Challenges for defining minimal clinically important difference (MCID) after spinal cord injury.

STUDY DESIGN: This is a review article. OBJECTIVES: This study discusses the following: (1) concepts and constraints for the determination of minimal clinically important difference (MCID), (2) the contrasts between MCID and minimal detectable difference (MDD), (3) MCID within the different domains of International Classification of Functioning, disability and health, (4) the roles of clinical investigators and clinical participants in defining MCID and (5) the implementation of MCID in acute versus chronic spinal cord injury (SCI) studies. METHODS: The methods include narrative reviews of SCI outcomes, a 2-day meeting of the authors and statistical methods of analysis representing MDD. RESULTS: The data from SCI study outcomes are dependent on many elements, including the following: the level and severity of SCI, the heterogeneity within each study cohort, the therapeutic target, the nature of the therapy, any confounding influences or comorbidities, the assessment times relative to the date of injury, the outcome measurement instrument and the clinical end-point threshold used to determine a treatment effect. Even if statistically significant differences can be established, this finding does not guarantee that the experimental therapeutic provides a person living with SCI an improved capacity for functional independence and/or an increased quality of life. The MDD statistical concept describes the smallest real change in the specified outcome, beyond measurement error, and it should not be confused with the minimum threshold for demonstrating a clinical benefit or MCID. Unfortunately, MCID and MDD are not uncomplicated estimations; nevertheless, any MCID should exceed the expected MDD plus any probable spontaneous recovery. CONCLUSION: Estimation of an MCID for SCI remains elusive. In the interim, if the target of a therapeutic is the injured spinal cord, it is most desirable that any improvement in neurological status be correlated with a functional (meaningful) benefit.

Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.

Menkes disease is an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty-one Menkes patients. Four patients lacking Mc1RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P-type cation-transporting ATPase. The gene product is most similar to a bacterial copper-transporting ATPase and additionally contains six putative metal-binding motifs at the N-terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.

The mottled gene is the mouse homologue of the Menkes disease gene.

The mottled mouse has been proposed as an animal model for Menkes disease, an X-linked disorder of copper transport. The recent isolation of a copper-transporting ATPase gene responsible for Menkes disease has allowed us to test this hypothesis. Here we report the isolation and sequence of the mouse homologue of this gene. We show that two mottled (Mo) alleles, dappled (Modp) and blotchy (Moblo), have abnormalities in the murine mRNA and that Modp has a partial gene deletion. These studies prove that the mottled mouse is the murine model for Menkes disease, providing the basis for future biochemical and therapeutic studies.

A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome.

Hallervorden-Spatz syndrome (HSS) is an autosomal recessive neurodegenerative disorder associated with iron accumulation in the brain. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals iron deposits in the basal ganglia. In this respect, HSS may serve as a model for complex neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, Huntington disease and human immunodeficiency virus (HIV) encephalopathy, in which pathologic accumulation of iron in the brain is also observed. Thus, understanding the biochemical defect in HSS may provide key insights into the regulation of iron metabolism and its perturbation in this and other neurodegenerative diseases. Here we show that HSS is caused by a defect in a novel pantothenate kinase gene and propose a mechanism for oxidative stress in the pathophysiology of the disease.

Cellular site of glucocorticoid-receptor complex formation.

The cellular site of binding of dexamethasone by specific glucocorticoid receptors in cultured hepatoma cells was investigated with the use of certain mercurials. p-Chloromercuribenzene sulfonate and p-chloromercuribenzoate inhibit the binding of steroid by receptors in cell-free extracts, but they allow the steroid-receptor complex to form in whole cells. In contrast, HgCl(2) inhibits binding both in extracts and cells. Since both organic mercury compounds, unlike HgCl(2), do not readily enter intact cells, it appears that the specific steroid binding occurs inside the cell rather than at the cell membrane.

The position of the ATP binding site on the (Ca2+ + Mg2+)-ATPase.

We present a convenient method to calculate the efficiency of fluorescence energy transfer in two-dimensional membrane systems. We apply it to the analysis of energy transfer between phospholipid molecules labelled with fluorescein and rhodamine groups, and of energy transfer in reconstituted membranes containing (Ca2+ + Mg2+)-ATPase purified from sarcoplasmic reticulum, with the ATPase labelled at the ATP binding site with fluorescein as donor, and rhodamine-labelled lipid as acceptor. The ATP binding site is found to be distant from the plane of the lipid/water interface of the membrane. It is suggested that the ATPase is present in the membrane as a dimer, with the two ATP binding sites in the dimer being close to the protein/protein interface. Addition of vanadate causes no change in quenching, suggesting that the ATP binding site does not move significantly with respect to the lipid/water interface in the E1-E2 conformational transition of the ATPase.

Crystallization and preliminary X-ray diffraction studies of colicin E3 immunity protein.

Immunity protein, an inhibitor of the ribonuclease activity of the protein antibiotic colicin E3, crystallizes in the orthorhombic space group C222 with cell dimensions a = 78.7 A, b = 54.1 A, c = 36.1 A and one molecule of Mr 9800 per asymmetric unit. The crystals are suitable for high resolution X-ray analysis.

Attenuation of the kaluretic properties of furosemide by triamterene (Dyrenium) in healthy volunteers.

OBJECTIVE: To examine if concomitant administration of furosemide, a loop diuretic, with the potassium- and magnesium-sparing diuretic triamterene would decrease loss of potassium and magnesium while improving diuresis. METHODS: In this open-label, three-way crossover study, healthy subjects were randomized to receive treatment with 40 mg furosemide, with 150 mg triamterene, or treatment with 40 mg furosemide and 150 mg triamterene. Urine samples were collected 24 hours before dosing and between 0 - 1, 1 - 2, 2 - 3, 3 - 4, 4 - 6, 6 - 8, 8 - 12, and 12 - 24 hours post-dosing. Sodium and potassium levels were measured by an ion-selective electrode method. Magnesium was measured colorimetrically using a xylidyl blue reaction. RESULTS: Co-administration of furosemide with triamterene resulted in enhanced diuresis, particularly in the first 0 - 12 hours post-dose, compared with either furosemide or triamterene alone. Compared to individual treatments, combination therapy significantly increased urinary sodium excretion (p = 0.0001) while significantly decreasing urinary potassium excretion (p = 0.0001); importantly, the magnesium-sparing characteristic of triamterene was retained with furosemide co-administration. CONCLUSION: Triamterene, when used in combination with the loop diuretic, furosemide, preserves intracellular potassium and magnesium while enhancing the natriuretic effect of furosemide.

Hydroxamic acids as potent inhibitors of endothelin-converting enzyme from human bronchiolar smooth muscle.

Hydroxamic acids 6a-h, derived from malonyl amino acids, and 25a-d, derived from succinyl amino acids, were synthesized as inhibitors of human bronchiolar smooth muscle endothelin-converting enzyme (HBSM ECE). Several unexpected side reactions were discovered, particularly in the synthesis of hydroxamates derived from succinates. In vitro evaluation against human bronchiolar ECE revealed that in all cases hydroxamates derived from malonate were more potent than hydroxamates derived from succinate. Isopropyl and isobutyl P1' side chains were suitable; omission of the P1' side chain seriously diminished potency. In the P2' position, several amino acids gave potent malonate-derived hydroxamate inhibitors (6b, d-h, IC50 = 0.2-6.8 nM), and beta-Ala provided an extremely potent inhibitor (6c, IC50 = 0.01 nM). C-terminus carboxylates are much more potent ECE inhibitors than the corresponding amides. Most of the hydroxamates were also potent inhibitors of thermolysin and neutral endopeptidase (NEP); however, the P2' beta-Ala derivative 6c uniquely inhibited HBSM ECE much more potently than NEP.

Regional dose response to pulmonary irradiation using a manual method.

PURPOSE: To better understand the dose dependence of radiation therapy (RT)-induced changes in regional lung perfusion and tissue density, using a manual method to reduce inaccuracies that might be present in previously described automated methods. MATERIALS AND METHODS: Patients who were to receive RT for tumors in and around the thorax, wherein portions of healthy lung would be incidentally irradiated, were prospectively studied. Changes in regional perfusion and tissue density were assessed by comparison of pre- and post-RT single photon emission computed tomography (SPECT), lung perfusion scans and computed tomography (CT) scans, respectively. The three-dimensional dose distribution was calculated on the pre-RT CT scan and correlated to the other scans via image registration. Study volumes were defined by hand and individually visualized on pre- and post-RT scans. The manually generated dose response data were compared to data generated using automated methods. The relationship between CT density and SPECT perfusion was also determined. RESULTS: Thirteen patients with lung cancer were evaluated for changes in tissue density and 11 patients were evaluated for changes in regional perfusion at 12 months post-RT. In general, density increases with increasing regional dose, with marked changes at >60 Gy. Regional perfusion decreases with increasing regional dose. In the low dose regions, relative perfusion increases by 35% on average. Manually measured dose responses correlated well with those determined automatically. The relationship between regional perfusion and CT density indicates a wide range of perfusion over a narrow range of CT density, with markedly reduced perfusion at CT densities of > -600 and < -900 H. CONCLUSIONS: The manually generated CT density dose response data broadly agree with data previously generated using automated methods. The manually generated perfusion dose response data are in fairly good agreement with automated data, lending credibility to the accuracy of the automated methods. Regional perfusion is markedly diminished where CT density is outside the range of normal lung tissue.

Cytoplasmic inclusions in leukocytes. An unusual manifestation of cryoglobulinemia.

Cryoglobulins are circulating immunoglobulins characterized by reversible, cold-induced precipitation. A variety of laboratory abnormalities, including hypocomplementemia, elevated erythrocyte sedimentation rate, rheumatoid factor activity, pseudoleukocytosis, and pseudothrombocytosis, are associated with cryoglobulinemia. Extracellular, faintly basophilic, amorphous deposits of cryoglobulins occasionally have been described in blood smears. In the present study, smears prepared from blood collected at room temperature from 6 patients with cryoglobulinemia exhibited neutrophil and, occasionally, monocyte inclusions containing clear, light pink, or faintly basophilic amorphous material. The inclusions were absent in smears from blood collected and maintained at 37 degrees C. Ultrastructural examination revealed that the material within the leukocyte inclusions was consistent with phagocytosed immunoglobulins. The identification of characteristic cytoplasmic inclusions in leukocytes may be an important clue in the early recognition of cryoglobulinemia.

Concurrent interferon-alpha and radiation for head and neck melanoma.

Melanoma cells are resistant to radiation in part due to their capacity to repair sublethal damage. A large fraction dose is therefore often utilized. However, if the tumour is located close to critical structures with modest tolerance, high fraction doses increase the risk for late complications compared with standard fractionation, but using the latter alone risks the desired outcome. Concurrent systemic biotherapy with standard radiation fractions may therefore represent an acceptable compromise. The outcome of concurrent systemic interferon-alpha (IFNalpha) and radiation in three patients with head and neck melanoma was evaluated. Standard radiation fractions were used because of the radiosensitizing properties of IFNalpha. Acute toxicity was significant and required treatment interruptions. However, all side effects subsided following treatment. All three patients achieved local control at follow-up periods of 24, 18 and 19 months, respectively. One patient developed widespread distant metastases. The combination of IFNalpha with radiation is considered feasible in terms of outcome and should be investigated with a larger cohort of patients. Toxicity is significant, and the addition of radioprotectors could be desirable.

hGFRalpha-4: a new member of the GDNF receptor family and a candidate for NBIA.

Hallervorden-Spatz syndrome (neurodegeneration with brain iron accumulation type 1; OMIM entry 234200) is a rare inherited neurodegenerative disease. In this article, evidence for a newly identified gene as a candidate for Hallervorden-Spatz syndrome is given. Previously Hallervorden-Spatz syndrome was mapped to a 4-cm region in 20p12.3-13. During positional cloning efforts a new member of the glial-derived neurotrophic factor receptor family was discovered in this region. Like other members of this receptor family, this new gene is predicted to be secreted and glycosyl-phosphatidylinositol linked, and it maintains conserved cysteine residues. However, cDNA and genomic studies in both humans and mice indicate that this gene lacks the sequence corresponding to exons 2 and 3 in other family members. In situ hybridization reveals that it is expressed primarily in the brain and bladder in the embryonic mouse. Mutation analysis of patients with Hallervorden-Spatz syndrome revealed two potentially significant amino acid changes in two patients but failed to identify mutations in the remaining 10 subjects. The implication of these findings for the relationship between this gene and Hallervorden-Spatz syndrome is discussed.

Discrepancies in birth weights between hospital records and health department data for low birth weight infants in New York City.

The study is one of the first to compare corresponding birth weights documented on New York City Health Department Vital Statistics (HDVS) birth tapes and the neonatal medical records of the hospital of birth. Only those infants with birth weights of 2,500 grams (g) or less were studied. Analyses were made of the scope, magnitude of error, and direction of the discrepancies observed. Concordance was considered present if the discrepancy in birth weight was 30 g or less. HDVS birth tapes and the hospital charts of 3,864 neonates were reviewed. The study population came from 48 of 53 hospitals in the metropolitan area. Hospitals were divided into three categories by the level of care offered. Each level of care was subdivided into groups by type of hospital ownership, that is, proprietary, voluntary, and municipal. Concordance was 87 percent overall and ranged from 67 to 96 percent among the study hospitals. More discrepancies were found for levels II and III hospitals than in level I hospitals, those with less sophisticated resources. Municipal hospitals had more discrepancies in birth weights than voluntary hospitals. Infants who had been transported from the birth facility to another facility had significantly higher concordance rates than the nontransported infants, after adjusting for levels of care, type of ownership of the hospital, and birth weight categories. Increased concordance rates were shown to be associated with increased birth weights.

Abnormal regulation of purine metabolism in a cultured mouse T-cell lymphoma mutant partially deficient in adenylosuccinate synthetase.

The isolation and characterization of a mutant mouse T-cell lymphoma (S49) with altered purine metabolism is described. This mutant, AU-100, was isolated from a mutagenized population of S49 cells by virtue of its resistance to 0.1 mM 6-azauridine in semisolid agarose. The AU-100 cells are resistant to adenosine mediated cytotoxicity but are extraordinarily sensitive to killing by guanosine. High performance liquid chromatography of AU-100 cell extracts has demonstrated that intracellular levels of GTP, IMP, and GMP are all elevated about 3-fold over those levels found in wild type cells. The AU-100 cells also contain an elevated intracellular level of pyrophosphoribosylphosphate (PPriboseP), which accounts for its resistance to adenosine. However AU-100 cells synthesize purines de novo at a rate less than 35% of that found in wild type cells. Furthermore, the intact cells of this mutant S49 cell line cannot efficiently incorporate labeled hypoxanthine into nucleotides since the salvage enzyme HGPRTase is inhibited in situ. The AU-100 cell line was found to be 80% deficient in adenylosuccinate synthetase, but these cells are not auxotrophic for adenosine or other purines. The significant alterations in the control of purine de novo and salvage metabolism caused by the defect in adenylosuccinate synthetase are mediated by the resulting increased levels of guanosine nucleotides.

Cognitive style of Eastern European Jewish males.

A distinctive cognitive style showing high verbal--low spatial analysis ability emerged on intelligence test performances of Jewish male subjects of Eastern European extraction. This style is somewhat different from that of the normative population. It is hypothesized that genetic factors making for differential development of the cerebral hemispheres in these subjects interact with subcultural emphasis on verbal skills to produce the evidenced differences.

The rights of the unborn child seen through the eyes of a psychologist.

There is a serious possibility that the developing foetus has become a sentient being long before his or her actual birth and that the most profound response patterns of our existence are already laid down in this early prenatal experience. Experiments over the last 50 to 60 years have shown that not alone is there life before birth, but that the quality of this life plays a determining role in the type of personality one may develop. Although for most of use, life in the womb remains a mysterious enigma, we can no longer afford to ignore the influences, both internal and external, which affect the growing child in its mother's womb. Often thought of as the ultimate haven--the refuge against all life's ills--it is perhaps disconcerting to have to consider that even here, one's first sanctuary, one may not be safe. The single parent is particularly at risk in this regard. Does the law offer sufficient protection for mother and child to ensure support for this critical process?