Validity and reproducibility of a new diagnostic motor performance test in children with suspected myopathy

To spare more children from painful muscle biopsy, a new non-invasive diagnostic motor performance test is undergoing development. Fifteen functional items were used to measure muscle strength and muscle endurance in 68 patients (47 males, 21 females; mean age 7y 8mo, SD 2y 2mo; range 4 to 11y), who had been referred to our specialist centre in the past 3 years on suspicion of myopathy. All the patients had undergone muscle biopsy. To correct the patients' outcomes for age, sex, and body size, regression prediction equations were obtained from a stratified random sample of 64 normally developing primary-school children aged 4 to 11 years (32 males, 32 females; mean age 8y 1mo, SD 2y 4mo). Feasibility was evaluated on the basis of five criteria. Validity was assessed using logistic regression analysis, receiver operating characteristic analysis, and sensitivity and specificity at a specifically chosen cut-off point. Reproducibility was evaluated by test-retest reliability in a stratified random sample of 40 patients who returned for re-measurements using the intraclass correlation coefficient. Seven items satisfied all five feasibility criteria, had high diagnostic power, and high test-retest reliability. The motor performance test can improve diagnostic procedure in children suspected of having myopathy.     

A new motor performance test in a prospective study on children with suspected myopathy

In the development of a new diagnostic motor performance test to spare more children from painful muscle biopsy, seven functional items were used to measure muscle strength and muscle endurance in a prospective study on new patients. Over a 2-year period, 22 patients (12 males, 10 females; mean age 8y 1mo [SD 2y 6mo], range 4-11y) were recruited for the study. They had all been referred with suspected myopathy. The motor performance test was administered before muscle biopsy. Validity of the seven items was assessed using logistic regression analysis and receiver operating characteristic (ROC) analysis. Two items were withdrawn from the test because they were not suitable for children aged 4 to 5 years. The five remaining items were: Heels, Circuit, Stairs, Jump, and Gowers. A full logistic regression model including these five items was fitted to the total population of 90 patients suspected of having myopathy (from this study and our previous study) to make the best prediction of whether myopathy was present. The ROC area under the curve of the diagnostic prediction model was 0.92 (95% confidence interval [CI] 0.87-0.98) and 0.89 (95% CI 0.87-0.92) after bootstrap correction. This indicated the high diagnostic power that can be expected for future, similar patients. This non-invasive and child-friendly motor performance test can improve diagnostic procedure and, therefore, spare more children from unnecessary muscle biopsy.     

Quality of life and psychopathology: investigations into their relationship

OBJECTIVE: Quality of life (QOL) has become a topic of growing interest in medical and psychiatric practice in general, and in research in particular. Although the body of knowledge about the complex relationship between QOL and psychiatric disorders is growing, understanding this relationship still remains difficult. Therefore, the aim of the present study was to get more and new insights into this relationship. It was hypothesized that QOL would be negatively related to the presence as well as the severity of psychopathology. METHOD: A random sample of Dutch adult psychiatric outpatients (n=410) completed the World Health Organization Quality of Life assessment instrument, abbreviated version (WHOQOL-Bref). In addition, DSM-IV axis I and II diagnoses were obtained. Comparisons were made between scores of the psychiatric outpatients, diagnostic subgroups within this population, and the scores of a general population. RESULTS: Compared with the general population, psychiatric outpatients scored significantly worse on all aspects of QOL. Within the group of outpatients, participants with DSM-IV diagnoses had worse scores than those without. Participants with comorbidity had the worst QOL. CONCLUSIONS: It is concluded that QOL scores are negatively related to both the presence and the severity of psychopathology, and that the presence of a personality disorder plays a role in subjectively experienced QOL.     

The dynamics of mitochondrial plasmids in a Hawaiian population of Neurospora intermedia

We analysed the distribution of mitochondrial plasmids among 82 Neurospora intermedia isolates from Hawaii; 74% of the isolates carried the neutral circular plasmid Han-2, whereas 38% contained the linear senescence-causing plasmid kalDNA. The distributions of the two plasmids are independent. There is no significant difference between the Kauaian population of 1972 and that of 1976. To further examine the reasons for this frequency distribution we studied the transmission of both Hawaiian plasmids through the maternal parent in a large series of crosses using non-Kalilo isolates as conidial parents. Plasmids can be lost during the sexual cycle. The Han-2 plasmid is transmitted more efficiently than kalDNA. No clear cases of autonomous or non-autonomous plasmid suppression were observed, so loss can be considered accidental. One Kalilo strain proved to be ineffectual as a maternal parent, and this reduced its ability to transmit kalDNA to the next generation. The dynamic balance of plasmids in natural populations over time is probably a result of the interplay of many forces, including those described in this work and those from several other studies on Neurospora plasmids.     

Dendritic degeneration, neurovascular defects, and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegeneration

Adeno-associated virus (AAV)-mediated expression of wild-type or mutant P301L protein tau produces massive degeneration of pyramidal neurons without protein tau aggregation. We probed this novel model for genetic and structural factors and early parameters of pyramidal neurodegeneration. In yellow fluorescent protein-expressing transgenic mice, intracerebral injection of AAV-tauP301L revealed early damage to apical dendrites of CA1 pyramidal neurons, whereas their somata remained normal. Ultrastructurally, more and enlarged autophagic vacuoles were contained in degenerating dendrites and manifested as dark, discontinuous, vacuolated processes surrounded by activated astrocytes. Dendritic spines were lost in AAV-tauP301L-injected yellow fluorescent protein-expressing transgenic mice, and ultrastructurally, spines appeared dark and degenerating. In CX3CR1(EGFP/EGFP)-deficient mice, microglia were recruited early to neurons expressing human tau. The inflammatory response was accompanied by extravasation of plasma immunoglobulins. α2-Macroglobulin, but neither albumin nor transferrin, became lodged in the brain parenchyma. Large proteins, but not Evans blue, entered the brain of mice injected with AAV-tauP301L. Ultrastructurally, brain capillaries were constricted and surrounded by swollen astrocytes with extensions that contacted degenerating dendrites and axons. Together, these data corroborate the hypothesis that neuroinflammation participates essentially in tau-mediated neurodegeneration, and the model recapitulates early dendritic defects reminiscent of "dendritic amputation" in Alzheimer's disease.     

Involvement of inhibin in the regulation of follicle-stimulating hormone concentrations in prepubertal and adult, male and female rats

Administration of steroid-free bovine follicular fluid (bFF), containing inhibin-like activity, depressed levels of FSH measured 4 h after injection in intact adult and 35-day-old female rats, but not in younger females. Suppression of FSH was also observed in intact male rats, aged 55 days, but not in older and younger male rats. Eight hours after injection of bFF, FSH levels were depressed in 15-day-old and older immature and adult rats of both sexes. Male and female rats, gonadectomized 2 days earlier, responded similarly to bFF treatment as did the intact animals. In a second experiment it was found that the rise of FSH levels, occurring within 8 h of gonadectomy, decreased with age in male and increased with age in female rats. Steroid treatment was found to prevent the rise in FSH levels partially in 15-day-old male and completely 25-day-old female rats, whereas treatment with bFF was fully effective in blocking the FSH rise in both immature and adult rats of both sexes. It is concluded that inhibin might be a major physiological factor in a fast-acting control of FSH concentrations from at least the age of 25 days onwards in female rats. In male rats its physiological significance might be limited to the prepubertal period, despite the fact that pituitary secretion of FSH is suppressed by exogenous inhibin-like activity at all ages studied.     

A mucoadhesive, cyclodextrin-based vaginal cream formulation of itraconazole

The development of vaginal medications, especially antifungal medications, requires that the drug is solubilized as well as retained at or near the mucosa for sufficient periods of time to ensure adequate bioavailability. Itraconazole is a broad-spectrum antifungal agent, which has been used for some time orally and intravenously but for which a vaginal formulation has not yet been developed. We present here a novel itraconazole formulation intended for vaginal use based on hydroxypropyl-β-cyclodextrin (HPβCD), a functional excipient that increases drug solubility and generates a mucoadhesive system in the presence of other ingredients. An aqueous phase was prepared by solubilizing itraconazole with HCl in the presence of propylene glycol and then adding an aqueous solution of HPβCD. After pH adjustment, the itraconazole/HPβCD solution was added to the oil phase (paraffin oil, trihydroxystearate, and cetyl dimethicon copolyol) and the desired cream containing 1%, 2%, and 2.5% drug obtained by homogenization. Primary irritation studies and subchronic toxicity studies using a rabbit vaginal model indicated that the formulation was safe, well tolerated, and retained in the vaginal space. Clinical investigations indicated that application of 5 g of a 2% cream was very well tolerated and itraconazole was not systemically absorbed. Additional studies in women found that the itraconazole cream was highly effective in reducing or eliminating fungal cultures with few adverse effects. These studies suggested that an HPβCD-based, emulsified wax cream formulation was a useful and effective dosage form for treating vaginal candidiasis.     

Coamplification of DAD-R, SOX5, and EKI1 in human testicular seminomas, with specific overexpression of DAD-R, correlates with reduced levels of apoptosis and earlier clinical manifestation

Seminomas and nonseminomas represent the invasive stages of testicular (TGCTs) of adolescents and adults. Although TGCTs are characterized by extra copies of the short arm of chromosome 12, the genetic basis for gain of 12p in the pathogenesis of this cancer is not yet understood. We have demonstrated that gain of 12p is related to invasive growth and that amplification of specific 12p sequences, i.e., 12p11.2-p12.1, correlates with reduced apoptosis in the tumors. Here we show that three known genes map within the newly determined shortest region of overlap of amplification (SROA): DAD-R, SOX5, and EKI1. Whereas EKI1 maps close to the telomeric region of the SROA, DAD-R is the first gene at the centromeric region within the 12p amplicon. Although all three genes are amplified to the same level within the SROA, expression of DAD-R is significantly up-regulated in seminomas with the restricted 12p amplification compared with seminomas without this amplicon. DAD-R is also highly expressed in nonseminomas of various histologies and derived cell lines, both lacking such amplification. This finding is of particular interest because seminomas with the restricted 12p amplification and nonseminomas are manifested clinically in the third decade of life and show a low degree of apoptosis. In contrast, seminomas lacking a restricted 12p amplification, showing significantly lower levels of DAD-R with pronounced apoptosis, manifest clinically in the fourth decade of life. A low level of DAD-R expression is also observed in normal testicular parenchyma and in parenchyma containing the precursor cells of this cancer, i.e., carcinoma in situ. Therefore, elevated DAD-R expression in seminomas and nonseminomas correlates with invasive growth and a reduced level of apoptosis associated with an earlier clinical presentation. These data implicate DAD-R as a candidate gene responsible in part for the pathological effects resulting from gain of 12p sequences in TGCTs. In addition, our results also imply differences in expression regulation of DAD-R between seminomas and nonseminomas.