Observed Improvement in Cognition During a Personalized Lifestyle Intervention in People with Cognitive Decline.

BACKGROUND: Alzheimer's disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach. OBJECTIVE: We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.). METHODS: Participants (n = 34) were recruited from the San Diego, CA area. The multimodal intervention included lifestyle changes (i.e., movement, diet, and stress management), nutraceutical support, and medications. It was delivered pragmatically over four clinical visits, and outcome measures were gathered at four study visits, occurring at baseline, one, three, and six months (primary endpoint). Study participants received weekly phone calls for nutrition support throughout study participation. Outcome measures included the Cambridge Brain Sciences (CBS) battery, and the Montreal Cognitive Assessment (MoCA). RESULTS: At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 (p = 0.013). Significant improvement was observed in mean scores of the CBS memory domain [25.2 (SD 23.3) to 35.8 (SD 26.9); p < 0.01] and CBS overall composite cognition score [24.5 (SD 16.1) to 29.7 (SD 20.5); p = 0.02]. All CBS domains improved. CONCLUSION: Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research.

Abdominal pain during the menopause transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: To assess the relationship between abdominal pain severity during the menopausal transition (MT) and age, MT stage, reproductive biomarkers, stress biomarkers, and stress perceptions. METHODS: Women ages 35-55 were recruited from multiethnic neighborhoods in the greater Seattle area from 1990 to 1992, for an original study cohort of 508. From 1990 to 2013, a subset of this cohort consented to ongoing annual data collection by annual health questionnaire, health diary, and daily menstrual calendar. Beginning in 1997, a portion of these women also provided a first morning voided urine specimen to be assayed for levels of estrone glucuronide (E1G), follicle stimulating hormone (FSH), testosterone, cortisol, norepinephrine, and epinephrine. To identify how changes in abdominal pain severity changed over time in relation to age, MT stage, reproductive biomarkers, stress-related biomarkers, and stress-related perceptions, mixed effects modeling was used. RESULTS: In a univariate model, E1G (p = 0.02) and testosterone (p = 0.02) were significantly and negatively related to abdominal pain severity, while perceived stress (p = 0.06), tension (p <  0.001), and anxiety (p <  0.001) were significantly and positively associated. In a multivariate model, increasing age (p = 0.001) and E1G (p = 0.04) were negatively associated with abdominal pain severity, and anxiety (p = 0.00) positively associated. Testosterone did not improve the fit to the final model, nor did tension or perceived stress. CONCLUSIONS: These results suggest that age, anxiety, and E1G each show a significant association with abdominal pain severity in the MT. In contrast, stress perception, tension, testosterone, stress biomarkers, and MT stage do not. These factors should be evaluated further in research on abdominal pain experienced during the MT and early postmenopause years.

Constipation and diarrhea during the menopause transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: To assess the relationship of constipation and diarrhea severity during the menopause transition (MT) with age, MT stage, reproductive biomarkers, stress-related biomarkers, and stress-related perceptions. METHODS: From 1990 to 1992, women aged 35 to 55 years were recruited from the greater Seattle area; 291 of them consented to ongoing (1990-2013) annual data collection by daily menstrual calendar, health diary, and annual health questionnaire. A subset (n = 131) provided a first morning voided urine specimen (1997-2013). These were assayed for levels of E1G, follicle-stimulating hormone, testosterone, cortisol, norepinephrine, and epinephrine. Mixed-effects modeling was used to identify how changes in constipation and diarrhea severity over time related to age, MT stage, reproductive biomarkers, stress-related biomarkers, and stress-related perceptions. RESULTS: In a univariate model, age, late reproductive (LR) stage, tension, and anxiety were all significantly and positively related to constipation severity, whereas cortisol was significantly and negatively associated. In a multivariate model, only tension and cortisol remained significant predictors of constipation severity (P < 0.05). In a univariate model, age, LR stage, and estrone glucuronide were significantly and negatively associated with diarrhea severity, whereas tension, anxiety, and perceived stress were significantly and positively related. In a multivariate model, only tension and age remained significant predictors of diarrhea severity. CONCLUSIONS: Key reproductive hormones do not play a significant role in constipation or diarrhea severity in the MT. In contrast, stress perception, tension, anxiety, and cortisol do. These factors should be evaluated in further research involving constipation and diarrhea.

Dental pulp as a stem cell reservoir.

Currently, much information is provided regarding the presence and the roles in tissue regeneration of stem cell niches residing in post-natal dental pulp. So far, three types of adult stem cells have been isolated from dental pulp. Correct evaluation of these cells is important in order to determine their potential use in clinical fields. The present study aims to review the origins and immunophenotype of these cells. The particularities of interstitial cells of the stem cell niches are also debated.

Calcipotriol treatment of confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome).

Gougerot-Carteaud syndrome or confluent and reticulated papillomatosis (CRP), was first described by Gougerot and Carteaud as dermatosis. It is generally considered a rare condition. The eruption consists confluent, flat, brown papules localized primarily to the intermammary and interscapular regions with subsequent spread to the breast and abdomen; at the periphery, the papules spread out forming a pigmented reticulated pattern. At present, the aetiology of CRP remains unknown. The two prominent theories are an abnormal host response to fungi and a keratinization defect. Other hypothesis include photosensitivity, genetic factor, amyloidosis cutis and endocrinopathy.

Familial occurrence of pseudoxanthoma-elasticum-like papillary dermal elastolysis.

We report the morphological, immunohistochemical and ultrastructural cutaneous findings of two sisters, aged 72-74, with pseudoxanthoma-elasticum-like papillary dermal elastolysis (PDE), recently defined as an age-related condition. To our knowledge, these are the first familial cases of PDE reported in the literature. The lesions appeared as small, asymptomatic, soft papules around the neck and axillary regions. The affected skin revealed a marked decrease of normal elastic network of papillary dermis without alterations in either the relevant collagen or reticular dermis. Ultrastructural and immunohistochemical examinations showed activated dermal fibroblasts with abundant elongated dendritic cytoplasmic processes and the absence of myofibroblasts. The well documented avoidance of sun exposure (the patients are both nuns), the rare incidence of the disorder (only six cases reported), and the familial occurrence suggest that genetic or inherited predisposition should also be considered in the pathogenesis of PDE.

Multidrug resistance and malignancy in human osteosarcoma.

In osteosarcoma, resistance to chemotherapy and metastatic spread are the most important mechanisms responsible for the failure of current multimodal therapeutic programs. We have shown previously that overexpression of the MDR1 gene product P-glycoprotein is the most important predictor of an adverse clinical course in patients with osteosarcoma. treated with chemotherapy. In this study, we analyzed the relationship between P-glycoprotein expression and local aggressiveness and systemic dissemination of multidrug-resistant (MDR) human osteosarcoma cells. Compared to parental sensitive cells, MDR cells showed a decreased tumorigenicity,and metastatic ability in athymic mice, together with a reduced migratory and invasive ability and a lower homotypic adhesion ability in vitro, suggesting that P-glycoprotein overexpression is associated with a less malignant phenotype. These experimental observations were confirmed by clinical data. In fact, the time of appearance of lung metastases in a series of osteosarcoma patients treated with chemotherapy was significantly shorter in the group of cases with no expression of P-glycoprotein in the primary lesion compared to the group with P-glycoprotein overexpression. Moreover, the incidence of P-glycoprotein overexpression was found to be higher among patients with localized disease at the clinical onset than in patients with evidence of metastasis at the time of diagnosis. These data indicate that, in osteosarcoma, the MDR phenotype is not associated with a more aggressive behavior both in vitro and in clinical settings, suggesting that the previously shown association of the MDR phenotype with a worse outcome in osteosarcoma is not related to a higher metastatic ability of cells with P-glycoprotein overexpression but is more likely due to their lack of responsiveness to cytotoxic drugs.

Evaluation of P-glycoprotein expression in soft tissue sarcomas of the extremities.

Soft tissue sarcomas comprise a heterogeneous group of mesenchymal tumors accounting for less than one-percent of adult neoplasms. In the last few years, the use of adjuvant chemotherapy has been proposed for the treatment of these lesions in order to obtain a better systemic control, but its usefulness is still controversial. In this study, we evaluated whether P-glycoprotein, a membrane protein strictly associated with multidrug resistance, is overexpressed in soft tissue sarcomas. By using human multidrug resistant sarcoma cell lines as controls, we analyzed P-glycoprotein expression in 34 primary and in 23 relapsed soft tissue sarcomas of the extremities. Overexpression of P-glycoprotein was found in 6 out of 34 primaries (18%) and in 8 out of 23 relapses (35%). In particular, in malignant fibrous histiocytoma, the most frequent soft tissue sarcoma of adults, P-glycoprotein overexpression was found in 23% of primary untreated cases, in agreement with the reported relapse rate of this tumor after surgery and chemotherapy. These data suggest that, in soft tissue sarcomas, overexpression of P-glycoprotein may be of prognostic value and that the assessment of P-glycoprotein expression may be useful for the design of chemotherapy protocols.

Solid alveolar rhabdomyosarcoma of the hand in adolescence: a clinical, histologic, immunologic, and ultrastructural study.

Rhabdomyosarcoma (RMS), a high-grade, malignant, skeletal muscle tumor, represents approximately 5% of neoplasms in children. The poorly differentiated forms of RMS are often not easily diagnosed and classified. Among the four histologic variants, alveolar RMS is the least frequently reported subtype. A poorly differentiated solid variant of alveolar RMS occurred on the right hand of a 16-year-old girl. Because of the tumor size, local invasiveness, and occurrence of cutaneous and breast metastases at presentation, the clinical staging was group IV (T2/NO/M1). Surgical excisions of the primary and metastatic locations were performed and chemotherapy with vincristine, dactinomycin, cyclophosphamide, and doxorubicin was administered. Light and electron microscopy studies revealed a solid proliferation with a focal alveolar pattern of monomorphous, small, round neoplastic cells without easily detectable muscular morphologic features. The skeletal muscle origin was revealed by the positive immunostaining for desmin, alpha-sarcomeric actin, muscle-specific actins, and enolase, and confirmed by immunoblotting for desmin. Despite the age of our patient, which is considered by some authors an independent predictor of outcome, all prognostic variables were unfavorable. However, a disease-free interval during three years of follow-up underlines the importance of multidisciplinary regimens for the treatment of this rare solid tumor of childhood and adolescence.

Intramuscular myxoma of the face: an unusual localization. A clinicopathological study.

BACKGROUND: Intramuscular myxoma is a rare benign mesenchymal lesion. Only very rare cases of cutaneous localization of this tumor have been described, in particular related to the somatic soft tissues of the face. This unusual localization may clinically mimic nodular or cystic facial lesions having different origins. OBJECTIVE: The aim of our work was to well characterize the phenotype of the spindle cells characteristic of intramuscular mixoma. METHODS: Tissue samples were processed for morphological and ultrastructural studies. Moreover, immunohistochemical stainings were performed to characterize the expression of different nonmuscular and muscular cytoskeletal proteins. RESULTS: The tumor was composed of sparse spindle cells embedded in a prominent mucoid matrix. Besides the predominance of a fibroblast-like appearance, some neoplastic cells displayed immunohistochemical and ultrastructural features resembling either myofibroblasts or primitive mesenchymal cells, with a modulation of cell actin expression. CONCLUSION: The presence of multiple phenotypes of nonmuscular, mesenchymal pathway of differentiation can be considered a peculiar feature of intramuscular myxoma.

Clinical relevance of Ki-67 expression in bone tumors.

BACKGROUND: The availability of Ki-67 monoclonal antibody has opened new possibilities for an extensive analysis of cell kinetics in human neoplasms. Ki-67 antibody reveals a nuclear antigen that is expressed in proliferating but not in quiescent cells. Although the reliability of Ki-67 immunostaining has been evaluated in different tumor types, little information has been reported on bone neoplasms. METHODS: Cell proliferation, as determined by Ki-67 expression, was measured by immunofluorescence on representative cytospins obtained from 205 patients with bone tumors. In each sample, the percentage of Ki-67-positive cells was quantified on at least 500 cells and expressed as Ki-67 labeling index (LI). RESULTS: Ki-67 LI was lower in benign and low grade lesions as compared with high grade malignant lesions. A correlation between Ki-67 LI and histologic grade was observed in osteosarcoma and chondrosarcoma. In osteosarcoma, among the 43 primary lesions included in this study, 30 patients, all treated with the same regimen of chemotherapy and limb-salvage surgery, were selected to establish the prognostic significance of cell proliferation. The Ki-67 labeling was higher in patients with a good histologic response to chemotherapy. However, at a 24-month follow-up, a worse prognosis was associated with a higher proliferative activity, whereas no correspondence was found between the histologic response to preoperative chemotherapy and the disease free survival, suggesting that in high grade osteosarcoma the biologic aggressiveness expressed by high levels of Ki-67 LI may be clinically more relevant than the responsiveness to antineoplastic agents. CONCLUSIONS: In bone tumors, the level of Ki-67 expression correlates with the level of malignancy and is diagnostically and prognostically useful.

Pachydermoperiostosis: study of epidermal growth factor and steroid receptors.

Pachydermoperiostosis is a rare osteo-cutaneous disease characterized by hypertrophy of bones and surrounding soft tissues. The cutaneous manifestations include coarsening of facial features, cutis verticis gyrata, digital clubbing, hyperhidrosis and seborrhoea. The pathogenetic mechanism of the disease is still debated, and proposed aetiological factors include genetic influences, anomalies in fibroblast activity, or alteration in peripheral blood flow. We studied a patient with the incomplete form of pachydermoperiostosis, assessing epidermal growth factor receptor (EGF-R) and sex hormone steroid receptors (SR) in the affected skin, and also evaluating the urinary excretion of EGF. The results showed high levels of nuclear steroid receptors, increased cytosolic oestrogen receptors, and no detectable progesterone and androgen cytosolic receptors. EGF-R was also undetectable, and the urinary excretion of EGF was elevated. These findings suggest that the increased tissue sensitivity to circulating sex-steroids could induce enhanced tissue EGF/transforming growth factor alpha (TGF-alpha) production and utilization. The SR-EGF-R system could therefore be involved in determining hypertrophy of the affected tissues.

Multidrug-resistance (MDR) phenotype of human osteosarcoma cells evaluated by quantitative morphological and electron microscopy analyses.

Multidrug-resistant (MDR) variants of a human osteosarcoma cell line (U-2 OS) have been recently obtained by continuous exposure to doxorubicin (DX). The growth and phenotypic characteristics of these cell lines have been demonstrated to be related to the level of expression of P-glycoprotein. In this work, the morphological changes associated with MDR have been evaluated by quantitative image analysis and transmission electron microscopy. Resistant cells present morphological changes with respect to sensitive cells at both cytoplasmic and nuclear level. Some of these changes appear to be related to the degree of resistance but not to the direct presence of DX, since deprived cells maintain some modified characters, while others are partly lost. These findings suggest that DX exposure affects cell metabolism causing progressive changes of the cell morphotype.

Abnormal Bcl-2 and "tissue" transglutaminase expression in psoriatic skin.

Cell death by apoptosis plays a key role in skin development and homeostasis. Previous studies have shown that increased apoptosis characterizes several pathologic conditions affecting human skin. Thus, the pathogenesis of cutaneous diseases may involve an imbalance in the homeostatic mechanisms determining whether the death of keratinocytes will occur by terminal differentiation or apoptosis. We investigated the involvement of apoptosis in psoriasis. For this purpose, we assessed, in addition to morphology and DNA fragmentation, the expression of two putative apoptotic genes, bcl-2 and "tissue" transglutaminase, in normal and psoriatic skin. A large number of keratinocytes showing biochemical and morphologic features of cells undergoing apoptosis was observed in all the suprabasal layers of the psoriatic epidermis. The plaques from all patients analyzed showed a dramatic reduction in the number of bcl-2-positive cells localized in the basal cell compartment. In contrast, the psoriatic lesions presented a marked induction in "tissue" transglutaminase, which was localized specifically to the cytoplasm of apoptotic keratinocytes. "Tissue" transglutaminase protein staining was undetectable in normal epidermis. The bcl-2 and "tissue" transglutaminase staining pattern observed in psoriasis also was found in the skin of patients affected by lichen planus. These findings indicate that these two genes are regulated in an opposite fashion in psoriatic keratinocytes undergoing apoptosis, thus confirming their antithetic role in the cascade of events leading to the establishment of the mature apoptotic phenotype.

Punctate porokeratotic keratoderma--its occurrence with internal neoplasia.

Punctate porokeratotic keratoderma (PPK) represents a diffuse involvement of palms and soles by multiple, accuminate keratotic papules and plugs, histologically identified by parakeratotic cornoid lamellae. A possible association between PPK and internal malignancy has been previously noted by Herman in 1973. A patient with a 3-month history of PPK is described in which a bronchial carcinoma was recently diagnosed. This association led us to speculate that PPK could be a sign of internal neoplasia, as already established for other forms of palmoplantar keratoderma. We suggest that the presence of an underlying malignancy must be screened for when a diagnosis of PPK is proposed.

Evaluation of serine alpha 1-antitrypsin and polymorphonuclear leukocyte elastase contents and their immunogenetic correlation in psoriasis.

The purpose of our study was to quantify the serum content of alpha 1-antitrypsin (alpha 1-AT) and polymorphonuclear leukocyte elastase (PMN-E) in of 21 patients affected by active and stationary psoriasis, and 12 normal controls. HLA typing was also performed to identify a correlation among HLA antigens, age at onset of psoriasis and biochemical results. alpha 1-AT levels were within the normal range in all patients, even in those with active, extensive, inherited and juvenile psoriasis, and in the controls. These data allow us to exclude, in our patients, the presence of rare or defective phenotypes, frequently associated with reduced serine levels of alpha 1-AT. The PMN-E serine content was greatly increased in 3 patients, increased in 2, and slightly modified in 6 cases. All patients with the highest PMN-E levels reported a positive family history and absence of pulmonary, hepatic and atopic diseases. An increased psoriatic inheritance has been observed in the CW6-positive subjects (7/20), comparing B13 and DR6 antigen frequency. No correlation among HLA antigens, age at onset, clinical phase, or biochemical results could be established.

Pachyonychia congenita with late onset of nail dystrophy--a new clinical entity?

Pachyonychia congenita syndrome (PCS) is a genetic disease with an autosomal dominant mode of transmission in which the main sign, pachyonychia, usually arises at birth or in childhood together with other disorders of keratinization. A 28-year-old woman developed subungual hyperkeratosis of all toe-nails and thumb-nails associated with pain on pressure and walking. She had a scrotal tongue with leucokeratotic areas, blister formation, plantar hyperkeratosis, palmoplantar hyperhidrosis and dental cavities since childhood. The present case, interpreted as PCS of late onset, could be a clinical variant of the Jadassohn-Lewandowsky syndrome with the late onset of pachyonychia or else an additional form of PCS due to the expression of a new and different allele.