Three clinical indicators of borderline personality disorder in anorexia nervosa: A pilot study.

OBJECTIVES: Co-occurrence of Anorexia Nervosa (AN) and borderline personality disorder (BPD) is frequent (8%-40%) and associated with specificities that impact the treatment process. Lifetime history of suicide attempt (HAS), substance use disorder (SUD) and the binge-purging subtype (B-P) might be good markers of such comorbidity. We made the hypothesis that in patients with AN, the presence of HAS, SUD and B-P have sufficient predictive power to efficiently detect an associated BPD comorbidity. METHODS: After a case report analysis on a pilot sample of 119 patients with AN, we performed a cross-sectional analysis on a confirmatory sample of 84 patients with AN in a single center specialized in eating disorders systematically assessing HAS, SUD, B-P and BPD using the Mini International Neuropsychiatric Interview for DSM-5 and the Diagnostic Interview for Borderline (DIB-R). RESULTS: B-P had a 100% negative predictive value, and the combination of SUD plus HAS had a 100% positive predictive value. On a quantitative level, B-P, HAS and SUD were independent explanatory factors of the DIB-R total score. CONCLUSIONS: The main limitations were the low number of patients, the single center analyses, the potential overlapping of assessments and the fact that data were exclusively declarative. In this study, every patient with B-P, SUD and HAS had been diagnosed with BPD.

Acute quadriplegic myopathy with thick filament loss spares moving muscles: an autopsy study.

Acute Quadriplegic Myopathy with selective Thick Filament Loss (AQM-TFL) is likely an under-recognized cause of acquired areflexic quadriplegia in the ICU setting. An autopsy study of a patient with AQM-TFL revealed widespread limb thick filament loss, but with complete diaphragmatic and cardiac sparing and relative intercostal muscle sparing, was observed. Due to increased lipid accumulation, biochemical studies were performed and showed an increased free carnitine percentage, suggesting possible impaired carnitine esterification. These findings suggest that moving muscles might be resistant to the deleterious effects of AQM-TFL. These findings may have therapeutic implications.

Enzyme replacement therapy in the mouse model of Pompe disease.

Deficiency of acid alpha-glucosidase (GAA) results in widespread cellular deposition of lysosomal glycogen manifesting as myopathy and cardiomyopathy. When GAA-/- mice were treated with rhGAA (20 mg/kg/week for up to 5 months), skeletal muscle cells took up little enzyme compared to liver and heart. Glycogen reduction was less than 50%, and some fibers showed little or no glycogen clearance. A dose of 100 mg/kg/week resulted in approximately 75% glycogen clearance in skeletal muscle. The enzyme reduced cardiac glycogen to undetectable levels at either dose. Skeletal muscle fibers with residual glycogen showed immunoreactivity for LAMP-1/LAMP-2, indicating that undigested glycogen remained in proliferating lysosomes. Glycogen clearance was more pronounced in type 1 fibers, and histochemical analysis suggested an increased mannose-6-phosphate receptor immunoreactivity in these fibers. Differential transport of enzyme into lysosomes may explain the strikingly uneven pattern of glycogen removal. Autophagic vacuoles, a feature of both the mouse model and the human disease, persisted despite glycogen clearance. In some groups a modest glycogen reduction was accompanied by improved muscle strength. These studies suggest that enzyme replacement therapy, although at much higher doses than in other lysosomal diseases, has the potential to reverse cardiac pathology and to reduce the glycogen level in skeletal muscle.

Surprises of genetic engineering: a possible model of polyglucosan body disease.

BACKGROUND: The authors previously reported the generation of a knockout mouse model of Pompe disease caused by the inherited deficiency of lysosomal acid alpha-glucosidase (GAA). The disorder in the knockout mice (GAA-/-) resembles the human disease closely, except that the clinical symptoms develop late relative to the lifespan of the animals. In an attempt to accelerate the course of the disease in the knockouts, the authors increased the level of cytoplasmic glycogen by overexpressing glycogen synthase (GSase) or GlutI glucose transporter. METHODS: GAA-/- mice were crossed to transgenic mice overexpressing GSase or GlutI in skeletal muscle. RESULTS: Both transgenics on a GAA knockout background (GS/GAA-/- and GlutI/GAA-/-) developed a severe muscle wasting disorder with an early age at onset. This finding, however, is not the major focus of the study. Unexpectedly, the mice bearing the GSase transgene, but not those bearing the GlutI transgene, accumulated structurally abnormal polysaccharide (polyglucosan) similar to that observed in patients with Lafora disease, glycogenosis type IV, and glycogenosis type VII. Ultrastructurally, the periodic acid-Schiff (PAS)-positive polysaccharide inclusions were composed of short, amorphous, irregular branching filaments indistinguishable from classic polyglucosan bodies. The authors show here that increased level of GSase in the presence of normal glycogen branching enzyme (GBE) activity leads to polyglucosan accumulation. The authors have further shown that inactivation of lysosomal acid alpha-glucosidase in the knockout mice does not contribute to the process of polyglucosan formation. CONCLUSIONS: An imbalance between GSase and GBE activities is proposed as the mechanism involved in the production of polyglucosan bodies. The authors may have inadvertently created a "muscle polyglucosan disease" by simulating the mechanism for polyglucosan formation.

Lipid profile in congenital adrenal hyperplasia.

Glucocorticoids have been reported to exert a marked effect on lipoprotein metabolism. Several studies have shown a potential risk of hyperlipidemia in patients under long-term glucocorticoid therapy. Current management of patients with congenital adrenal hyperplasia (CAH) includes the use of glucocorticoids to attenuate the increased production of undesirable adrenal hormones. A case-control study was designed to compare the serum lipid profiles of 14 patients with CAH under glucocorticoid therapy and 14 normal controls and to determine the characteristics of the profiles. A total of 9 patients (64.3%) had serum total cholesterol (TC) greater than 4.4 mmol/L (170 mg/dL), compared with 6 individuals in the control group (42.3%). Nine patients with CAH (64.3%) had serum triglycerides (TGs) more than 1.0 mmol/L (90 mg/dL), compared with only 2 in the control group (14.3%). Similarly, the mean serum TG was higher in the CAH group versus the controls, 1.33 mmol/L (118 mg/dL) versus 0.75 mmol/L (67 mg/dL), respectively. Serum low-density lipoprotein, (LDL-C) and high-density, lipoprotein (HDL-C) cholesterol were determined in 13 children with CAH and in the 14 controls. Nine CAH patients (69.2%) and 8 controls (57%) had LDL-C greater than 2.8 mmol/L (<110 mg/dL). For HDL-C, 2 children with CAH (15.4%) and 4 controls (28.6%) had levels less than 0.9 mmol/L (35 mg/dL). There were no significant differences for the cholesterol index, 0.24 for the controls and 0.22 for the CAH group. In the CAH group, the mean serum TG level and the percentage of individuals with TGs greater than 1.0 mmol/L were statistically significant compared with the controls. The mean serum TC and LDL-C, as well as the percentage of subjects with levels over the cutoff point, although slightly higher in the CAH group, were of no statistical significance. The results of this pilot study suggest that long-term glucocorticoid therapy in patients with CAH may induce abnormalities in the serum lipid profile characterized mainly by an increment in serum TGs.

Recent advances in the diagnosis and treatment of precocious puberty.

In the last two decades, the diagnosis and treatment of precocious puberty has undergone important changes. The use of supersensitive assays to determine gonadotropins and gonadal hormones has increased the sensitivity and decreased the number of blood samples required to assess the diagnosis. The introduction of gonadotropin-releasing hormone (GnRH) agonists produced a revolution in the diagnosis and treatment of this disorder. Recently, the use of long acting GnRH agonists improved the adherence of patients to medical treatment and decreased the need for uncomfortable repeated doses. The medications in the treatment of the GnRH independent causes of precocious puberty, and the important revelations in the pathophysiology of these disorders, have advanced our knowledge and management of the affected children.

Clenbuterol reduces degeneration of exercised or aged dystrophic (mdx) muscle.

Evidence of dystrophic muscle degeneration in the hind limb muscles of young (20-week-old) treadmill-exercised or aged (87-week-old) sedentary mdx mice was greatly reduced by treatment with clenbuterol, a beta(2)-adrenoceptor agonist. Daily treadmill exercise for 10 weeks increased the size of regions within the mdx plantaris but not the soleus or gastrocnemius muscles, in which necrotic muscle fibers or the absence of fibers was observed. Clenbuterol reduced the size of these abnormal regions from 21% of total muscle cross-sectional area to levels (4%) found in sedentary mdx mice. In addition, the muscles obtained from aged clenbuterol-treated mdx or wild-type mice did not display the extensive fibrosis or fiber loss observed in untreated mdx mice. These observations are consistent with a mechanism of dystrophic muscle degeneration caused by work load-induced injury that is cumulative with aging and is opposed by beta(2)-adrenoceptor activation. Optimization of beta(2)-agonist treatment of muscular dystrophy in mdx mice may lead to a useful therapeutic modality for human forms of the disease.

Heterotopic neogenesis of skeletal muscle induced in the adult rat diaphragmatic peritoneum: ultrastructural and transplantation studies.

During the course of a mild chemical peritonitis, new skeletal muscle fibers develop and persist over a twelve-month interval in the diaphragmatic peritoneum. Light and electron microscopic studies revealed that the ectopic fibers developed from myoblasts and myotubes to fully differentiated muscle cells in the same manner as normally situated skeletal muscle. The ectopic fibers were separated from the intrinsic muscle by dense connective tissue and an elastic lamina. Diaphragms taken from normal rats and transplanted to the omentum of isogeneic recipients also developed skeletal muscle neogenesis in the same ectopic location as in the normal diaphragm. Satellite cells, reactive fibroblasts in the peritoneum, mesenchymal stem cells or blood-borne myoblast precursor cells could be the source of these ectopic muscle fibers. The results of the present studies, however, cannot provide conclusive evidence for the origin of the new muscle fibers. Regardless of their source, the methods employed may represent a unique model for the development and prolonged maintenance of skeletal muscle fibers in a heterotopic location in vivo.

Serum inhibin B levels and the response to gonadotropin stimulation test in pubertal boys with varicocele.

PURPOSE: The impact of varicoceles on gonadal function in adolescents has been evaluated using several parameters, including size of testes, hormonal levels and provocative endocrine testing. Inhibin B has been demonstrated to be decreased in men with testicular damage from conditions other than varicocele. We determine whether inhibin B levels are low in adolescent boys with varicocele, and if there is a relationship between inhibin B and an exaggerated response to gonadotropin-releasing hormone (Gn-RH) stimulation testing, testicular hypertrophy and/or varicocele bilaterality. MATERIALS AND METHODS: We studied 9 boys at Tanner stages III to V of pubertal development who had either left or bilateral varicoceles. Basal inhibin B, follicle-stimulating hormone, luteinizing hormone and testosterone were measured. Each patient underwent Gn-RH stimulation testing. RESULTS: All patients had essentially normal inhibin B levels for Tanner stage. Of the 9 boys 4 had an exaggerated response to Gn-RH stimulating testing. Inhibin B levels did not vary significantly either with the presence of bilateral or unilateral varicoceles or asymmetric testis. CONCLUSIONS: The lack of correlation between inhibin B levels and the aforementioned parameters failed to suggest that inhibin B has a significant role in the clinical assessment of testicular function in adolescents with varicocele. Further studies of larger populations may further elucidate the value of inhibin B levels and varicoceles.

Comprehensive assessment of the components of energy expenditure in infants using a new infant respiratory chamber.

BACKGROUND: Current methods for energy expenditure (EE) measurements in term infants do not include simultaneous measurements of basal and sleeping metabolic rates (BMR and SMR) or a measure of physical activity (PA). Furthermore, prediction equations for calculating EE are not appropriate for use in infants with metabolic disorders. OBJECTIVE: To develop and utilize a new infant respiratory chamber for simultaneous measurements of EE (kJ/d), preprandial BMR (kJ/d), SMR (kJ/d) and an index of PA (oscillations/min/kg body weight) in infants with a variety of metabolic disorders, for up to four hours in a hospital setting, while allowing parental interaction in a comfortable environment. METHODS: We obtained simultaneous measurements of EE, BMR, SMR and PA in 21 infants (66+/-73 days of age, 4.5+/-1.7 kg body weight, 55+/-8 cm in length and 16+/-7% body fat) using our new infant respiratory chamber. Six of these infants were healthy, seven had thyroid dysfunction, five were HIV-exposed, one had AIDS, one had intrauterine and postnatal growth retardation and one was a hypothermic preterm infant. Energy expenditure, BMR and SMR were extrapolated for 24 hours. Body composition was estimated by skin-fold thickness, using age-appropriate formulae. Basal metabolic rate obtained with the infant respiratory chamber was compared to BMR that was calculated using the appropriate World Health Organization (WHO) equations. RESULTS: In all infants both extrapolated 24-hour EE and BMR correlated with fat-free mass (r = 0.89, p<0.01 and r = 0.88, p<0.01 respectively). Twenty-four hour EE also correlated with PA (r = 0.52, p<0.05). The HIV-exposed infants had higher BMR (p<0.05) than that calculated by the appropriate WHO equation. We found that the caloric requirements for the infant with growth retardation were underestimated based on the infant's weight and age. CONCLUSIONS: The infant respiratory chamber can measure all of the main components of EE. Some of the results obtained differed significantly from those obtained by the WHO equations; therefore, the new infant respiratory chamber is necessary for estimating EE in infants with metabolic and growth disorders.

IL-10 production in common variable immunodeficiency.

Common variable immunodeficiency, (CVI) is a heterogeneous primary immunodeficiency disease in which there are T and B cell defects. Since IL-10 in conjunction with anti-CD40 promotes secretion of IgG, IgA, and IgM by CVI B cells, these studies were performed to investigate IL-10 production in CVI. Mitogen or anti-CD3 stimulated CVI peripheral blood mononuclear cells, or isolated T cells produced an insignificant amount of IL-10 over background levels. CVI monocyte IL-10 production was substantial and greater than that of normal controls. Anti-IL-10-neutralizing antibody strongly enhanced CVI T cell proliferative responses to PHA, but only to an insignificant extent, soluble antigens. IL-2 plus anti-IL-10 enhanced CVI proliferative responses to antigens significantly more over baseline than for cells of similarly tested normal controls. These data suggest that CVI T cell secretion of IL-10 is deficient, but that monocyte-derived IL-10, plus a relative lack of IL-2 production, could contribute to the defects of cell proliferation in this disorder.

Sequential muscle biopsy changes in a case of congenital myopathy.

Muscle biopsies at age 7 months in a set of dizygotic male twins born floppy showed typical features of congenital fiber-type disproportion (CFTD). One of the twins died at age 1 year due to respiratory complications. The second one subsequently developed facial diplegia and external ophthalmoplegia. He never walked, remained wheelchair bound, and required continuous ventilatory support. He underwent repeat biopsies at ages 2 and 4, which showed many atrophic type 1 muscle fibers containing central nuclei and severe type 2 fiber deficiency compatible with centronuclear myopathy (CNM). Two-dimensional gel electrophoresis of muscle showed decreases of type II myosin light chains 2 and 3, suggestive of histochemical type I fiber deficiency. The progressive nature of morphological changes in one of our patients cannot be explained by maturational arrest. Repeat biopsies in cases of CFTD with rapid clinical deterioration may very well show CNM.

Use of fructose-2,6-diphosphate to assay for phosphofructokinase activity in human muscle.

OBJECTIVE: Use fructose-2,6-diphosphate (fru-2,6-P2) for measuring phosphofructokinase (PFK) activity in muscles. DESIGN AND METHODS: PFK activity was measured at 2 mmol/L MgCl2 and 5 mmol/L adenosine triphosphate (ATP) (mol/L MgCl2:mol/L ATP 0.4) without and with fru-2,6-P2. RESULTS: Human muscle extracts had little PFK activity when assayed at mol/L MgCl2:mol/L ATP of 0.4 to 0.78 without fru-2,6-P2; 1.83 +/- 0.91 units/g muscle. Addition of fru-2,6-P2 produced an immediate 20- to 57-fold increase in activity; 52.8 +/- 12.5 units/g muscle. Raising the mol/L ratio of MgCl2 to ATP to 0.87 and higher without fru-2,6-P2 produced 34%-76% of the PFK activity seen with fru-2,6-P2. A PFK deficiency patient had a trace of activity, which was independent of mol/L MgCl2:mol/L ATP and not activated by fru-2,6-P2. CONCLUSION: The almost complete absence of activity without fru-2,6-P2 at 0.40 mol/L MgCl2:mol/L ATP, and the restoration of maximum activity by fru-2,6-P2 provides an assay for verified PFK activity that could lead to a more accurate diagnosis in patients with PFK deficiency.

Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations.

Zidovudine-induced myopathy is characterized by reversible muscle weakness, wasting, myalgia, fatigue, and elevated creatine kinase (CK). Some zidovudine-treated patients with normal muscle strength experience excessive fatigue, myalgia, or transient mild CK elevations that improve when zidovudine is stopped. To determine the cause of these symptoms, we studied 13 physically fit, HIV-infected men who developed fatigue, myalgia, and reduced endurance, while taking zidovudine for a mean period of 20 months (2-39 months), with neurological evaluation and muscle biopsy processed for enzyme histochemistry and electron microscopy (EM). All subjects had normal muscle strength. In 6 of the 13 patients, muscle biopsies were normal by enzyme histochemistry. EM, however, demonstrated proliferation of normal or abnormal mitochondria, and increased amounts of lipid, glycogen, and lipofuscin. Electromyographic (EMG) studies (5/5) and serum CK (6/6) were normal. The other 7 individuals had signs of moderate to severe mitochondrial abnormalities shown by both light microscopy and EM, characterized by severe destruction, vacuolization, and rare paracrystalline inclusions. Most had elevated CK (4 out of 7) and normal EMG (5 out of 7). The severity of morphological abnormalities did not correlate with duration of HIV infection, zidovudine therapy, or zidovudine dosage. We conclude that in zidovudine-treated patients, symptoms of fatigue, myalgia, reduced endurance, and exercise intolerance represent early signs of zidovudine-induced mitochondriotoxicity, which causes an energy shortage within the muscle fibers even when muscle strength is still normal. Zidovudine, a DNA chain terminator, results in overt myopathy when a critical threshold of molecular, histological, and biochemical dysfunction of mitochondria is crossed, which seems to vary between individuals.

Identification of coelomocyte unconventional myosin and its association with in vivo particle/vesicle motility.

Sea urchin coelomocytes undergo an inducible structural transformation from petalloid to filopodial form during the 'clotting' response in sea urchins. Using a petalloid coelomocyte model, stimulated coelomocytes exhibited bidirectional particle/vesicle motility with a broad distribution of velocities, ranging from 0.02 to 0.12 microns s-1 in the outward bound direction. Coelomocytes treated with the microtubule-disrupting drug, nocodazole, continued to exhibit outward particle/vesicle movements along linear paths with an average velocity of 0.028 +/- 0.006 microns s-1. We partially purified a 110 kDa polypeptide possessing K+EDTA-, Ca2(+)-, Mg2(+)- and F-actin-activated Mg(2+)-ATPase activities characteristic of myosin-like motor proteins. The 110 kDa protein immuno-crossreacted with both affinity-purified, anti-brush border unconventional myosin-I polyclonal antibodies and anti-Acanthamoeba myosin head monoclonal antibodies. By indirect immunofluorescence, the 110 kDa unconventional myosin was localized to clusters of particles/vesicles within the perinuclear region of unstimulated coelomocytes, an area containing numerous mitochondria, acidic, lysosomal and Golgi organelles. Indirect immunofluorescence of partially transformed and filopodial coelomocytes detected a diminution of perinuclear staining with a concomitant appearance of stained linear arrays of particles/vesicles, enhanced staining of peripheral lamellae, and staining of the entire length of the filopodia. Subfractionation of unstimulated coelomocyte homogenates on linear sucrose gradients identified distinct peaks of ATPase activity associated with fractions containing conventional and 110 kDa unconventional myosin. Unconventional myosin-containing fractions were found to have numerous particles that stained with anti-brush border unconventional myosin-I antibodies and the lipophilic dye, DiOC6. Thus, coelomocytes demonstrate activatable movements of particles/vesicles in cells devoid of microtubules and possess an unconventional myosin, which may be the motor protein driving particle/vesicle translocation.

Prednisone dose limitation of growth hormone treatment of steroid-induced growth failure.

Seven children with prednisone-induced growth failure were treated with recombinant growth hormone to improve linear growth. Six of seven patients had an increase in linear growth during therapy with recombinant growth hormone. The response to recombinant growth hormone was found to be related to the prednisone dose. When the prednisone dose was greater than 0.35 mg/kg per day, recombinant growth hormone did not increase the linear growth rate. At lower doses the response was inversely related to the amount of prednisone taken.

An updated protocol for abortion surveillance with ultrasound and immediate pathology.

OBJECTIVE: To modify and improve a protocol for surveillance of patients presenting for routine elective abortion services. METHODS: Six hundred seventy-four women presenting for routine elective first-trimester abortions were studied. All were 84 or fewer days after the last menstrual period, had no history of bleeding, and had positive urine pregnancy tests. Each woman was scanned initially with an empty-bladder transabdominal technique. If no sac was seen, endovaginal ultrasonography was performed. All terminations had modified gross examination of tissue (3x magnification) as well as staining for microscopic analysis. RESULTS: Six hundred twelve patients (90.8%) demonstrated intrauterine gestations on transabdominal ultrasound, 595 of which were 12 or fewer weeks. Suction and sharp curettage and examination of tissue revealed products of conception in all. Seventeen subjects (2.5%) were found to be 13 or more weeks despite bimanual examinations and last menstrual period suggesting 12 or fewer weeks. Sixty-two patients had no sac seen on transabdominal ultrasound, 34 of whom had definitive intrauterine gestations on endovaginal ultrasound. Curettage revealed chorionic villi in all. Two had unruptured definitive ectopic pregnancies seen on endovaginal ultrasound. Twenty-one women with no sac seen on endovaginal ultrasound underwent curettage as the next step in triage; chorionic villi proved an intrauterine gestation in 17. The additional four had decidua only on pathology. Rising hCG levels in two of these four led to a diagnosis of ectopic pregnancy, whereas falling hCG levels in the other two led to a presumptive diagnosis of complete abortion, possibly tubal pregnancy in light of the lack of vaginal bleeding. CONCLUSION: Pre-abortion sonography eliminates inadvertent second-trimester cases, and immediate postoperative examination of curettage material expedites the diagnosis of ectopic pregnancy when present.

Symptomatic non-insulin-dependent diabetes mellitus during therapy with recombinant human growth hormone.

In a 12-year-old girl, hyperglycemia and an elevated glycohemoglobin concentration developed after therapy with growth hormone for familial short stature. Both clinical and biochemical abnormalities disappeared after therapy was discontinued. The insulin response to an oral glucose tolerance test was abnormal 3 months after discontinuation of growth hormone; 18 months later, it remained delayed but was normal quantitatively.