Feasibility of a New Wearable Device to Estimate Acute Stress in Novices During High-fidelity Surgical Simulation.

BACKGROUND: Stress associated with learning of a psychomotor task can influence the trainees learning ability. Surgical simulation is a validated training milieu designed to replicate real-life situations, prevent biases and provide objective metrics. However, the complexity of stress mechanisms and the absence of a reliable detection method make stress estimation difficult to quantify and to interpret. AIM: a) To assess the feasibility of a new watch-sized device to noninvasively measure stress parameters in novices during a simulation task and b) to compare its derived cardiac stress parameters to those of an ambulatory Holter monitor. MATERIALS AND METHODS: Twenty-one novices were trained on a basic skills module. During base line, exercise, and recovery phases, all subjects wore a wearable device and data regarding blood volume pressure, heart rate, inter beat interval, electrodermal activity, and skin temperature were recorded. Additionally, Holter Monitoring was used to concomitantly capture heart rate, R-R intervals and heart rate variability. Before and after each experiment, all subjects completed the short, six-item STAI scale. RESULTS: Data analysis showed: a) when compared to STAI, electrodermal activity exhibited the best correlation, sensitivity and specificity and b) the device derived cardiac parameters highly correlated with the reciprocal Holter values during all experiment phases. CONCLUSION: This wearable device is an easy to use and well accepted by the participants noninvasive tool, which can provide accurate stress estimation in our simulation setting. Additionally, it can replicate Holter derived stress related heart parameters, thus eliminating the need to wear a rather cumbersome device.

Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis.

AIMS: To further characterize the clinical signs and symptoms of nephrogenic systemic fibrosis, a new and serious disease affecting renal failure patients and caused by some Gd-containing contrast agents, including gadodiamide. MATERIAL: 22 cases of gadodiamide-related nephrogenic systemic fibrosis followed at the nephrology department of Copenhagen University Hospital Herlev. METHOD: Retrospective cohort study based on medical records, personal interviews and physical examinations. RESULTS: Typical first signs of the disease were skin discoloration, induration and warmth, itching, constant pain and other neuropathic symptoms localized to the lower legs. First sign appeared in a median of 14 days (range 0 â 53 days) after gadodiamide exposure. Associated early symptoms included sleeplessness and transient, diffuse hair loss. The predominant late symptom was symmetrical skin stiffness of extremities with or without restricted joint motion. Ten of 22 patients (45, 95% CI: 27 â 66%) were severely disabled due to contractures on the average of 29 months after being exposed to gadodiamide. Four patients died (18, 95% CI: 6 â 41). Patients perceived that intensive physiotherapy was effective in limiting disabling contractures. CONCLUSIONS: Signs and symptoms of nephrogenic systemic fibrosis vary over time and between patients. The disease leads to severe disability in a significant proportion of affected patients. Intensive physiotherapy may limit the development of contractures.

Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis.

BACKGROUND: Gadolinium (Gd)-based magnetic resonance contrast agents (GBMCA), including gadodiamide, have been identified as the probable causative agents of the serious disease, nephrogenic systemic fibrosis (NSF). OBJECTIVES: To investigate retained Gd-containing deposits in skin biopsies from patients with NSF and to determine their relative concentrations over time from administration of GBMCA. METHODS: An investigator-blinded retrospective study, analysing 43 skin biopsies from 20 patients with gadodiamide-related NSF and one NSF-negative gadodiamide-exposed dialysis patient, ranging from 16 days to 1991 days after Gd contrast dose. Utilizing automated quantitative scanning electron microscopy/energy-dispersive X-ray spectroscopy we determined the concentration of Gd and associated elements present as insoluble deposits in situ in the tissues. RESULTS: We detected Gd in skin lesions of all 20 patients with NSF, whereas Gd was undetectable in the NSF-negative patient. Gd concentration increased over time in 60% of patients with multiple sequential biopsies (n=10), decreasing only when the initial sampling time was >23 months after first gadodiamide dose. All Gd-containing deposits contained phosphorus, calcium and sodium. The ratio of Gd to calcium in tissue deposits correlated positively with the gadodiamide dose and with serum ionized calcium at the time of Gd exposure. CONCLUSIONS: These findings demonstrate the in vivo release (through transmetallation) of the toxic free Gd3+ from gadodiamide, and its retention in apatite-like deposits. We suggest that Gd may be mobilized over time from bone stores, explaining variably delayed onset of NSF and increasing skin concentration over time in patients with NSF.

FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival.

FOXP3 is a unique marker for CD4+CD25+ regulatory T cells (Tregs). In solid tumours, high numbers of Tregs are associated with a poor prognosis. Knowledge about the implications of Tregs for the behaviour of haematological malignancies is limited. In this study, skin biopsies from 86 patients with mycosis fungoides (MF) and cutaneous T-cell lymphoma (CTCL) unspecified were analysed for the expression of FOXP3 on tumour cells and tumour-infiltrating Tregs. Labelling of above 10% of the neoplastic cells was seen in one case classified as an aggressive epidermotropic CD8+ cytotoxic CTCL. In the remaining 85 cases, the atypical neoplastic infiltrate was either FOXP3 negative (n=80) or contained only very occasional weakly positive cells (n=5). By contrast, all biopsies showed varying numbers of strongly FOXP3+ tumour-infiltrating Tregs. MF with early or infiltrated plaques had significantly higher numbers of FOXP3+ Tregs than CTCL unspecified or advanced MF with tumours or transformation to large cell lymphoma. An analysis of all patients demonstrated that increasing numbers of FOXP3+ Tregs were associated with improved survival in both MF and CTCL unspecified. In conclusion, our data indicate that the presence of FOXP3+ Tregs in CTCL is associated with disease stage and patient survival.

Expression of T-cell activation marker CD134 (OX40) in lymphomatoid papulosis.

BACKGROUND: CD134/OX40 and CD30 are transmembrane proteins from the tumour necrosis factor receptor (TNFR) family present selectively on activated T cells. TNFR-related proteins are crucially involved in the regulation of proliferation and survival of normal and malignant lymphohaematopoietic cells. CD30 has been used for the immunophenotyping and subclassification of cutaneous lymphomas; virtually nothing is known, however, about the expression pattern of CD134 in lymphoid skin malignancies. OBJECTIVES: To determine CD134 expression in cutaneous lymphoma and benign inflammatory disorders. METHODS: Biopsy material was obtained from patients with lymphomatoid papulosis (LyP, n = 42), mycosis fungoides (n = 21), Jessner's infiltrates (n = 10) and non-specific dermatitis (n = 14). The expression of CD134 and CD30 was scored after immunohistochemical staining with appropriate monoclonal antibodies. The proportion of G2 + S phase cells was determined by laser scanning cytometry from nuclei obtained from paraffin-embedded biopsies. RESULTS: Few, single and scattered CD134+ cells (< 10%) were observed in the benign inflammatory infiltrations and in mycosis fungoides. A subset of 16 patients with LyP presented with clusters of CD30+ CD134+ cells. There was no correlation between the magnitude of CD134 expression and the histological type or the proportion of G2 + S cells in LyP. CD134 immunoreactivity was lower than expected in patients with LyP and another lymphoid malignancy (P < 0.001, Fisher's exact test). CONCLUSIONS: CD134 is strongly expressed in a proportion (38%) of patients with LyP, but not in mycosis fungoides or benign lymphocytic infiltrations. Loss of CD134 expression in LyP may be a marker of an increased risk of second lymphoid malignancy.

Ber-EP4 immunoreactivity depends on the germ layer origin and maturity of the squamous epithelium.

AIM: To map the expression of Ber-EP4 in well-differentiated squamous epithelia, metaplastic squamous epithelia and dysplastic squamous epithelia of different origins. METHODS AND RESULTS: Squamous epithelium of different origin was stained using a standard immunohistochemistry method applied to paraffin sections. We found that normal squamous epithelium of the oral cavity, oesophagus, uterine cervix, vagina, anal canal, and branchial cysts are Ber-Ep4-negative, as are the mature squamous metaplasia of bronchial mucosa, urinary bladder mucosa and uterine cervical mucosa. In contrast, immature squamous metaplasia of bronchial mucosa, or uterine cervical mucosa, and squamous dysplasia of oral mucosa of endodermal origin, or uterine cervical mucosa in most cases expressed Ber-EP4. CONCLUSION: Squamous epithelia of ectodermal origin never express Ber-EP4, whether normal, hyperplastic, dysplastic or neoplastic. In contrast, squamous epithelium of endodermal origin sometimes contains the target glycoproteins of Ber-EP4 when immature, metaplastic, dysplastic or neoplastic. The results indicate that the differences in expression of Ber-EP4 in squamous epithelium depend primarily on germ layer origin, and on the maturity of the epithelium.

Stereoselective synthesis of styrene oxides via a Mitsunobu cyclodehydration.

[reaction: see text] The Mitsunobu cyclodehydration of chiral phenethane-1,2-diols (4), readily accessed from the styrene derivative (5), has been demonstrated to provide the corresponding styrene oxides (2) with high levels of stereoretention (up to 99%). Optimized reaction conditions are described, from which the combination of tricyclohexylphosphine (Chx(3)P) and diisopropylazodicarboxylate (DIAD) in THF and R = EWG provides the best results.

A practical synthesis of a COX-2-specific inhibitor.

A number of synthetic strategies to the Cox-2 specific inhibitor 1 have been described. These studies have led to the identification of a novel pyridine construction using annulation of ketone 2 using a vinamidinium species 29 and ammonia in 97% assay yield. Three approaches to the synthesis of ketone 2 are described that allow for its preparation in large quantities in >65% overall yield from methyl 6-methylnicotinate.

Annulation of ketones with vinamidinium hexafluorophosphate salts: an efficient preparation of trisubstituted pyridines.

alpha-Aryl ketones react with vinamidinium hexafluorophosphate salts to give access to the corresponding 3-arylpyridines. The annulation reactions proceed in good to excellent yields with vinamidinium salts containing electron-withdrawing groups at the beta-position (R(2)). The reaction was applied to the preparation of the COX-2 specific inhibitor 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine (1), as well as a series of analogues.

[Diagnosis and growth evaluation of vestibular schwannomas by SPECT combined with TL-201 thallium]. / Vestibularis-schwannomers diagnostik og vaekst bedømt ved SPECT kombineret med TL-201 Thallium.

The value of SPECT scanning in diagnosis and growth potential of vestibular schwannoma (VS) was investigated in a series of 29 patients. SPECT demonstrated all tumours > 0.8 cm3, but had limitations as a diagnostic modality of small intracanalicular tumours, when compared to gadolinium DTPA enhanced MR. SPECT was found to be valuable in determining VS growth potential as it reflects tumour vascularity, which is essential for tumour growth. A high radioactive tracer uptake in the tumour corresponded to high tumour vascularity, indicating a high growth rate and vice versa. It seems that we now have an in vivo functional radiological modality capable of providing data on VS vascularity and determination of growth potential in the individual tumour.

Evaluation of cardiac troponin I immunoreaction in autopsy hearts: a possible marker of early myocardial infarction.

Postmortem diagnosis of early myocardial infarctions is an ever recurrent problem in pathology. In the present study we determined the troponin I expression in 46 autopsy hearts using an immunohistochemical technique. Troponin I has, as a specific cardiac muscle protein, become a widespread used marker in testing patients with acute chest pain. The hearts were divided into three groups based on the macroscopical findings: definite signs of infarction, possible signs of infarction and no signs of infarction. All 14 cases of definite myocardial infarction showed a well-defined area with loss of troponin I. Twenty-three of 24 cases of possible myocardial infarction also showed a well-defined area with loss of troponin I. None of the eight non-cardiac death controls showed loss of troponin I expression. The results suggest troponin I expression as a sensitive test in diagnosis of early myocardial infarction.

[Intestinal ganglioneuromatosis--a rare cause of chronic diarrhea]. / Intestinal ganglioneuromatose--en sjoelden årsag til kronisk diaré.

A case of intestinal ganglioneuromatosis is reported. The symptoms were watery diarrhoea and abdominal pain of several months duration. Endoscopic examination of the oesophagus, ventricle, duodenum, colon and rectum was normal. Mucosal biopsies from colon and rectum revealed ganglia cells and thin nerve fibres in the lamina mucosa, giving the diagnosis ganglioneuromatosis. As a consequence of the diagnosis thyroid scintigraphy, CT-scanning of the thyroid and adrenal glands and measurement of serum calcitonin and gastrin were performed. The tests revealed an intrathoracic nodular struma, and beyond this no abnormalities. The relation of intestinal ganglioneuromatosis to Multiple Endocrine Neoplasia type II b is discussed and the necessity of performing mucosal-biopsy from endoscopically normal colonic mucosa in cases of chronic diarrhoea is emphasised.

BAX protein is not expressed by basal cell carcinomas.

BAX and related proteins encoded by the BCL2 gene family are involved in the regulation of apoptosis. BAX is an apoptosis-promoting protein. The slow growth of basal cell carcinoma (BCC) has so far been explained by a high apoptotic activity. We investigated immunohistochemically 27 BCCs for expression of the apoptosis-promoting BAX protein. BCC did not express detectable amounts of BAX immunohistochemically. The results indicate that apoptosis in BCC does not involve BAX protein. We propose that the apoptotic pathway in BCC is regulated by either less common members of the BCL2 gene family or bypasses the regulation of the BCL2 gene family.

Thallium chloride 201Tl combined with single photon emission computed tomography (SPECT) in the evaluation of vestibular schwannoma growth.

Thallium chloride 201Tl combined with SPECT was performed in a series of 29 patients with neuroradiological evidence of vestibular schwannoma (VS). The relative tumor uptake (U) and relative tumor concentration (C) of the radiotracer 201Tl was determined, and the cerebellum served as a reference. The relative tracer concentration and uptake were correlated to tumor volume determined by gadolinium DTPA enhanced MR, to prediagnostic duration of symptoms, to tumor vascularity expressed by the average number of intratumoral vessels using the endothelial marker CD31, and to the proliferative activity in the tumors expressed by positive staining with the monoclonal antibody MIB-1 for Ki-67. A positive 201TI enhancement was detected in 17 tumors (n = 17). Tumors U and C were statistically unrelated to tumor volume (p = 0.236 and p = 0.439). SPECT demonstrated all tumors > 0.8 cm3, but it had its limitation as a diagnostic modality of small intracanalicular tumors, when compared with gadolinium DTPA enhanced MR. Relating U and C in all tumors (n = 29) and the prospectively registered data on the prediagnostic duration of symptoms, a statistical significance was found (p = 0.012 and p = 0.015). No statistically significant correlation was observed between U and C and the proliferative activity of the tumors expressed by positive staining with the monoclonal antibody MIB-1 for Ki-67 (p = 0.063 and p = 0.086). A statistically significant correlation was noted between C and U in the operated group (n = 12) and tumor vascularity expressed by the average number of the intratumoral vessels (p = 0.003 and p = 0.014). SPECT was found to be superior to MR in determining VS growth potentials as it expresses tumor vascularity, which is essential for tumor growth. It seems that we now have an in vivo functional radiological modality capable of providing data on VS vascularity and determination of growth potential in the individual tumor. A high radioactive tracer uptake in the tumor corresponded to high tumor vascularity, indicating a high growth rate and vice versa.

Metallothionein expression in basaloid proliferations overlying dermatofibromas and in basal cell carcinomas.

Basaloid proliferations overlying dermatofibromas which morphologically resemble superficial basal cell carcinomas have been interpreted as both reactive/regressive and frankly malignant. Metallothioneins (MTs) are low-molecular-weight proteins with a selective binding affinity for heavy metal ions. MTs has been proposed to represent a biological marker of carcinogenesis and, in a variety of human tumours, a correlation between immunohistochemically overexpression of MT and aggressive clinical behaviour has been shown. In order to clarify the nature of basaloid proliferations overlying dermatofibromas, we examined, immunohistochemically, 10 dermatofibromas with overlying simple hyperplasia, 16 dermatofibromas with overlying basaloid proliferation, and 35 basal cell carcinomas, for expression of MT. In normal epidermis, the basal keratinocytes showed cytoplasmatic MT immunoreactivity. The staining intensity was stronger in the basal cells of the rete ridges, an observation which is in accordance with the high proportion of S-phase cells in this area. Simple hyperplasia showed the same MT expression pattern as normal epidermis. Basaloid proliferations stained like superficial and nodular basal cell carcinomas. Of nodular basal cell carcinomas, 92% (12 of 13) showed decreased/absent MT immunoreactivity, while 86% (six of seven) of infiltrating/morphoea-like basal cell carcinomas showed overexpression of MT (P = 0.001, Fisher's exact test). The results demonstrate that MT overexpression in basal cell carcinomas is correlated with infiltrative growth pattern. The similar expression of MT in basaloid proliferations and 'non-infiltrating' basal cell carcinomas suggests that these lesions share a common change in metabolism and/or differentiation.

Bcl-2 overexpression in basaloid proliferations overlying dermatofibromas and basal cell carcinomas.

Basaloid proliferations overlying dermatofibromas resembling superficial basal cell carcinomas have been interpreted both as reactive/regressive and frankly malignant. Basal cell carcinoma is a slow-growing tumour, which so far has been regarded as an actively proliferating lesion with a high apoptotic activity. We examined immunohistochemically 6,dermatofibromas with overlying simple hyperplasia, 12 dermatofibromas with overlying basaloid proliferations, and 24 basal cell carcinomas for expression of Ki-67 protein, and bcl-2 protein. The Ki-67 labelling index represents an estimate of proliferative activity. Bcl-2 protein suppresses apoptosis. The Ki-67 labelling indexes of basaloid proliferations, basal cell carcinomas, and normal epidermis were similar (11-15%, p < 0.05, Mann-Whitney test). Bcl-2 protein was expressed in all cells of basaloid proliferations, similar to the expression pattern in basal cell carcinomas. We suggest that basaloid proliferations overlying dermatofibromas might have achieved a phenotype that equals an early stage of BCC carcinogenesis.