/day (95%CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 umol/L, 95%CI -5 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenace and ketorolac (or indomethacin). No cases of postoperative renal failure requiring dialysis were described. The trials were homogeneous for the primary outcome. REVIEWERS' CONCLUSIONS: NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.
OBJECTIVE: To describe the distribution of direct medical care costs of rheumatoid arthritis (RA) over 1-year and 11-year periods, and to evaluate the impact of poor function and functional decline on direct costs. METHODS: The present study uses data from the University of California, San Francisco, RA Panel Study in which 1,156 persons with RA have been followed up for as long as 15 years through annual structured interviews and periodic updates on severity from rheumatologists. We present annual direct medical care cost data for the years 1995 and 1996 and estimates of cumulative costs for the period 1986-1996 for the 272 persons followed up continuously for this period. RESULTS: Medical care costs for RA averaged $5,919 a year from a societal perspective; persons with RA incur another $2,582 in medical care costs for non-RA reasons. Of the RA total costs, hospital admissions account for more than half. Costs are highly skewed, with the costs in the 90th, 95th, and 100th percentiles totaling $8,209, $31,059, and $85,469 a year, respectively. Cumulative costs for the period 1986-1996 averaged $57,201, with cumulative costs in the 90th, 95th, and 100th percentiles totaling $114,844, $142,563, and $191,540, respectively. Persons with RA in the worst quartile of function experienced total annual direct costs that were 2.55 times as high and total hospital costs that were 6.97 times as high as those in the best (e.g., the first) quartile. Poor baseline functional status and declining functional status had similar, large effects on cumulative medical care costs. CONCLUSION: Medical care costs for RA over 1 year and 1 decade are highly skewed. Persons with RA with poor and declining function experience much higher costs of care.
OBJECTIVES: 1) To determine the importance of psychological adjustment and family functioning in primary juvenile fibromyalgia by assessing these factors in children with fibromyalgia and in their parents, compared with children with juvenile rheumatoid arthritis (JRA) and with pain-free control children and their parents. 2) To examine which of these factors predict functional disability. METHODS: Fifteen children in each of the 3 study groups, and their parents, completed self-report questionnaires and pain diaries. A medical evaluation of each child was performed, including assessment of tender points by palpation and by dolorimetry. RESULTS: All children in the fibromyalgia group met the Yunus and Masi criteria for fibromyalgia, and 11 met the American College of Rheumatology criteria. There were almost no significant group differences in the children's or parents' psychological adjustment, ratings of family functioning, or coping strategies. Significant group differences in functional disability, pain, fatigue, tender point threshold, and control point tolerance were found. A number of the psychological adjustment, pain, fatigue, and coping variables were significantly associated with functional disability. CONCLUSION: The notion that fibromyalgia is a psychogenic condition is not supported by these results. Fibromyalgia is associated with disability of a magnitude comparable to that of other chronic pain conditions. Disability among children with fibromyalgia or JRA is a function of the children's psychological adjustment and physical state, and of the parents' physical state and method of coping with pain.
Functional recovery in cytoprotected somatosensory cortex in a rat stroke model was studied using functional MRI (fMRI). Calcium antagonist treatment (isradipine) following permanent middle cerebral artery occlusion (pMCAO) reduced the infarct volume by 33 +/- 9%. The somatosensory cortex representing the forepaws was spared from infarction; however, cerebral blood flow (CBF) was significantly reduced in this area 24 hr following pMCAO. Neural function was assessed at days 1, 2, 5, and 12 following pMCAO by fMRI using electrical stimulation of both forepaws. Vehicle-treated rats did not show fMRI responses in the infarcted somatosensory cortex throughout the study. Several of the isradipine-treated animals displayed functional recovery in the cytoprotected cortex at days 5 (3/5 rats) and 12 (5/10). Correlations with fMRI signals showed that normal T2 and ADC values in the respective brain areas are necessary, but not sufficient prerequisites for functionality. Recovery of neural function is associated with normalization of CBF in the cytoprotected brain area.
To explain how symptoms, lung function, mood, and social support affect level of functioning, patients (N = 143) with chronic obstructive pulmonary disease (COPD) completed measures assessing their symptoms (Bronchitis-Emphysema Symptom Checklist), mood (Profile of Mood States), social support (Personal Resource Questionnaire), and functioning (Sickness Impact Profile). Those who were receiving oxygen therapy (n = 52) had significantly lower FEV1 scores and experienced significantly poorer functioning than those who were not receiving oxygen therapy (n = 91). Results of path analyses indicated that symptoms and mood directly, and social support indirectly, influenced the functioning of those who were not receiving oxygen. For those who were receiving oxygen, only symptoms directly, and FEV1 indirectly, influenced their functioning. These models need to be confirmed using other samples of patients with COPD.
Saccharomyces cerevisiae YFR021w, YGR223c and YPL100w are paralogous ORFs of unknown function. Phenotypic analysis of overexpression, single-, double- and triple-ORF deletion strains under various growth conditions indicated mitochondria-related functions for all three ORFs. Two-hybrid screens of a yeast genomic library identified potentially interacting proteins for the three ORFs. Among these, the transcriptional activator Rtg3p interacted with both Yfr021wp and Ypl100wp and both ORF single deletions reduced the constitutive expression of the RTG-regulated CIT2 and DLD3 genes and caused typical retrograde response of CIT2 and DLD3 under growth conditions requiring functional mitochondria, indicating that YFR021w and YPL100w are also involved in unidentified mitochondrial functions. Ptr3p, a component of the amino acid sensor Ssy1p/Ptr3p, was also found as a two-hybrid interactant of Yfr021wp. Of the three single-ORF deletions, ypl100w Delta exhibited ptr3 Delta-similar phenotypes. These findings, combined with the fact that RTG-dependent expression is modulated by specific amino acids, suggested possible relations of Yfr021wp and Ypl100wp to amino acid signalling pathways. Under most conditions examined, the effects of the single- and double-ORF deletions indicated that YFR021w, YPL100w and YGR223c are not parts of the same pathway. We found no unique phenotype attributed to the deletion of YGR223c. However, its function interferes with the function of the other two ORFs, as revealed by the effects of double- and triple-ORF deletions.
Members of the UNC-5 protein family are transmembrane receptors for UNC-6/netrin guidance cues. To analyze the functional roles of different UNC-5 domains, we sequenced mutations in seven severe and three weak alleles of unc-5 in Caenorhabditis elegans. Four severe alleles contain nonsense mutations. Two weak alleles are truncations of the cytodomain, but one is a missense mutation in an extracellular immunoglobulin domain. To survey the function of different regions of UNC-5, wild-type and mutant unc-5::HA transgenes were tested for their ability to rescue the unc-5(e53) null mutant. Our data reveal partial functional requirements for the extracellular domains and identify a portion of the cytoplasmic juxtamembrane (JM) region as essential for rescue of migrations. When nine cytodomain tyrosines, including seven in the JM region, are mutated to phenylalanine, UNC-5 function and tyrosine phosphorylation are largely compromised. When F482 in the JM region of the mutant protein is reverted to tyrosine, UNC-5 tyrosine phosphorylation and in vivo function are largely recovered, suggesting that Y482 phosphorylation is critical to UNC-5 function in vivo. Our data also show that part of the ZU-5 motif is required for UNC-40-independent signaling of UNC-5.
In a previous investigation of functional limbic pathways in the human mesial temporal lobe, we found evidence for strong connections between ipsilateral mesial temporal structures, but none for contralateral functional connections (Wilson et al. 1990). In the present study, we focused specifically upon the question of functional commissural linkages between these structures by systematic stimulation of a total of 390 electrode placements in 74 epileptic patients with temporal lobe depth electrodes implanted for surgical diagnosis. Eight standard electrode placement regions were targeted: amygdala, entorhinal cortex, anterior, middle and posterior hippocampus, subicular cortex, middle parahippocampal gyrus, and posterior parahippocampal gyrus. Three to six electrodes were implanted bilaterally in each patient, and each electrode was individually stimulated while recording from all the other sites. Out of the 390 electrodes stimulated, 78% were effective in evoking clear responses in adjacent ipsilateral structures, and 75% of 581 ipsilateral recording sites were responsive to stimulation. Only one of the stimulated electrode sites was effective in evoking responses in contralateral recording sites, and only two of 511 contralateral recording sites were responsive to that stimulation. The effective stimulation site was in presubicular cortex, and the responsive contralateral recording sites were in entorhinal and presubicular cortices. Response to this stimulation site was intermittent and variable in latency. The relative ease of obtaining functional verification of significant ipsilateral anatomical pathways in the human limbic system, and the sharply contrasting difficulty of functionally activating commissural pathways to contralateral limbic sites are discussed in the context of decreases in hippocampal contribution to commissural pathways in the primate brain compared to sub-primate mammals, and the significance of this change to normal limbic system function as well as to mechanisms of seizure spread in epilepsy.
Previous self-report measures of female sexual function have been either overly restrictive or inappropriate for use in large-scale clinical trials. Accordingly, we have developed the Brief Index of Sexual Functioning for Women (BISF-W), a 22-item, self-report instrument for the assessment of current levels of female sexual functioning and satisfaction. The BISF-W was administered at monthly intervals to a standardization sample of 269 women, ages 20-73 years. A principal components analysis yielded a three-factor solution--interest/desire, sexual activity, and satisfaction--which accounted for 51.2% of the variance. Concurrent validity was demonstrated by means of a comparison with the Derogatis Sexual Function Inventory. In addition, the BISF-W was compared to the Brief Sexual Function Questionnaire, a similar self-report measure of sexual functioning for men. Major advantages of the BISF-W are its ease of administration and scoring, suitability for use in both clinical and nonclinical samples, and assessment of key dimensions of female sexuality. However, based on its moderate test-retest reliability and internal consistency, further development of the instrument is indicated.
AIM: This study was designed to analyze the functional and clinical outcomes of straight coloanal anastomosis compared with colonic J-pouch performed after low anterior resection. MATERIALS AND METHODS: Between September 1989 and June 1996, all patients who underwent low anterior resection with anastomosis less than 4 cm from the dentate line were classified into two groups based on the restoration of intestinal continuity: "straight" coloanal anastomosis (n = 39) or colonic J-pouch (n = 44). Both groups were assessed according to the level of anastomosis, anastomotic complications (stricture, leak, pelvic abscess), age, and gender. For comparison of functional outcome, daily bowel movements, tenesmus, urgency, incontinence score (range, 0-20), and anorectal manometric findings were evaluated preoperatively and at six months, and one and two years after surgery. RESULTS: There were no significant differences between the groups relative to age: (coloanal anastomosis, 66.3 +/- 10.1 (range, 46-86), vs. colonic J-pouch, 64.9 +/- 13.2 (range, 39-88) years); gender (females): (coloanal anastomosis, 46.2 percent vs. colonic J-pouch; 38.6 percent); diagnosis: (rectal carcinoma: coloanal anastomosis, 84.6 percent, vs. colonic J-pouch, 77.3 percent); preoperative incontinence score (coloanal anastomosis, 1.5 +/- 4.6, vs. colonic J-pouch, 1.1 +/- 4); bowel movements: (coloanal anastomosis, 2.1 +/- 2.3, vs. colonic J-pouch, 2.1 +/- 1.9/day); level of anastomosis: (coloanal anastomosis, 1.8 +/- 1.3, vs. colonic J-pouch, 1.5 +/- 1.3 cm from the dentate line); history of perioperative radiation therapy: (coloanal anastomosis, 15.4 percent, vs. colonic J-pouch, 20.5 percent); or manometric findings. There was also no significant difference in postoperative mortality: (coloanal anastomosis, 5.1 percent, vs. colonic J-pouch, 2.3 percent); or anastomotic complications: (coloanal anastomosis, 7/39 (17.9 percent), vs. colonic J-pouch, 2/44 (4.5 percent) P = 0.08); strictures: (10.3 vs. 0 percent); leaks: (5.1 vs. 2.3 percent); bleeding: (2.6 vs. 0 percent); rectovaginal fistula: (0 vs. 2.3 percent). Also, in the colonic J-pouch group, two patients developed pouchitis, and one patient experienced difficult evacuation one year after surgery. There was a statistically significant better function judged by less frequent bowel movements (4 +/- 2 vs. 2.4 +/- 1.3/day; P < 0.005) and urgency (36.7 vs. 7.7 percent; P < 0.05), incontinence score (2.2 +/- 3.7 vs. 0.8 +/- 1.6; P < 0.05) up to one year after surgery. At two years, the coloanal anastomosis group did not show statistical improvement in functional results compared with one year postoperatively. Rectal compliance in manometric findings was significantly increased in the coloanal anastomosis group at one year after surgery (12.4 +/- 12.6 vs. 4.2 +/- 1.5 ml/mmHg; P < 0.05). However, these differences were less profound after two years. CONCLUSION: The functional superiority of the colonic J-pouch was greatest at one year after surgery. By two years, adaptation of the "straight" coloanal anastomosis yielded similar functional results. However, the almost fourfold reduction in anastomotic complications in the colonic J-pouch group reveals a second potential advantage of this technique.
OBJECTIVE: We have developed a program to quantify regional left ventricular (LV) function and wall motion synchrony using ECG-gated myocardial perfusion SPECT (MPS). This preliminary study was undertaken to validate the use of this program for estimating regional LV systolic function. METHODS: Patients were subjected to MPS by 99mTc-sestamibi at rest. The study included 20 patients who were confirmed to have a low probability of coronary artery disease (LPG; low probability group), 19 heart disease patients who were examined by MPS and equilibrium radionuclide angiography (ERNA) (ERG; ERNA group), and 24 patients who were examined by MPS and 2-dimensional echocardiography (2DE) (2DEG; 2DE group). The values of the ejection fraction (EF) and peak ejection rate (PER) were estimated. The global functions evaluated by this program were compared with those obtained by ERNA in the ERG. For regional assessment, the reference values of the functional indices were obtained for 17 LV segments in LPG. The Z score, (reference average value of the segment--patient's value of the segment)/reference standard deviation of the segment, was used for the evaluation of regional functions; a score equal to or greater than 2 was defined as abnormal. Semiquantitative visual interpretation of 2DE was used as the standard to assess wall motion. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these criteria and the relationship between 2DE grading and Z scoring were validated in 2DEG. RESULTS: The values of the global EF and PER evaluated by this program correlated with those determined by ERNA (r = 0.76 and 0.58, respectively; p < 0.005 and 0.01, respectively). The sensitivities of regional EF and PER for segmental wall motion abnormalities were 86.7% and 68.7%, respectively; their specificities were 86.7% and 95.5%, respectively; their PPVs were 64.3% and 79.2%, respectively; and their NPVs were 96.0% and 91.7%, respectively. The Z scores of these indices significantly correlated with the scores determined by 2DE (rs = 0.70 and 0.68, respectively; p < 10(-10)). CONCLUSION: The potential of this program to quantify the regional systolic function was validated.