Lynn H. Gerber

Phenotype and course of Hutchinson-Gilford progeria syndrome

BACKGROUND Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription. METHODS We enrolled 15 children between 1 and 17 years of age, representing nearly half of the worlds known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006. RESULTS Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening. CONCLUSIONS Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)

Biochemicals Associated With Pain and Inflammation are Elevated in Sites Near to and Remote From Active Myofascial Trigger Points

OBJECTIVES To investigate the biochemical milieu of the upper trapezius muscle in subjects with active, latent, or absent myofascial trigger points (MTPs) and to contrast this with that of the noninvolved gastrocnemius muscle. DESIGN We used a microanalytic technique, including needle insertions at standardized locations in subjects identified as active (having neck pain and MTP), latent (no neck pain but with MTP), or normal (no neck pain, no MTP). We followed a predetermined sampling schedule; first in the trapezius muscle and then in normal gastrocnemius muscle, to measure pH, bradykinin, substance P, calcitonin gene-related peptide, tumor necrosis factor alpha, interleukin 1beta (IL-1beta), IL-6, IL-8, serotonin, and norepinephrine, using immunocapillary electrophoresis and capillary electrochromatography. Pressure algometry was obtained. We compared analyte concentrations among groups with 2-way repeated-measures analysis of variance. SETTING A biomedical research facility. PARTICIPANTS Nine healthy volunteer subjects. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Preselected analyte concentrations. RESULTS Within the trapezius muscle, concentrations for all analytes were higher in active subjects than in latent or normal subjects (P<.002); pH was lower (P<.03). At needle insertion, analyte concentrations in the trapezius for the active group were always higher (pH not different) than concentrations in the gastrocnemius muscle. At all times within the gastrocnemius, the active group had higher concentrations of all analytes than did subjects in the latent and normal groups (P<.05); pH was lower (P<.01). CONCLUSIONS We have shown the feasibility of continuous, in vivo recovery of small molecules from soft tissue without harmful effects. Subjects with active MTPs in the trapezius muscle have a biochemical milieu of selected inflammatory mediators, neuropeptides, cytokines, and catecholamines different from subjects with latent or absent MTPs in their trapezius. These concentrations also differ quantitatively from a remote, uninvolved site in the gastrocnemius muscle. The milieu of the gastrocnemius in subjects with active MTPs in the trapezius differs from subjects without active MTPs.

Constraint-Induced Therapy in Stroke: Magnetic-Stimulation Motor Maps and Cerebral Activation

Constraint-induced movement therapy (CI), a standardized intensive rehabilitation intervention, was given to patients a year or more following stroke. The goal was to determine if CI was more effective than a less-intensive control intervention in changing motor function and/or brain physiology and to gain insight into the mechanisms underlying this recovery process. Subjects were recruited and randomized more than 1 year after a single subcortical infarction. Clinical assessments performed before and after the intervention and at 6 months postintervention included the Wolf Motor Function Test (WMFT), the Motor Activity Log (MAL), and the Assessment of Motor and Process Skills (AMPS). Transcranial magnetic stimulation was used to map the motor cortex. Positron emission tomography was used to measure changes in motor task-related activation due to the intervention. MAL increased by 1.08 after CI therapy and decreased by 0.01 after control therapy. The difference between groups was significant (P < 0.001). Changes in WMFT and AMPS were not significantly different between groups. Cerebral activation during a motor task decreased significantly, and motor map size increased in the affected hemisphere motor cortex in CI patients but not in control patients. Both changes may reflect improved ability of upper motor neurons to produce movement.

Preoperative assessment enables the early diagnosis and successful treatment of lymphedema

The incidence of breast cancer (BC)‐related lymphedema (LE) ranges from 7% to 47%. Successful management of LE relies on early diagnosis using sensitive measurement techniques. In the current study, the authors demonstrated the effectiveness of a surveillance program that included preoperative limb volume measurement and interval postoperative follow‐up to detect and treat subclinical LE.

High Prevalence of Osteonecrosis of the Femoral Head in HIV-Infected Adults

Context Osteonecrosis (avascular necrosis) of the hip is an uncommon but painful and disabling condition that sometimes requires total hip replacement. Contribution This large survey showed that an unusually high percentage of HIV-infected adults (4.4% [95% CI, 2.5% to 7.2%]) had osteonecrosis of the hip, as detected by magnetic resonance imaging. Implications Although screening asymptomatic HIV-infected patients is not warranted, osteonecrosis should be considered in HIV-infected patients with persistent groin or hip pain. The Editors The natural history of HIV infection has changed substantially with the wide use of highly active antiretroviral regimens that include potent protease inhibitors or non-nucleoside reverse transcriptase inhibitors (1). The incidence of HIV-related deaths and HIV-associated opportunistic infections has decreased dramatically. As survival and quality of life have improved, the focus of health care providers has shifted to management of the increasingly complex drug regimens and their associated drug interactions and toxicities. Previously unrecognized or underrecognized complications related to HIV infection or therapies for HIV infection, such as lactic acidosis, hyperlipidemia, and fat redistribution, are increasingly being recognized (2). Osteonecrosis of the hip (also known as avascular necrosis) is a disabling condition that frequently requires total hip replacement (3-5). Osteonecrosis in HIV-infected patients was first reported in 1990 (6). Subsequent anecdotal reports have suggested that osteonecrosis is being diagnosed with increasing frequency in the setting of HIV infection (7-31). Between May 1999 and November 2000, six HIV-infected patients followed at the Warren Grant Magnuson Clinical Center of the U.S. National Institutes of Health (NIH) presented with groin or hip pain and received a diagnosis of osteonecrosis. The first two of these patients received their diagnosis within a 4-day period and were the first HIV-infected patients ever to receive such a diagnosis at the NIH Clinical Center. We also learned that an increasing number of cases of osteonecrosis were being reported to the U.S. Food and Drug Administrations Adverse Event Reporting System. We were concerned that osteonecrosis might be becoming a major HIV-related complication. We hypothesized that, if this were true, additional patients may have developed clinically silent osteonecrosis. Because magnetic resonance imaging (MRI) has been used to study asymptomatic osteonecrosis of the hip in other high-risk populations (32-37), we undertook a prospective MRI-based study to determine the prevalence of and evaluate possible risk factors for asymptomatic osteonecrosis of the hip in a sample of HIV-infected patients. Methods Participant Recruitment and Questionnaire Between 1 June and 15 December 1999, adults who were enrolled in studies of the treatment or natural history of HIV infection at the NIH Clinical Center or who were receiving health care services at the National Naval Medical Center in Bethesda, Maryland, were invited to participate in an MRI-based screening study of osteonecrosis of the hip. All patients seen in the outpatient clinics of the National Institute of Allergy and Infectious DiseasesNIH Clinical Center HIV program during the study period were informed of the protocol and encouraged to participate. Because this study focused on asymptomatic patients, we excluded persons with current groin or hip pain. Because the incidence of osteonecrosis was unknown, we considered several possible sample sizes (100 to 300 patients) and estimations of the 95% CI for low prevalence rates of asymptomatic osteonecrosis (0.1% to 3.5%). We determined that a sample size of at least 300 HIV-infected participants would be reasonable and attainable. Before undergoing MRI, participants completed a standard questionnaire on joint symptoms; medical history; medication use; and personal habits, including ethanol use, cigarette smoking, and routine exercise regimens. Questions related to medication use made a clear distinction between corticosteroids and other types of steroids, such as androgenic and anabolic steroids. Patients were asked why corticosteroids were prescribed and the route, frequency, and duration of use. The Institutional Review Board of the National Institute of Allergy and Infectious Diseases approved the protocol. All participants gave written informed consent. Data Collection We retrieved laboratory and clinical data from patient databases. Laboratory values obtained within 4 months of the MRI date were used in the analyses; for certain variables, we also analyzed the highest or lowest values recorded in a laboratory database that contained data back to 1984. Physiatrist Evaluation After approximately 150 patients were scanned and asymptomatic osteonecrosis was detected in 4 patients, we prospectively determined whether subtle physical findings might identify patients with MRI evidence of osteonecrosis of the hip. Patients enrolled after 12 July 1999 were asked (but not required) to be examined by a physiatrist who was unaware of the MRI results. The examination included evaluation of range of motion in the hip, which involved testing in all planes to end range with and without resistance and joint-loading maneuvers; pain was assessed in each test (38). MRI Scanning HIV-Infected Participants Magnetic resonance imaging was performed by using an LX Horizon 1.5-T MRI system (General Electric Medical Systems, Milwaukee, Wisconsin). We modeled the protocol for screening MRI on a previously described method for bilateral screening of the hips for osteonecrosis (37). Coronal T1-weighted spin-echo sequences were done with a repetition time of 400 ms and an echo time of 8 ms (using a 256 192 matrix). These were followed by coronal fatsuppressed T2-weighted fast spin-echo inversion recovery sequences with a repetition time of 3266 ms, an echo time of 38 ms, and an inversion time of 150 ms (256 224 matrix). Other variables used for both screening sequences included three excitations, a 40.0 40.0cm field of view, and 5-mm contiguous sections. All MRI scans were initially interpreted by one of the investigators. Positive scans were later intermixed with 35 randomly selected negative scans of HIV-infected participants and were reviewed by a second radiologist, who was unaware of the previous interpretation. Patients with osteonecrosis on the screening MRI underwent dedicated high-resolution MRI of the affected hip or the more abnormal hip. HIV-Negative Participants We assumed that asymptomatic osteonecrosis of the hip detectable only by MRI must occur infrequently in healthy adult humans with no known risk factors. To document this, we recruited persons without hip or groin pain who had no known risk factors for osteonecrosis. Exclusion criteria for this comparison group were a history of alcohol abuse, hip or leg fracture, pancreatitis, diabetes mellitus, hypertriglyceridemia (requiring therapy), systemic lupus erythematosus, blood-clotting disorders, or systemic corticosteroid use during the previous year or for greater than 1 month ever (total lifetime use). We recruited these participants from an NIH healthy volunteer database and by posting flyers at the NIH Clinical Center. The participants in the comparison group were approximately matched for age and sex to participants in the screening study HIV-infected patients; the comparison group underwent the MRI screening and consented to participate using the same protocol and procedures that were used in the HIV group. Hematologic Evaluation Participants with MRI evidence of osteonecrosis were evaluated for a possible hypercoagulable state by using the following assays: two assays for the presence of a lupus anticoagulant (DRVVT, American Diagnostica, Inc., Greenwich, Connecticut, and Staclot, Diagnostica Stago, Asnieres-Sur-Seine, France); assays for immunoglobulin (Ig)G and IgM anticardiolipin antibodies (Quantilite, Innova, San Diego, California); functional assays for protein C, protein S, and antithrombin III levels (Diagnostica Stago; an assay for thrombinantithrombin complex levels [Dade Behring Marburg, Marburg, Germany]; an assay for functional plasma activator inhibitor-1 levels (Biopool, Umea, Sweden); and routine laboratory assays for serum homocysteine and serum lipoprotein(a) levels. These patients were also evaluated for genetic predisposition to hypercoagulability by using restriction enzyme-based genetic tests for factor V Leiden, a prothrombin gene abnormality (G20210A), and for the heat-labile folate reductase (5,10 methylene tetrahydrofolate reductase) gene abnormality, which may lead to hyperhomocystinemia (39-41). For a comparison group, we measured anticardiolipin antibodies, lupus anticoagulant, and protein S levels in a sample of 50 controls with HIV infection who had no evidence of osteonecrosis on MRI. These controls were randomly selected from patients who had been previously scanned as part of the study and who were seen in our clinics for routine visits over a 3-week period (19 November to 9 December 1999). Statistical Analysis We used the method of Clopper and Pearson (42) to calculate exact CIs for proportions. Associations of osteonecrosis with categorical variables were evaluated by using a two-sided Fisher exact test or, for variables with more than two categories, the FisherFreemanHalton test (43). Associations with continuous variables were evaluated by using a two-sided Wilcoxon rank-sum test with continuity correction. Confidence intervals for relative risks for osteonecrosis were estimated by using the likelihood score method (44). For CIs of odds ratios, we estimated variance according to the method of Robins and colleagues (45). For these calculations, we used the NCSS 2000 software package (Number Cruncher Statistical Systems, Kaysville, Utah) and the StatXact 4 software package (Cytel Software Corp., Cambridge, Mass

Cancer-related fatigue: Implications for breast cancer survivors

Cancer‐related fatigue (CRF) has been documented as 1 of the most distressing symptoms reported by breast cancer survivors. CRF affects functioning and impacts quality of life. Possible causal factors include physical conditions, affective and cognitive states, proinflammatory cytokines, and metabolic factors. Several common problems are associated with CRF in women with breast cancer, including treatment side effects, obesity, arm/upper quadrant symptoms, sleep disturbances, psychological effects, and comorbid conditions. In this article, the authors review the state of the knowledge regarding these issues and nonpharmacologic and pharmacologic interventions for CRF. Physical activity and psychosocial interventions are recommended for practice. Numerous limitations of past studies need to be considered in the design of future studies. CRF is prevalent in preoperative, postoperative, and ongoing surveillance phases. Throughout the continuum of care for women with breast cancer, clinicians must screen, further assess as indicated, and treat CRF, because it is associated with emotional distress and limits function and willingness to exercise. Cancer 2012;118(8 suppl):.

Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement.

Bisphosphonates have been widely administered to children with OI based on observational trials. A randomized controlled trial of q3m intravenous pamidronate in children with types III and IV OI yielded positive vertebral changes in DXA and geometry after 1 year of treatment, but no further significant improvement during extended treatment. The treated group did not experience significantly decreased pain or long bone fractures or have increased motor function or muscle strength.

Surface movement errors in shank kinematics and knee kinetics during gait

Abstract The movement of surface mounted targets (SMT) on a shell at the mid-shank and of bone mounted targets attached to the distal shank using a Percutaneous Skeletal Tracker (PST) were simultaneously measured during free-speed walking of three adult subjects having different body types. Surface movement errors in shank kinematic estimates were determined by expressing the segmental motion derived from the SMT relative to the PST-based segment coordinate system (SCS) located at the segment center of gravity. The greatest errors were along and around the shank longitudinal axis, with peak magnitudes of 10 mm of translation and 8° of rotation in one subject. Estimates of knee joint center locations differed by less than 11 mm in each SCS direction. Differences in estimates of net knee joint forces and moments were most prominent during stance phase, with magnitudes up to 39 N in the shank mediolateral direction and 9 N.m about the mediolateral axis. The differences in kinetics were primarily related to the effect of segment position and orientation on the expression of joint forces and on the magnitude and expression of joint moments.

Extraspinal Tendon and Ligament Calcification Associated with Long-Term Therapy with Etretinate

Isotretinoin, a synthetic retinoid that has been prescribed for over 500,000 patients with cystic acne, has been associated with both spinal hyperostosis and a disorder similar to diffuse idiopathic skeletal hyperostosis. We describe a syndrome of tendon and ligament calcification, primarily in extraspinal locations, that we have observed after long-term therapy for psoriasis and disorders of keratinization with etretinate, another synthetic retinoid. Of 38 patients who had received etretinate (average dose, 0.8 mg per kilogram of body weight per day; average duration, 60 months), 32 (84 percent) had radiographic evidence of extraspinal tendon and ligament calcification. The most common sites of involvement were the ankles (29 patients [76 percent]), pelvis (20 patients [53 percent]), and knees (16 patients [42 percent]); spine involvement was uncommon in this group of etretinate-treated patients. Involvement tended to be bilateral and multifocal. Fifteen (47 percent) of the 32 affected patients had no bone or joint symptoms at the sites of radiographic abnormality. Thus, tendon and ligament calcification can occur without vertebral involvement as well as in association with it (for example, as part of the spectrum of diffuse idiopathic skeletal hyperostosis). We have identified extraspinal tendon and ligament calcification as a toxic effect that is commonly associated with long-term etretinate therapy.

Psychosocial and physical outcomes of primary breast cancer therapy: Mastectomy vs excisional biopsy and irradiation

SummaryThirty-eight patients treated for primary breast cancer as part of a prospective randomized clinical trial were questioned retrospectively as to their psychosocial adaptation to treatment. Twenty patients had received mastectomy and eighteen had received excisional biopsy plus radiation of the intact breast. Aside from body image concerns, there were no marked psychosocial differences detected between these groups. Previous studies emphasizing serious psychological problems in mastectomy patients and fewer such problems in nonmastectomy patients may be influenced by biases that are not present in a randomized study design.