Geometric and analytic views in existence theorems for optimal control. III. Weak solutions

Existence theorems are proved for weak optimal solutions of problems of optimization with distributed and boundary control. Many examples are given. Application is made of recent remarks on closure properties of linear and nonlinear operators. Recent geometric, topological, and analytical views are brought to bear on the underlying seminormality conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45209/1/10957_2004_Article_BF00934060.pd

Pituitary Macroadenoma and Severe Hypothyroidism: The Link between Brain Imaging and Thyroid Function

In case of primary hypothyroidism, reactive pituitary hyperplasia can manifest as pituitary (pseudo) macroadenoma. We report the case of a 12-year-old boy who was evaluated for impaired growth velocity and increased body weight. Because of low insulin-like growth factor 1 levels and poor response to the growth hormone stimulation test, brain magnetic resonance imaging was performed and a pituitary macroadenoma was found. Treatment with levothyroxine was started, and thyroid function was evaluated approximately every 40 days to titrate the dosage. After few months of therapy, the size of the macroadenoma decreased and growth hormone secretion normalized. The pituitary returned to normal size in approximately 5 years. The boy went through puberty spontaneously and reached a normal adult height. In a patient affected by primary hypothyroidism, reactive pituitary hyperplasia can cause growth hormone deficiency; however, growth hormone secretion usually normalizes after starting levothyroxine treatment. Pituitary macroadenoma can be difficult to distinguish from severe pituitary hyperplasia; however, pituitary macroadenomas are rare in childhood, and our clinical case underlines how the hormonal evaluation is essential to achieve a correct diagnosis and prevent unnecessary surgery in a context of pituitary mass

Mean first passage time analysis reveals rate-limiting steps, parallel pathways and dead ends in a simple model of protein folding

We have analyzed dynamics on the complex free energy landscape of protein folding in the FOLD-X model, by calculating for each state of the system the mean first passage time to the folded state. The resulting kinetic map of the folding process shows that it proceeds in jumps between well-defined, local free energy minima. Closer analysis of the different local minima allows us to reveal secondary, parallel pathways as well as dead ends.Comment: 7 page

Geometric and analytic views in existence theorems for optimal control. II. Distributed and boundary controls

Existence theorems are proved for Lagrange problems of optimization in a given domain G with possibly unbounded distributed controls in G and on the boundary of G , and with functional relations on G and on the boundary represented by closed operators, not necessarily linear. The case where the functional relations are partial differential equations is emphasized. Recent work concerning the reduction or elimination of seminormality requirements is taken into account. Many examples are given.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45200/1/10957_2004_Article_BF00933208.pd

Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation

Recently, mesenchymal stromal stem cells (MSCs) have been proposed as therapeutic agents because of their promising preclinical features and good safety profile. However, their introduction into clinical practice has been associated with a suboptimal therapeutic profile. In this review, we address the biodistribution of MSCs in preclinical studies with a focus on the current understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of MSCs as key aspects to overcome unsatisfactory clinical benefits of MSC application. Beginning with evidence of MSC biodistribution and highlighting PK and PD factors, a new PK-PD model is also proposed. According to this theory, MSCs and their released factors are key players in PK, and the efficacy biomarkers are considered relevant for PD in more predictive preclinical investigations. Accounting for the PK-PD relationship in MSC translational research and proposing new models combined with better biodistribution studies could allow realization of the promise of more robust MSC clinical translation. The number of clinical trials based on MSCs that are publicly available exceeds 800; however, data regarding MSC pharmacodynamics (PD), pharmacokinetics (PK), and biodistribution are still scarce. For this reason, we dissected the PD and PK properties of MSCs, presenting factors that may influence MSC-based PK studies to then conceive a new PK-PD model that would support better and more robust MSC clinical translation

Efficacy of Nutritional Interventions as Stand-Alone or Synergistic Treatments with Exercise for the Management of Sarcopenia

Sarcopenia is an age-related and accelerated process characterized by a progressive loss of muscle mass and strength/function. It is a multifactorial process associated with several adverse outcomes including falls, frailty, functional decline, hospitalization, and mortality. Hence, sarcopenia represents a major public health problem and has become the focus of intense research. Unfortunately, no pharmacological treatments are yet available to prevent or treat this age-related condition. At present, the only strategies for the management of sarcopenia are mainly based on nutritional and physical exercise interventions. The purpose of this review is, thus, to provide an overview on the role of proteins and other key nutrients, alone or in combination with physical exercise, on muscle parameters

Frailty Index and incident mortality, hospitalization and institutionalization in Alzheimer's disease: data from the ICTUS study.

BACKGROUND: The identification of an objective evaluation of frailty capable of predicting adverse outcomes in Alzheimer's disease is increasingly discussed. The purpose of this study was to investigate whether the Frailty Index (FI) predicts hospitalization, institutionalization, and mortality in Alzheimer's disease patients. METHODS: A prospective multicenter cohort study (follow-up = 2 years) that included 1,191 participants with Alzheimer's disease was carried out. The outcomes of interest were incident hospitalization, institutionalization, and mortality. The FI was calculated as the ratio of actual to thirty potential deficits, that is, deficits presented by the participant divided by 30. Severity of dementia was assessed using the Clinical Dementia Rating score. Cox proportional hazard models were performed. RESULTS: Mean age of the study sample was 76.2 (SD = 7.6) years. A quadratic relationship of the FI with age was reported at baseline (R 2 = .045, p < .001). The FI showed a statistically significant association with mortality (age- and gender-adjusted hazard ratio [HR] = 1.019, 95% confidence interval [CI] = 1.002-1.037, p = .031) and hospitalization (age- and gender-adjusted HR = 1.017, 95% CI = 1.006-1.029, p = .004) and a borderline significance with institutionalization. When the Clinical Dementia Rating score was simultaneously included in the age- and gender-adjusted models, the FI confirmed its predictive capacity for hospitalization (HR = 1.019, 95% CI = 1.006-1.032, p = .004), whereas the Clinical Dementia Rating score was the strongest predictor for mortality (HR = 1.922, 95% CI = 1.256-2.941, p = .003) and institutionalization (HR = 1.955, 95%CI = 1.427-2.679, p < .001). CONCLUSIONS: The FI is a robust predictor of adverse outcomes even after the stage of the underlying dementia is considered. Future work should evaluate the clinical implementation of the FI in the assessment of demented individuals in order to improve the personalization of care

Lipid Peroxidation and Depressed Mood in Community-Dwelling Older Men and Women

It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but\ud epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin\ud F2a (8-iso-PGF2a), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older\ud adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal\ud study of older persons (aged 70–79 years). The present analyses was based on a subsample of 1027 men and 948 women\ud free of mobility disability. Urinary concentration of 8-iso-PGF2a was measured by radioimmunoassay methods and adjusted\ud for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/\ud or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men\ud presented higher urinary concentrations of 8-iso-PGF2a than non-depressed men even after adjustment for multiple\ud sociodemographic, lifestyle and health factors (p=0.03, Cohen’s d = 0.30). This association was not present in women\ud (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in\ud older men from a large sample of the general population. Further studies are needed to explore whether the modulation of\ud oxidative stress may break down the link between late-life depression and its deleterious health consequences

Age-related changes of elastic fibers in shoulder capsule of patients with glenohumeral instability: A pilot study

Background. Recurrent shoulder dislocations occur much more frequently in adolescents than in the older population but a clear explanation of this incidence does not exist. The aim of the present study was to define the age-related distribution of the elastic fibers (EFs) in the shoulder capsule's extracellular matrix as a factor influencing shoulder instability. Materials and Methods. Biopsy specimens were obtained from the shoulder capsule of patients divided preoperatively into three groups: Group 1 consisted of 10 male patients undergoing surgery for unidirectional traumatic anterior instability (TUBS); Group 2 consisted of 10 male patients undergoing surgery for multidirectional instability (MDI); Group 3 represents the control, including 10 patients with no history of instability. In addition to the group as a whole, specific subgroups were analyzed separately on the basis of the age of subjects: > 22 or < to 22 years. All the samples were analyzed by histochemical (Weigert's resorcinol fuchsin and Verhoeff's iron hematoxylin), immunohistochemical (monoclonal antielastin antibody), and histomorphometric methods. Results. Both the elastin density and the percentage of area covered by EFs were significantly higher in younger subjects (<22 years old). Furthermore, the elastin density and the percentage of area covered by EFs were significantly higher in specimens of group of patients affected by multidirectional shoulder instability in comparison to the other two groups. Conclusion. Data of the present study confirmed the presence of an age-related distribution of EFs in the human shoulder capsule. The greater amount of EFs observed in younger subjects and in unstable shoulders could play an important role in predisposing the joint to first dislocation and recurrence

Age-related changes of elastic fibers in shoulder capsule of patients with glenohumeral instability: A pilot study

Background. Recurrent shoulder dislocations occur much more frequently in adolescents than in the older population but a clear explanation of this incidence does not exist. The aim of the present study was to define the age-related distribution of the elastic fibers (EFs) in the shoulder capsule's extracellular matrix as a factor influencing shoulder instability. Materials and Methods. Biopsy specimens were obtained from the shoulder capsule of patients divided preoperatively into three groups: Group 1 consisted of 10 male patients undergoing surgery for unidirectional traumatic anterior instability (TUBS); Group 2 consisted of 10 male patients undergoing surgery for multidirectional instability (MDI); Group 3 represents the control, including 10 patients with no history of instability. In addition to the group as a whole, specific subgroups were analyzed separately on the basis of the age of subjects: &gt; 22 or &lt; to 22 years. All the samples were analyzed by histochemical (Weigert's resorcinol fuchsin and Verhoeff's iron hematoxylin), immunohistochemical (monoclonal antielastin antibody), and histomorphometric methods. Results. Both the elastin density and the percentage of area covered by EFs were significantly higher in younger subjects (&lt;22 years old). Furthermore, the elastin density and the percentage of area covered by EFs were significantly higher in specimens of group of patients affected by multidirectional shoulder instability in comparison to the other two groups. Conclusion. Data of the present study confirmed the presence of an age-related distribution of EFs in the human shoulder capsule. The greater amount of EFs observed in younger subjects and in unstable shoulders could play an important role in predisposing the joint to first dislocation and recurrence