Reduced neuronal efficacy in progressive mild cognitive impairment: a prospective fMRI study on visuospatial processing

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimer's disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma

AIM: To compare the plasma levels of endothelin-1 (ET-1) between patients with primary open angle glaucoma with visual field progression despite normal or normalised intraocular pressure and patients with stabile visual fields in a retrospective study. METHODS: The progressive group consisted of 16 primary open angle glaucoma patients and the group with stable visual field consisted of 15 patients. After a 30 minute rest in a supine position, venous blood was obtained for ET-1 dosing. Difference in the plasma level of ET-1 between two groups was compared by means of analysis of covariance (ANCOVA), including age, sex, and mean arterial blood pressure as covariates. RESULTS: ET-1 plasma levels were found to be significantly increased in patients with deteriorating (3.47 (SD 0.75) pg/ml) glaucoma when compared to those with stable (2.59 (SD 0.54) pg/ml) visual fields (p = 0.0007). CONCLUSIONS: Glaucoma patients with visual field progression in spite of normal or normalised intraocular pressure have been found to have increased plasma endothelin-1 levels. It remains to be determined if this is a secondary phenomenon or whether it may have a role in the progression of glaucomatous damage.

Effectiveness of selective dorsal rhizotomy in 2 patients with progressive spasticity due to neurodegenerative disease

Selective dorsal rhizotomy at the lumbar level is a neurosurgical procedure, which reduces spasticity in the legs. Its effect has mainly been studied in children with spastic cerebral palsy. Little is known about the outcome of selective dorsal rhizotomy in patients with neurodegenerative disorders. We report the clinical course after selective dorsal rhizotomy in 2 patients with progressive spasticity. Leg spasticity was effectively and persistently reduced in both patients, facilitating care and improving sitting comfort. However, spasticity of the arms and other motor disturbances, such as spontaneous extension spasms and the ataxia, increased gradually in time. Selective dorsal rhizotomy leads to a disappearance of leg spasticity in patients with a neurodegenerative disease. Other motor signs are not influenced and may increase due to the progressive nature of the underlying disease.

Motesanib diphosphate in progressive differentiated thyroid cancer

BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. METHODS: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS: Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)

Past is Prologue: Montana’s Historic Women’s Movement Re-emerges in the Progressive 1970s -- Dorothy Bradley, Marilyn Wessel & Jane Jelinski “In the Crucible of Change”

One-hundred years ago, in 1914, male voters in Montana (MT) extended suffrage (voting rights) to women six years before the 19th Amendment to the US Constitution was ratified and provided that right to women in all states. The long struggle for women’s suffrage was energized in the progressive era and Jeanette Rankin of Missoula emerged as a leader of the campaign; in 1912 both major MT political party platforms supported women suffrage. In the 1914 election, 41,000 male voters supported woman suffrage while nearly 38,000 opposed it. MT was not only ahead of the curve on women suffrage, but just two years later in 1916 elected Jeanette Rankin as the first woman ever elected to the United States Congress. Rankin became a national leader for women's equality. In her commitment to equality, she opposed US entry into World War I, partially because she said she could not support men being made to go to war if women were not allowed to serve alongside them. During MT’s initial progressive era, women in MT not only pursued equality for themselves (the MT Legislature passed an equal pay act in 1919), but pursued other social improvements, such as temperance/prohibition. Well-known national women leaders such as Carrie Nation and others found a welcome in MT during the period. Women's role in the trade union movement was evidenced in MT by the creation of the Women's Protective Union in Butte, the first union in America dedicated solely to women workers. But Rankin’s defeat following her vote against World War I was used as a way for opponents to advocate a conservative, traditionalist perspective on women's rights in MT. Just as we then entered a period in MT where the “copper collar” was tightened around MT economically and politically by the Anaconda Company and its allies, we also found a different kind of conservative, traditionalist collar tightened around the necks of MT women. The recognition of women's role during World War II, represented by “Rosie the Riveter,” made it more difficult for that conservative, traditionalist approach to be forever maintained. In addition, women's role in MT agriculture – family farms and ranches -- spoke strongly to the concept of equality, as farm wives were clearly active partners in the agricultural enterprises. But rural MT was, by and large, the bastion of conservative values relative to the position of women in society. As the period of “In the Crucible of Change” began, the 1965 MT Legislature included only three women. In 1967 and 1969 only one woman legislator served. In 1971 the number went up to two, including one of our guests, Dorothy Bradley. It was only after the Constitutional Convention, which featured 19 women delegates, that the barrier was broken. The 1973 Legislature saw 9 women elected. The 1975 and 1977 sessions had 14 women legislators; 15 were elected for the 1979 session. At that time progressive women and men in the Legislature helped implement the equality provisions of the new MT Constitution, ratified the federal Equal Rights Amendment in 1974, and held back national and local conservatives forces which sought in later Legislatures to repeal that ratification. As with the national movement at the time, MT women sought and often succeeded in adopting legal mechanisms that protected women’s equality, while full equality in the external world remained (and remains) a treasured objective. The story of the re-emergence of Montana’s women’s movement in the 1970s is discussed in this chapter by three very successful and prominent women who were directly involved in the effort: Dorothy Bradley, Marilyn Wessel, and Jane Jelinski. Their recollections of the political, sociological and cultural path Montana women pursued in the 1970s and the challenges and opposition they faced provide an insider’s perspective of the battle for equality for women under the Big Sky “In the Crucible of Change.” Dorothy Bradley grew up in Bozeman, Montana; received her Bachelor of Arts Phi Beta Kappa from Colorado College, Colorado Springs, in 1969 with a Distinction in Anthropology; and her Juris Doctor from American University in Washington, D.C., in 1983. In 1970, at the age of 22, following the first Earth Day and running on an environmental platform, Ms. Bradley won a seat in the 1971 Montana House of Representatives where she served as the youngest member and only woman. Bradley established a record of achievement on environmental & progressive legislation for four terms, before giving up the seat to run a strong second to Pat Williams for the Democratic nomination for an open seat in Montana’s Western Congressional District. After becoming an attorney and an expert on water law, she returned to the Legislature for 4 more terms in the mid-to-late 1980s. Serving a total of eight terms, Dorothy was known for her leadership on natural resources, tax reform, economic development, and other difficult issues during which time she gained recognition for her consensus-building approach. Campaigning by riding her horse across the state, Dorothy was the Democratic nominee for Governor in 1992, losing the race by less than a percentage point. In 1993 she briefly taught at a small rural school next to the Northern Cheyenne Indian Reservation. She was then hired as the Director of the Montana University System Water Center, an education and research arm of Montana State University. From 2000 - 2008 she served as the first Gallatin County Court Administrator with the task of collaboratively redesigning the criminal justice system. She currently serves on One Montana’s Board, is a National Advisor for the American Prairie Foundation, and is on NorthWestern Energy’s Board of Directors. Dorothy was recognized with an Honorary Doctorate from her alma mater, Colorado College, was named Business Woman of the Year by the Bozeman Chamber of Commerce and MSU Alumni Association, and was Montana Business and Professional Women’s Montana Woman of Achievement. Marilyn Wessel was born in Iowa, lived and worked in Los Angeles, California, and Washington, D.C. before moving to Bozeman in 1972. She has an undergraduate degree in journalism from Iowa State University, graduate degree in public administration from Montana State University, certification from the Harvard University Institute for Education Management, and served a senior internship with the U.S. Congress, Montana delegation. In Montana Marilyn has served in a number of professional positions, including part-time editor for the Montana Cooperative Extension Service, News Director for KBMN Radio, Special Assistant to the President and Director of Communications at Montana State University, Director of University Relations at Montana State University and Dean and Director of the Museum of the Rockies at MSU. Marilyn retired from MSU as Dean Emeritus in 2003. Her past Board Service includes Montana State Merit System Council, Montana Ambassadors, Vigilante Theater Company, Montana State Commission on Practice, Museum of the Rockies, Helena Branch of the Ninth District Federal Reserve Bank, Burton K. Wheeler Center for Public Policy, Bozeman Chamber of Commerce, and Friends of KUSM Public Television. Marilyn’s past publications and productions include several articles on communications and public administration issues as well as research, script preparation and presentation of several radio documentaries and several public television programs. She is co-author of one book, 4-H An American Idea: A History of 4-H. Marilyn’s other past volunteer activities and organizations include Business and Professional Women, Women's Political Caucus, League of Women Voters, and numerous political campaigns. She is currently engaged professionally in museum-related consulting and part-time teaching at Montana State University as well as serving on the Editorial Board of the Bozeman Daily Chronicle and a member of Pilgrim Congregational Church and Family Promise. Marilyn and her husband Tom, a retired MSU professor, live in Bozeman. She enjoys time with her children and grandchildren, hiking, golf, Italian studies, cooking, gardening and travel. Jane Jelinski is a Wisconsin native, with a BA from Fontbonne College in St. Louis, MO who taught fifth and seventh grades prior to moving to Bozeman in 1973. A stay-at-home mom with a five year old daughter and an infant son, she was promptly recruited by the Gallatin Women’s Political Caucus to conduct a study of Sex-Role Stereotyping in K Through 6 Reading Text Books in the Bozeman School District. Sociologist Dr. Louise Hale designed the study and did the statistical analysis and Jane read all the texts, entered the data and wrote the report. It was widely disseminated across Montana and received attention of the press. Her next venture into community activism was to lead the successful effort to downzone her neighborhood which was under threat of encroaching business development. Today the neighborhood enjoys the protections of a Historic Preservation District. During this time she earned her MPA from Montana State University. Subsequently Jane founded the Gallatin Advocacy Program for Developmentally Disabled Adults in 1978 and served as its Executive Director until her appointment to the Gallatin County Commission in 1984, a controversial appointment which she chronicled in the Fall issue of the Gallatin History Museum Quarterly. Copies of the issue can be ordered through: http://gallatinhistorymuseum.org/the-museum-bookstore/shop/. Jane was re-elected three times as County Commissioner, serving fourteen years. She was active in the Montana Association of Counties (MACO) and was elected its President in 1994. She was also active in the National Association of Counties, serving on numerous policy committees. In 1998 Jane resigned from the County Commission 6 months before the end of her final term to accept the position of Assistant Director of MACO, from where she lobbied for counties, provided training and research for county officials, and published a monthly newsletter. In 2001 she became Director of the MSU Local Government Center where she continued to provide training and research for county and municipal officials across MT. There she initiated the Montana Mayors Academy in partnership with MMIA. She taught State and Local Government, Montana Politics and Public Administration in the MSU Political Science Department before retiring in 2008. Jane has been married to Jack for 46 years, has two grown children and three grandchildren.

Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study

BACKGROUND: We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996. METHODS: From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007). RESULTS: The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P = .007) but similar CD4+ T cell counts (60 vs. 71 cells/microL; P = .25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P < .001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/microL, 0.52; 95% CI, 0.32-0.85; P = .010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P = .006). CONCLUSIONS: cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependent on cART use and baseline CD4+ T cell count.

JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4(+) T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4(+) T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4(+) T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.

Progressive regression of left ventricular hypertrophy two years after bariatric surgery.

BACKGROUND: Obesity is a systemic disorder associated with an increase in left ventricular mass and premature death and disability from cardiovascular disease. Although bariatric surgery reverses many of the hormonal and hemodynamic derangements, the long-term collective effects on body composition and left ventricular mass have not been considered before. We hypothesized that the decrease in fat mass and lean mass after weight loss surgery is associated with a decrease in left ventricular mass. METHODS: Fifteen severely obese women (mean body mass index [BMI]: 46.7+/-1.7 kg/m(2)) with medically controlled hypertension underwent bariatric surgery. Left ventricular mass and plasma markers of systemic metabolism, together with body mass index (BMI), waist and hip circumferences, body composition (fat mass and lean mass), and resting energy expenditure were measured at 0, 3, 9, 12, and 24 months. RESULTS: Left ventricular mass continued to decrease linearly over the entire period of observation, while rates of weight loss, loss of lean mass, loss of fat mass, and resting energy expenditure all plateaued at 9 [corrected] months (P <.001 for all). Parameters of systemic metabolism normalized by 9 months, and showed no further change at 24 months after surgery. CONCLUSIONS: Even though parameters of obesity, including BMI and body composition, plateau, the benefits of bariatric surgery on systemic metabolism and left ventricular mass are sustained. We propose that the progressive decrease of left ventricular mass after weight loss surgery is regulated by neurohumoral factors, and may contribute to improved long-term survival.

Desmoplastic small round cell tumor: A rare cause of a progressive brachial plexopathy.

Introduction: Desmoplastic small round cell tumor (DSRCT) is an uncommon, embryonic-type neoplasm, typically presenting as an abdominal mass in young men. A single case of DSRCT arising in the peripheral nervous system has been reported. Methods: The clinical course, imaging, electrophysiological, intraoperative, histopathological, molecular findings, and postoperative follow-up are reported. Results: A 43-year-old man presented with slowly progressive right brachial plexopathy. Magnetic resonance imaging revealed an enlarged medial cord with heterogeneous contrast enhancement. Histology showed a "small round cell" neoplasm with a polyphenotypic immunoprofile, including epithelial and mesenchymal markers. A pathognomonic fusion of Ewing sarcoma breakpoint region 1 and Wilms tumor 1 genes (EWSR1/WT1) was present. Treatment involved gross total excision and local radiotherapy. Conclusion: Our findings confirm the occurrence of DSRCT as a primary peripheral nerve tumor. Despite its usually very aggressive clinical course, prolonged recurrence-free survival may be reached. Histomorphology and immunoprofile of DSRCT may lead to misdiagnosis as small cell carcinoma. © 2013 Wiley Periodicals, Inc.

Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression.

An 80-year-old man with no history of an immune-compromising disorder was diagnosed with progressive multifocal leukoencephalopathy (PML). He presented with dysphagia and left-sided weakness; magnetic resonance imaging demonstrated marked signal abnormality in the subcortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was negative for John Cunningham (JC) virus. On brain biopsy, foamy macrophages infiltrating the white matter were identified, staining positive for anti-simian virus 40 antibodies. Postoperatively, PCR for JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Extensive investigation for an occult immunocompromising disorder was negative. The patient's neurologic deficits rapidly increased throughout his hospital stay, and he died 3.5 months after his diagnosis.

Effect of progressive mandibular advancement on pharyngeal airway size in anesthetized adults.

BACKGROUND: General anesthesia in adult humans is associated with narrowing or complete closure of the pharyngeal airway. The purpose of this study was to determine the effect of progressive mandibular advancement on pharyngeal airway size in normal adults during intravenous infusion of propofol for anesthesia. METHODS: Magnetic resonance imaging was performed in nine normal adults during wakefulness and during propofol anesthesia. A commercially available intraoral appliance was used to manually advance the mandible. Images were obtained during wakefulness without the appliance and during anesthesia with the participants wearing the appliance under three conditions: without mandibular advancement, advancement to 50% maximum voluntary advancement, and maximum advancement. Using computer software, airway area and maximum anteroposterior and lateral airway diameters were measured on the axial images at the level of the soft palate, uvula, tip of the epiglottis, and base of the epiglottis. RESULTS: Airway area across all four airway levels decreased during anesthesia without mandibular advancement compared with airway area during wakefulness (P < 0.007). Across all levels, airway area at 50% advancement during anesthesia was less than that at centric occlusion during wakefulness (P = 0.06), but airway area with maximum advancement during anesthesia was similar to that during wakefulness (P = 0.64). In general, anteroposterior and lateral airway diameters during anesthesia without mandibular advancement were decreased compared with wakefulness and were restored to their wakefulness values with 50% and/or maximal advancement. CONCLUSIONS: Maximum mandibular advancement during propofol anesthesia is required to restore the pharyngeal airway to its size during wakefulness in normal adults.