Management of complications of androgen deprivation therapy in the older man

Prostate cancer is the most common malignancy in older men. With the aging of the population, the number of older men with prostate cancer will grow rapidly. Androgen deprivation therapy (ADT) is the mainstay of treatment for men with systemic disease and is increasingly utilized as primary therapy or in combination with other therapies for localized disease. Side effects of therapy are multifold and include hot flashes, osteoporosis, and adverse psychological and metabolic effects. Recent research has illustrated that ADT can negatively impact the functional, cognitive, and physical performance of older men. Patients with prostate cancer, despite recurrence of the disease, have a long life expectancy and may be subjected to the side effects of ADT for many years. This review highlights the complications of ADT and approaches to management. We also provide recommendations for assessment and management of ADT complications among the most vulnerable and frail older male patients.     

Induction of HSP72 in Rat Liver by Chronic Ethanol Consumption Combined with Exercise: Association with the Prevention of Ethanol-Induced Fatty Liver by Exercise

Ethanol-induced fatty liver in rats was attenuated by repeated running exercise, and the protective effect of exercise was associated with the synergistic expression of heat shock proteins (HSP72). Rats were placed in four groups of six. The two ethanol-fed groups of rats received a liquid diet (Lieber-DeCarli formulation) in which 36% of the calories were derived from ethanol. One group remained sedentary (S/E), whereas the other was trained to run on a rodent treadmill at a speed of 27 m/min, 1 hr/day, 5 days/week, for 7 weeks (R/E). Two other groups–one exercised as previously mentioned (R/C) and one sedentary (S/C)–received control-liquid diets in which the ethanol was isocalorically substituted with a dextran/maltose mixture. The degree of fatty infiltration in liver sections stained with hematoxylin and eosin was graded on a 0–4 scale and the data analyzed by ANOVA on ranks. Ethanol significantly induced fatty infiltration in the S/E group, whereas fatty infiltration in the livers of the R/E group was not different from the S/C group. Electrophoresis and Western blotting of liver homogenates demonstrated that HSP72 was not expressed in either the S/C or S/E groups and was only slightly expressed in the R/C group. The combination of exercise and ethanol, however, resulted in an elevated expression of HSP72 in the R/E group. The content of HSP73 was unaffected by any treatment.     

Geriatrics and physical medicine and rehabilitation: common principles,complementary approaches,and 21st century demographics

The demographic changes occurring in the United States transcend the capabilities of any specific medical specialty to provide optimum care for the elderly. This commentary discusses a statement of principles drafted by representatives of the American Academy of Physical Medicine and Rehabilitation who collaborated with members of 9 other medical and surgical specialties. In this commentary, we argue that geriatrics and physical medicine and rehabilitation (PM&R) share common principles and complementary approaches. We urge physiatrists and other rehabilitation professionals to address the needs of elderly patients and recommend that these principles be incorporated into PM&R practice.     

N400-like magnetoencephalography responses modulated by semantic context,word frequency,and lexical class in sentences

Words have been found to elicit a negative potential at the scalp peaking at approximately 400 ms that is strongly modulated by semantic context. The current study used whole-head magnetoencephalography (MEG) as male subjects read sentences ending with semantically congruous or incongruous words. Compared with congruous words, sentence-terminal incongruous words consistently evoked a large magnetic field over the left hemisphere, peaking at approximately 450 ms. Source modeling at this latency with conventional equivalent current dipoles (ECDs) placed the N400 m generator in or near the left superior temporal sulcus. A distributed solution constrained to the cortical surface suggested a sequence of differential activation, beginning in Wernicke's area at approximately 250 ms, spreading to anterior temporal sites at approximately 270 ms, to Broca's area by approximately 300 ms, to dorsolateral prefrontal cortices by approximately 320 ms, and to anterior orbital and frontopolar cortices by approximately 370 ms. Differential activity was exclusively left-sided until >370 ms, and then involved right anterior temporal and orbital cortices. At the peak of the N400 m, activation in the left hemisphere was estimated to be widespread in the anterior temporal, perisylvian, orbital, frontopolar, and dorsolateral prefrontal cortices. In the right hemisphere, the orbital, as well as, weakly, the right anterior temporal cortices were activated. Similar but weaker field patterns were evoked by intermediate words in the sentences, especially to low-frequency words occurring in early sentence positions where there is little preceding context. The locations of the N400 m sources identified with the distributed solution correspond well with those previously demonstrated with direct intracranial recordings, and suggested by functional magnetic resonance imaging (fMRI). These results help identify a distributed cortical network that supports online semantic processing.     

Using Standardized Oral Examinations to Evaluate General Competencies

Emergency medicine residency programs are required by the Accreditation Council for Graduate Medical Education (ACGME) to formally evaluate each resident with oral and written examinations. The Michigan State University Emergency Medicine Residency Program in Lansing conducts monthly standardized oral examinations (SOEs) as part of each resident's evaluation. Recently, the ACGME has advanced six areas, termed "general competencies," that should be acquired during graduate medical education. According to the ACGME, these competencies should be included in the educational process of all residency programs. In promulgating these competencies, the ACGME did not provide examples of core content, strategies for implementation, or methods of evaluation; rather, individual residency programs are required to develop their own methods. The authors describe a modification of an existing SOE strategy that assesses residents' knowledge, skills, experiences, and attitudes as reflected in the general competencies.     

End-tidal Carbon Dioxide Predicts the Presence and Severity of Acidosis in Children with Diabetes

BACKGROUND: Patients with diabetic ketoacidosis (DKA) hyperventilate, lowering their alveolar (PACO(2)) and arterial carbon dioxide (PaCO(2)). This ventilatory response lessens the severity of their acidemia in a predictable way. Because end-tidal CO(2) (ETCO(2)) closely approximates PaCO(2), measured ETCO(2) levels should allow for predictions about the presence and severity of acidosis in diabetic patients. OBJECTIVES: 1) To evaluate the relationship between measured serum bicarbonate (HCO(3)) and ETCO(2) measured via nasal capnography in children with suspected DKA; and 2) to assess the ability of capnography to predict DKA. METHODS: Children being evaluated in a pediatric emergency department for suspected DKA (known or suspected diabetes presenting with hyperglycemia with or without ketonuria) were enrolled in a cross-sectional, prospective, observational study. Prior to the availability of venous HCO(3) results, ETCO(2) values were measured using a Nellcor NPB-70 Handheld Capnograph. RESULTS: Forty-two patients were enrolled. Linear regression analysis revealed a significant relationship between HCO(3) and ETCO(2) (R(2) = 0.80, p < 0.0001). Mean ETCO(2) was 37 torr (95% CI = 35.5 to 37.9 torr) in the children without DKA and 22 torr (95% CI = 17.4 to 26.9 torr) in the children with DKA (p < 0.0001). An ETCO(2) cut-point of <29 torr correctly classified the most patients (95%), with a sensitivity of 0.83 (95% CI = 0.52 to 0.98) and a specificity of 1.0 (95% CI = 0.88 to 1.0). No patient with an ETCO(2) of > or =36 torr had DKA, for a sensitivity of 1.0 (95% CI = 0.74 to 1.0). CONCLUSIONS: End-tidal CO(2) is linearly related to HCO(3) and is significantly lower in children with DKA. If confirmed by larger trials, cut-points of 29 torr and 36 torr, in conjunction with clinical assessment, may help discriminate between patients with and without DKA, respectively.     

Abscisic acid-induced stomatal closure mediated by cyclic ADP-ribose

Abscisic acid (ABA) is a plant hormone involved in the response of plants to reduced water availability. Reduction of guard cell turgor by ABA diminishes the aperture of the stomatal pore and thereby contributes to the ability of the plant to conserve water during periods of drought. Previous work has demonstrated that cytosolic Ca²⁺ is involved in the signal transduction pathway that mediates the reduction in guard cell turgor elicited by ABA. Here we report that ABA uses a Ca²⁺-mobilization pathway that involves cyclic adenosine 5′-diphosphoribose (cADPR). Microinjection of cADPR into guard cells caused reductions in turgor that were preceded by increases in the concentration of free Ca²⁺ in the cytosol. Patch clamp measurements of isolated guard cell vacuoles revealed the presence of a cADPR-elicited Ca²⁺-selective current that was inhibited at cytosolic Ca²⁺ ≥ 600 nM. Furthermore, microinjection of the cADPR antagonist 8-NH₂-cADPR caused a reduction in the rate of turgor loss in response to ABA in 54% of cells tested, and nicotinamide, an antagonist of cADPR production, elicited a dose-dependent block of ABA-induced stomatal closure. Our data provide definitive evidence for a physiological role for cADPR and illustrate one mechanism of stimulus-specific Ca²⁺ mobilization in higher plants. Taken together with other recent data [Wu, Y., Kuzma, J., Marechal, E., Graeff, R., Lee, H. C., Foster, R. & Chua, N.-H. (1997) Science 278, 2126–2130], these results establish cADPR as a key player in ABA signal transduction pathways in plants.     

The distribution of oriented contours in the real world

In both humans and experimental animals, the ability to perceive contours that are vertically or horizontally oriented is superior to the perception of oblique angles. There is, however, no consensus about the developmental origins or functional basis of this phenomenon. Here, we report the analysis of a large library of digitized scenes using image processing with orientation-sensitive filters. Our results show a prevalence of vertical and horizontal orientations in indoor, outdoor, and even entirely natural settings. Because visual experience is known to influence the development of visual cortical circuitry, we suggest that this real world anisotropy is related to the enhanced ability of humans and other animals to process contours in the cardinal axes, perhaps by stimulating the development of a greater amount of visual circuitry devoted to processing vertical and horizontal contours.     

Predicting subcutaneous glucose concentration using a latent-variable-based statistical method for type 1 diabetes mellitus

Background

Accurate prediction of future glucose concentration for type 1 diabetes mellitus (T1DM) is needed to improve glycemic control and to facilitate proactive management before glucose concentrations reach undesirable concentrations. The availability of frequent glucose measurements, insulin infusion rates, and meal carbohydrate estimates can be used to good advantage to capture important information concerning glucose dynamics.

Methods

This article evaluates the feasibility of using a latent variable (LV)-based statistical method to model glucose dynamics and to forecast future glucose concentrations for T1DM applications. The prediction models are developed using a proposed LV-based approach and are evaluated for retrospective clinical data from seven individuals with T1DM and for In silico simulations using the Food and Drug Administration-accepted University of Virginia/University of Padova metabolic simulator. This article provides comparisons of the prediction accuracy of the LV-based method with that of a standard modeling alternative. The influence of key design parameters on the performance of the LV-based method is also illustrated.

Results

In general, the LV-based method provided improved prediction accuracy in comparison with conventional autoregressive (AR) models and autoregressive with exogenous input (ARX) models. For larger prediction horizons (≥30 min), the LV-based model with exogenous inputs achieved the best prediction performance based on a paired t-test (α = 0.05).

Conclusions

The LV-based method resulted in models whose glucose prediction accuracy was as least as good as the accuracies of standard AR/ARX models and a simple model-free approach. Furthermore, the new approach is less sensitive to changing conditions and the effect of key design parameters.     

Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγ null mice is enhanced by transgenic expression of membrane-bound human SCF

Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common γ chain (IL2rg) gene, including NOD-scid IL2rγ(null) (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of stem cell factor (SCF), which is critical for HSC engraftment, proliferation, and survival. We hypothesized that transgenic expression of human membrane-bound stem cell factor Tg(hu-mSCF)] would increase levels of human HSC engraftment in nonirradiated NSG mice and eliminate complications associated with irradiation. Surprisingly, detectable levels of human CD45(+) cell chimerism were observed after transplantation of cord blood-derived human HSCs into nonirradiated adult as well as newborn NSG mice. However, transgenic expression of human mSCF enabled heightened levels of human hematopoietic cell chimerism in the absence of irradiation. Moreover, nonirradiated NSG-Tg(hu-mSCF) mice engrafted as newborns with human HSCs rejected human skin grafts from a histoincompatible donor, indicating the development of a functional human immune system. These data provide a new immunodeficient mouse model that does not require irradiation preconditioning for human HSC engraftment and immune system development.