Home-based exercise in autoimmune myasthenia gravis: A randomized controlled trial.

The tolerance of exercise and its effects on quality of life in myasthenia gravis are not currently backed up by strong evidence. The aim of this study was to determine whether exercise as an adjunct therapy is well tolerated and can improve health-related quality of life (HRQoL) in stabilized, generalized autoimmune myasthenia gravis (gMG). We conducted a parallel-group, multi-center prospective RCT using computer-generated block randomization. Adults with stabilized, gMG, and no contra-indication to exercise, were eligible. Participants received usual care alone or usual care and exercise. The exercise intervention consisted of 3-weekly 40 min sessions of an unsupervised, moderate-intensity home rowing program over 3 months. The primary endpoint was the change in HRQoL from randomization to post-intervention. Assessor-blinded secondary endpoints were exercise tolerance and effects on clinical, psychological and immunological status. Of 138 patients screened between October 2014 and July 2017, 45 were randomly assigned to exercise (n = 23) or usual care (n = 20). Although exercise was well tolerated, the intention-to-treat analysis revealed no evidence of improved HRQoL compared to usual care (MGQOL-15-F; mean adjusted between-groups difference of -0.8 points, 95%CI -5.4 to 3.7). Two patients hospitalized for MG exacerbation were from the usual care group.

Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia.

Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 - LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co-segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non-syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.

Activation of cAMP-dependent protein kinase A in prefrontal cortex impairs working memory performance.

Activation of the adenylyl cyclase-cAMP-protein kinase A (PKA) intracellular signaling cascade is necessary for long-term memory consolidation in brain regions such as the hippocampus. However, the role of the PKA cascade in the working memory functions of the prefrontal cortex (PFC) is unknown. The present study examined the effects of manipulating PKA activity in the PFC using the cAMP stereoisomers Sp-cAMPS and Rp-cAMPS, which activate and inhibit PKA, respectively. Animals received bilateral infusions of Sp-cAMPS and/or Rp-cAMPS into the PFC immediately before testing on the delayed alternation task, a test of spatial working memory that depends on the integrity of the PFC. Low doses of Sp-cAMPS (0.21, 2. 1, or 21 nmol/0.5 microl) produced a marked, dose-dependent impairment in working memory performance. The impairment produced by infusion of Sp-cAMPS (21 nmol/0.5 microl) was fully reversed by co-infusion of Rp-cAMPS (21 nmol/0.5 microl), consistent with actions on PKA. Rp-cAMPS (21 or 42 nmol/0.5 microl) by itself had no effect on performance. These results indicate that activation of the PKA intracellular signaling cascade in the PFC impairs working memory performance. The current findings contrast with studies of long-term memory consolidation, in which inhibition of PKA with agents such as Rp-cAMPS impaired memory consolidation (Bernabeu et al., 1997; Bourtchouladze et al., 1998), whereas enhancement of the PKA pathway improved memory (Bernabeu et al., 1997; Barad et al., 1998). These results demonstrate that discrete cognitive processes subserved by different cortical regions are mediated by distinct intracellular mechanisms.

Fetal tachycardia and intramyocardial tumors.

The two-dimensional echocardiographic diagnosis of multiple cardiac rhabdomyomas and evaluation of tachycardia in a fetus are presented. Prenatal echocardiographic examination defined the extent of tumor involvement and mechanism of the tachycardia and demonstrated the lack of fetal hemodynamic compromise. Perinatal, clinical and therapeutic implications are discussed.

Peptide screening.

Since late 1990, there have been several advances in preparing and screening large numbers of various peptides. Developments have continued in methods of peptide screening based on peptides exposition on coat proteins, produced via fusion coliphage constructs. Further developments have been made in increasing the multitude of peptides produced by the chemical synthetic strategy, including light-directed, spatially addressable chemical synthesis, single-bead, single-peptide synthesis, as well as iterative peptide selection and synthesis.

Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC.

We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.

A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in the prefrontal cortex.

BACKGROUND: Stress exacerbates many neuropsychiatric disorders associated with prefrontal cortical (PFC) dysfunction. Stress also impairs the working memory functions of the PFC. Although stress research has focused on dopaminergic mechanisms, stress also increases norepinephrine (NE) release in PFC, and intra-PFC infusions of NE alpha-1-adrenoceptor agonists impair working memory. The current study examined whether NE alpha-1-adrenoceptor actions in PFC contribute to stress-induced deficits in working memory performance. METHODS: Rats were treated with a pharmacological stressor, FG7142 (30 mg/kg) or vehicle 30 min before testing on a test of spatial working memory, delayed alternation. The alpha-1-adrenoceptor antagonist, urapidil (0.1 microgram/0.5 microL), or saline vehicle, was infused into the PFC 15 min before delayed alternation testing. RESULTS: As observed previously, FG7142 significantly impaired the accuracy of delayed alternation performance, and induced a perseverative pattern of responding consistent with PFC dysfunction. FG7142 also slowed motor response times. Infusion of urapidil into the PFC completely reversed the FG7142-induced impairment in delayed alternation performance, but did not alter the slowed motor responding. CONCLUSIONS: These findings indicate that alpha-1-adrenoceptor stimulation in the PFC contributes to stress-induced impairments in PFC cognitive functions. These neurochemical actions may contribute to symptoms of working memory impairment, poor attention regulation, or disinhibited behaviors in neuropsychiatric disorders sensitive to stress exposure.

Recent polymorphic insertion of an Alu repeat in the baboon lipoprotein lipase (LPL) gene.

We have identified a polymorphic insertion in the lipoprotein lipase (LPL) gene in a captive baboon colony. Mapping and nucleotide (nt) sequence analysis of the polymorphism showed that it is due to the presence or absence of an Alu repetitive element in intron 7 of the baboon LPL gene. This polymorphic Alu repeat has not been reported in humans, and we did not detect the repeat in a survey of the LPL intron 7 gene region in other non-human primates. Comparison of nt at diagnostic positions in this Alu insertion with different Alu subfamily consensus sequences showed that it most closely resembles the young AluY subfamily. These data suggest that this polymorphic Alu repeat inserted independently in the baboon lineage.

Baboon lecithin cholesterol acyltransferase (LCAT): cDNA sequences of two alleles, evolution, and gene expression.

Lecithin cholesterol acyltransferase (LCAT) is a key enzyme of cholesterol metabolism that catalyzes esterification of cholesterol for packaging in high-density lipoprotein (HDL) particles. In this study, we cloned and sequenced LCAT cDNA from baboon, a nonhuman primate model of atherosclerosis. LCAT sequences have been highly conserved over approximately 25 million years since the divergence of the baboon and human lineages. The baboon and human sequences are 97% identical at the nucleotide (nt) level and 98% identical at the amino acid (aa) level. Only 18% of the nt substitutions change the aa sequence (nonsynonymous substitutions). The substitutions between baboon and human LCAT do not alter key functional sites including the interfacial substrate active site, asparagine-linked glycosylation sites, or sites at which rare mutations cause human familial LCAT deficiencies. We also sequenced LCAT cDNA for a less common allele that is associated with higher LCAT activities and altered lipoprotein phenotypes. There were no sequence differences between the two alleles, which suggests that genotypic effects are most likely due to allelic differences in gene expression. The tissue specificity of LCAT expression was investigated using an RNase protection assay calibrated with known amounts of synthetic human LCAT RNA. In a survey of baboon tissues, the highest levels of LCAT mRNA were found in the cerebellum and liver and trace amounts in the ileum, spleen and cerebral cortex.

Combined surgery and radiation in endometrial carcinoma: an analysis of prognostic factors.

From 1969 to 1979, 300 patients with the diagnosis of endometrial cancer operated elsewhere were referred for treatment to the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center. All the patients were staged according to FIGO classification. One hundred and seventy-three patients were Stage IA, 105 patients were Stage IB, and 22 patients were Stage II. Within Stage IA, 141 patients had well differentiated tumor (G1), 20 had moderately well differentiated tumor (G2), and 12 patients had poorly differentiated (G3). One hundred and thirty-three patients had superficial myometrial invasion and 40 patients had deep myometrial invasion. Within Stage IB, 69 patients had G1 tumor, 23 had G2, and 13 had G3 tumors. Seventy-four patients in this group had superficial myometrial invasion and 31 patients had deep myometrial invasion. Two hundred and eighty-three patients had adenocarcinoma, 13 patients had adenoacanthoma, 4 patients had adenosquamous and other histological types. All of the patients received combined surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) and radiation. The radiation treatments consisted of external pelvic radiation and intravaginal vault radiation. External pelvic radiation was delivered with a megavoltage apparatus for a total dose of 4,000 cGy in 4 weeks preoperatively (47 patients) or postoperatively (105 patients) in patients presenting with high grade (G2,G3), more than 1/3 myometrial invasion, Stage II and extrauterine extension of disease at surgery. All patients received in addition, postoperative intravaginal vault irradiation consisting of 2100 cGy in 3 fractions over 4 weeks with a high dose rate remote afterloading technique. The follow-up in these patients ranged from 5-14 years. Survival data was calculated according to Kaplan-Meier Method and Cox regression multivariate analysis to identify the prognostic factors. The 10-year survival rate in Stage IA was 91%; in Stage IB 75%; and in Stage II it was 71%. Eleven patients (4%) developed recurrent disease with either local and/or distant metastasis. Nine-percent of the patients developed mild to moderate complications which resolved with conservative treatment. Patients with gross extra-uterine pelvic extension of disease had a poor survival compared with those presenting with microscopic involvement (40% vs. 80% at 5-years). No statistically significant difference in survival was observed between patients who received either preoperative or postoperative external pelvic irradiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Conservative treatment of uveal melanoma: probability of eye retention after proton treatment.

Enucleation was performed after proton treatment in 57 of 1006 (5.7%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986. Only 2% of 99 patients with small tumors and 4% of 566 patients with intermediate size tumors underwent enucleation after treatment; 10% of 341 patients with large tumors lost the treated eye. No eyes were removed after 52 months, with 89% of enucleations performed during the first 36 months after treatment. Eye retention rates at 60 months were 89.1 +/- 3.0% for the entire group, and 97 +/- 3.7%, 92.7 +/- 3.1%, and 78.3 +/- 7.0% in patients with small, intermediate, and large tumors, respectively. Significantly greater enucleation rates were observed in patients with large tumors than in those with intermediate tumors (p = less than .0001), in patients with tumor height greater than 8 mm relative to those with tumors less than or equal to 8 mm, p = (less than .0001), with tumor diameter greater than 16 mm compared to less than or equal to 16 mm, (p = less than .0001), and with tumor involvement of the ciliary body compared to involvement of the choroid only (p = less than .0001). Possible strategies to decrease the likelihood of enucleation in patients at apparently increased risk of losing the eye after conservative therapy, that is, those with large tumors involving the ciliary body, might include a lower total dose, a more protracted treatment course, or a lower radiation dose and adjuvant treatment with chemotherapy and/or immunotherapy, with hyperthermia, or with other radiation sensitizers.

A dose response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy.

The low tolerance of the central nervous system (CNS) limits the radiation dose which can be delivered in the treatment of many patients with brain and head and neck tumors. Although there are many reports concerning the tolerance of the CNS, few have examined individual substructures of the brain and fewer still have had detailed dose information. This study has both. A three dimensional planning system was used to develop the combined proton beam/photon beam treatments for 27 patients with skull-base tumors. The cranial nerves and their related nuclei were delineated on the planning CT scans and the radiation dose to each was determined from three dimensional dose distributions. In the 594 CNS structures (22 structures/patient in 27 patients), there have been 17 structures (in 5 patients) with clinically manifest radiation injury, after a mean follow-up time of 74 months (range 40-110 months). From statistical analyses, dose is found to be a significant predictor of injury. Using logistic regression analysis, we find that, for each cranial nerve, at 60 Cobalt Gray Equivalent (CGE) the complication rate is 1% (0.5-3% with 95% confidence) and that the 5% complication rate occurs at 70 CGE (64-81 CGE with 95% confidence). The slope of the dose response curve (at 50%) is 3.2 (2.2-5.4 with 95% confidence). No significant relationship between dose and latency period for nerve injury was found.

Neurovisual outcome following proton radiation therapy.

From February 1981 to January 1984, 20 patients with a tumor of the upper clivus received proton irradiation at the Harvard Cyclotron Laboratory. For 15 patients with known neurovisual status (including visual acuity, color vision, visual field, and fundus examinations) we obtained a cumulative dose-volume histogram (DVH) of the optic nerves (ON) and the optic chiasm. The prescribed tumor doses ranged from 66.6 to 74.4 Cobalt Gray Equivalent (CGE) with a daily fraction size of 1.8 to 2.1 CGE. CGE is used because modulated protons have an RBE of 1.1 compared to 60Co. The follow-up ranged from 30 to 68 months (median 52). Two patients developed, 10 and 36 months post irradiation, a progressive visual deterioration affecting both eyes. This was attributed to an ON and a chiasm injury in one patient and to bilateral ON injury in the other patient. In the first patient, the dose-volume analysis indicated that approximately half of the ON and of the chiasm had received 65 CGE and 55 CGE, respectively. In the second patient, it indicated that a quarter of the left ON (LON) had received 55 CGE whereas the dose to the right ON (RON) was significantly less. This patient had diabetes mellitus which may be a predisposing factor. From this study, a complication rate of 20% (1/5) is observed when a substantial portion of the ON is taken to 65 CGE, while it doesn't exceed 12.5% (2/16) and 7.5% (1/13) at 55 CGE for the ON and for the chiasm, respectively. This suggests a tolerance dose implying a 10% rate of major complications close to 55 CGE. When a tumor requires a high radiation-dose, the exclusion of these structures at 55 to 60 Gy is recommended.

Conservative treatment of uveal melanoma: local recurrence after proton beam therapy.

Twenty-three of 1006 (2.3%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986 received additional treatment for documented (15 patients) or suspected (eight patients) tumor growth in the irradiated eye. Growth within the initially irradiated volume was documented at Massachusetts Eye and Ear Infirmary in 12 patients. Documented growth occurred in nine of 665 (1.4%) patients with small and intermediate size tumors, at times after treatment ranging from 6 to 48 months (median 16 months), and in three of 341 (.9%) patients with large tumors at 7, 11, and 12 months after treatment. Melanoma growing totally outside the treated volume was also documented in three additional patients at 7, 9, and 45 months; two of these were thought to be "ring melanomas". Eight patients had the treated eye removed elsewhere for suspected tumor growth. The additional treatment in these 23 patients was conservative in nine patients (repeat proton irradiation in five and laser photocoagulation in four). Thirteen underwent immediate enucleation and one had orbital exenteration. Ultimately, 17 of the 23 eyes (74%) were removed. Estimated probability of local control of the melanoma within the irradiated eye at 60 months was 96.3 +/- 1.5%. Dose distributions to the 12 patients with documented local failure within the irradiated volume were analyzed. Ten tumors recurred marginally in an area receiving less than the prescribed dose of 70 CGE (CGE = Cobalt Gray Equivalents = proton Gy X RBE 1.1), whereas only two recurred in the volume receiving full dose. Based on these data, it appears that a dose of 70 CGE in five fractions is associated with very high rates of local control in human uveal melanoma. It is reasonable to consider initiating studies using a lower total dose or a more protracted course, to determine if some of the observed complications are dose-related.

Endocrine function following high dose proton therapy for tumors of the upper clivus.

The endocrine status of patients receiving proton radiation for tumors of the upper clivus was reviewed to evaluate the effect of high dose treatment on the pituitary gland. The fourteen patients had chordomas or low grade chondrosarcomas and were all treated by the same techniques. The median tumor dose was 69.7 Cobalt Gray Equivalent (CGE) with a range from 66.6 to 74.4 CGE. (CGE is used because modulated protons have an RBE of 1.1 compared to 60Co). The daily fraction size was 1.8-2.1 CGE. The median follow-up time is 48 months, ranging from 30 to 68 months. All treatments were planned using a computerized multi-dimensional system with the position of the pituitary outlined on the planning CT scan. Review of the dose distribution indicated that the dose to the pituitary ranged from 60.5 to 72.3 CGE, with a median of 67.6 CGE. One female patient had decreased thyroid and gonadotropin function at the time of diagnosis and has been on hormone replacement since that time. The other three females were all pre-menopausal at the time of radiotherapy. At this time four patients (3 males and 1 female) have developed endocrine abnormalities 14 to 45 months after irradiation. All four had evidence of hypothyroidism and two have also developed corticotropin deficiency. The three males had decreased testosterone levels; the female patient developed amenorrhea and hyperprolactinemia. All four are asymptomatic with ongoing hormone replacement.

Sacral colpopexy for vaginal vault prolapse.

Sacral colpopexy has become the treatment of choice for post-hysterectomy vaginal vault prolapse at the New York Hospital--Cornell Medical Center. A review of the institutional experience with this technique since 1972 indicates that 20 of 21 patients obtained good vaginal support and preservation of functional capabilities with minimal complications.

Unilateral tubo-ovarian abscess and intrauterine contraceptive devices.

The association of unilateral tubo-ovarian abscess and the presence or use of an intrauterine contraceptive device (IUD) appears to be a definite clinical entity. Four cases of unilateral tubo-ovarian abscess in patients using the IUD are presented. Three patients had a Dalkon Shield IUD and one had a Lippes Loop. Two patients had unilateral salpingo-oophorectomy while the other 2 had total abdominal hysterectomy and bilateral salpingo-oophorectomy. The differential diagnosis, possible etiology, route and mode of infection, and management are discussed.

PIP: 4 cases of unilateral tuboovarian abscess in patients using an IUD are presented; 3 of the 4 patients had a Dalkon shield and 1 had a Lippes loop. These cases present the problem of diagnosis and treatment as the presence of pelvic mass in an IUD user may be due to an ectopic pregnancy, ovarian cyst, or a pelvic or tuboovarian abscess. Unruptured tuboovarian abscess requires conservative treatment with antibiotics initially and surgery if there is an unsatisfactory response. These patients display a high fever and purulent cervical discharge. An ascending infection is associated with IUD use and recent investigations implicate the tail, especially the compound variety. Trauma to the endometrium by the IUD may initiate the infection and the finlike projections of the IUD may cause further trauma. The connection of unilateral tubooovarian inflammatory mass with the IUD user should alert more clinicians to this possibility.

Patent ductus arteriosus ligation: are we doing better?

Limitation on health care resource use is stimulating critical evaluation of previous preoperative standards. We retrospectively reviewed the clinical and hospital financial records of all children admitted for patent ductus arteriosus ligation from July 1984 to April 1994 for age, perioperative length of stay, readmissions for postoperative surgical problem, and hospital charges adjusted to 1994 dollars. Patients with an isolated patent ductus arteriosus, greater than 3 months of age, without preoperative or postoperative complications were included in this study and stratified into two groups based on date of operation. Group I had operation before January 1, 1991, and group II had operation on or after January 1, 1991. Comparison of these two groups revealed a significant difference in perioperative length of stay (group I, 3.9 +/- 1.2 days [mean +/- standard deviation]; group II, 2.7 +/- 0.9 days; p < 0.0001) and in hospital charges (group I, $8,700 +/- $2,100; group II, $6,600 +/- $1,000; p < 0.0001). These data support the premise that children older than 3 months undergoing elective ligation of a patent ductus arteriosus have been treated with improved efficiency and less charge without an increase in postdischarge morbidity. Health care policy decisions have forced us to evaluate the standards of perioperative care more critically.

Modulation of the acoustic startle reflex by infusion of corticotropin-releasing hormone into the nucleus reticularis pontis caudalis.

The amplitude of the acoustic startle reflex can be modulated by exposure to aversive stimuli or other conditions which evoke a state of fear. The neurotransmitters involved in this modulation are currently being investigated. Unilateral local infusion of corticotropin-releasing hormone (CRH; 0, 10, 20, 40 and 80 ng) into the nucleus reticularis pontis caudalis (PnC), an obligatory synapse in the acoustic startle reflex, significantly elevated startle amplitude in a dose-dependent manner. The facilitation of startle began immediately following infusion, reached asymptote approximately 20-25 min later, and persisted throughout the remaining 60 min test session. This CRH-enhanced startle effect was blocked by infusion of the CRH antagonist, alpha-helical CRH9-41, immediately prior to CRH infusion. These results support an involvement of CRH at the level of the PnC in modulating the acoustic startle reflex.

Fractionated proton radiation therapy of chordoma and low-grade chondrosarcoma of the base of the skull.

Sixty-eight patients with chordoma or low-grade chondrosarcoma at the base of the skull received fractionated high-dose postoperative radiation delivered with a 160-MeV proton beam. Protons have favorable physical characteristics which allow the delivery of high doses of radiation to these critically located tumors. The methods employed for these treatments are described. These patients have been followed for at least 17 months and for a median of 34 months. The median tumor dose was 69 CGE (cobalt Gy equivalent): CGE is the dose in proton Gy multiplied by 1.1, which is the relative biological effectiveness for protons compared to cobalt-60. The daily dose was 1.8 to 2.1 CGE. For this group the 5-year actuarial local control rate is 82% and disease-free survival rate is 76%. The incidence of treatment-related morbidity has been acceptable.