Primary Sézary syndrome commonly shows low-grade cytologic atypia and an absence of epidermotropism

The dermatopathologic findings in cases of Sézary syndrome (SS) that arise in patients without a previous diagnosis of mycosis fungoides have not been well characterized. We evaluated the histologic findings in skin biopsy specimens from 31 patients with such primary SS and correlated them with clinical and hematologic parameters at the time of biopsy. The most characteristic histologic finding was the presence of a dermal perivascular lymphoid infiltrate, usually with mild to moderate cytologic atypia and variable numbers of eosinophils; epidermotropism was absent or minimal in 19 cases (61%). Reactive epidermal changes such as spongiosis, parakeratosis, and acanthosis also were present frequently (27 [87%], 17 [55%], 19 [61%] cases, respectively). The number of eosinophils present in skin biopsy specimens correlated with the level of peripheral blood lymphocytosis. In erythrodermic patients or patients with persistent xerosis and pruritus, it is important to carefully evaluate the degree of lymphocyte atypia in the dermal perivascular infiltrate and correlate with blood flow cytometric findings to diagnose primary SS. Many cases will lack the epidermotropism usually seen in mycosis fungoides.     

Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury

Hepatic fibrin(ogen) has been noted to occur after acetaminophen (APAP)-induced liver injury in mice. Deficiency in plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of fibrinolysis, increases APAP-induced liver injury in mice. However, the roles of fibrinogen and fibrinolysis in APAP-induced liver injury are not known. We tested the hypothesis that hepatic fibrin(ogen) deposition reduces severity of APAP-induced liver injury. APAP-induced (300 mg/kg) liver injury in mice was accompanied by thrombin generation, consumption of plasma fibrinogen, and deposition of hepatic fibrin. Neither fibrinogen depletion with ancrod nor complete fibrinogen deficiency [via knockout of the fibrinogen alpha chain gene (Fbg(-/-))] affected APAP-induced liver injury. PAI-1 deficiency (PAI-1(-/-)) increased APAP-induced liver injury and hepatic fibrin deposition 6 hours after APAP administration, which was followed by marked hemorrhage at 24 hours. As in PAI-1(-/-) mice, administration of recombinant tissue plasminogen activator (tenecteplase, 5 mg/kg) worsened APAP-induced liver injury and hemorrhage in wild-type mice. In contrast, APAP-induced liver injury was reduced in both plasminogen-deficient mice and in wild-type mice treated with tranexamic acid, an inhibitor of plasminogen activation. Activation of matrix metalloproteinase 9 (MMP-9) paralleled injury, but MMP-9 deficiency did not affect APAP-induced liver injury. The results indicate that fibrin(ogen) does not contribute to development of APAP-induced liver injury and suggest rather that plasminogen activation contributes to APAP-induced liver injury.     

Selective opiate modulation of nociceptive processing in the human brain

Fentanyl, a mu-opioid receptor agonist, produces analgesia while leaving vibrotactile sensation intact. We used positron emission tomography (PET) to study the mechanisms mediating this specific effect in healthy, right-handed human males (ages 18-28 yr). Subjects received either painful cold (n = 11) or painless vibratory (n = 9) stimulation before and after the intravenous injection of fentanyl (1.5 microgram/kg) or placebo (saline). Compared with cool water (29 degrees C), immersion of the hand in ice water (1 degrees C) is painful and produces highly significant increases in regional cerebral blood flow (rCBF) within the contralateral second somatosensory (S2) and insular cortex, bilaterally in the thalamus and cerebellum, and medially in the cerebellar vermis. Responses just below the statistical threshold (3.5 < Z < 4.0) are seen in the contralateral anterior cingulate, ipsilateral insular cortex, and dorsal medial midbrain. The contralateral primary sensory cortex (S1) shows a trend of activation. Except for slight changes in intensity, this pattern is unchanged following a saline placebo injection. Fentanyl reduces the average visual analogue scale ratings of perceived pain intensity (47%) and unpleasantness (50%), reduces pain-related cardioacceleration, and has positive hedonic effects. After fentanyl, but not placebo, all cortical and subcortical responses to noxious cold are greatly reduced. Subtraction analysis [(innocuous water + fentanyl) - (innocuous water + no injection)] shows that fentanyl alone increases rCBF in the anterior cingulate cortex, particularly in the perigenual region. Vibration (compared with mock vibration) evokes highly significant rCBF responses in the contralateral S1 cortex in the baseline (no injection) and placebo conditions; borderline responses (3.5 < Z < 4. 0) are detected also in the contralateral thalamus. Fentanyl has no effect on the perceived intensity or unpleasantness of vibratory stimulation, which continues to activate contralateral S1. Fentanyl alone [(mock vibration + fentanyl) - (mock vibration + no injection)] again produces highly significant activation of the perigenual and mid-anterior cingulate cortex. A specific comparison of volumes of interest, developed from activation peaks in the baseline condition (no injection), shows that fentanyl strongly attenuates both the contralateral thalamic and S1 cortical responses to noxious cold stimulation (P < 0.048 and 0.007, respectively) but fails to affect significantly these responses to vibrotactile stimulation (P > 0.26 and 0.91, respectively). In addition, fentanyl, compared with placebo, produces a unique activation of the mid-anterior cingulate cortex during fentanyl analgesia, suggesting that this region of the cingulate cortex participates actively in mediating opioid analgesia. The results are consistent with a selective, fentanyl-mediated suppression of nociceptive spinothalamic transmission to the forebrain. This effect could be implemented directly at the spinal level, indirectly through cingulate corticofugal pathways, or by a combination of both mechanisms.     

Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy

Objective:

Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X‐adrenoleukodystrophy (X‐ALD).

Methods:

X‐ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X‐ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X‐AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X‐ALD.

Results:

Here, we prove the capability of the antioxidants N‐acetyl‐cysteine, α‐lipoic acid, and α‐tocopherol to scavenge VLCFA‐dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.

Interpretation:

We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease‐driving factor in X‐AMN warrants translation into clinical trials for X‐AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor. Ann Neurol 2011;     

Magnetic resonance imaging performs better than endocervical curettage for preoperative prediction of cervical stromal invasion in endometrial carcinomas

Objective

Preoperative identification of cervical stromal invasion in endometrial carcinoma is important to select patients for primary radical hysterectomy. The objective of this prospective implementation study was to assess if introduction of magnetic resonance imaging (MRI) in addition to the standardly applied endocervical curettage (ECC), improved the preoperative prediction of cervical stromal invasion.

Methods

Over a six-year period, a total of 338 patients were surgically staged after preoperative assessment of the uterine cervix by ECC (years 1 through 3), and a combination of MRI and ECC (years 4 through 6). Suggested presence of cervical stromal invasion based on ECC (n = 321) and MRI (n = 146) were compared for diagnostic performance applying surgical FIGO stage 2009 as reference standard.

Results

For assessment of cervical stromal invasion sensitivity (specificity) [accuracy] values were 65% (79%) [77%] for ECC and 59% (91%) [84%] for MRI. Among patients diagnosed with both preoperative tests (n = 129), MRI yielded significantly higher specificity (p = 0.001) and accuracy (p = 0.005) than ECC. MRI independently predicted cervical stromal invasion with an odds ratio (OR) of 11.2 (p < 0.001) compared to OR of 2.7 (p = 0.07) for ECC.

Conclusions

The diagnostic performance of MRI compares favorably to that of ECC for preoperative assessment of cervical stromal invasion in endometrial carcinoma. Thus, the findings in this prospective implementation study support the value of preoperative MRI for assessment of cervical stromal invasion before radical hysterectomy.     

Stress urinary incontinence six months after first vaginal delivery

Objective

To determine the prevalence, severity and impact on quality of life of stress urinary incontinence (SUI) six months after the first vaginal delivery, as well as to investigate the risk factors associated with it.

Study design

We designed a prospective study that included 396 women who had their first vaginal delivery in the Hospital Donostia. Diagnosis and identification of the type of urinary incontinence were carried out considering the 2002 ICS definitions. Women were interviewed and examined twice, at term and six months after delivery. The severity of the symptoms was evaluated with the Incontinence Severity Index (ISI) and the impact on quality of life was evaluated with the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form. The statistical analysis included comparison of means (Student's t-test or analysis of variance) and proportions (Chi square and Fisher's exact tests). Multiple logistic regression analysis was performed using variables that were close to statistical significance.

Results

15.1% of the women reported SUI six months after their first vaginal delivery. The ISI was slight or moderate in the majority of the cases and the impact on quality of life was low. The presence of SUI in pregnant women at term was the only independent risk factor associated with SUI after delivery (OR: 3.71; 95% IC: 1.95–7.06). The type of vaginal delivery did not influence in SUI six months after the birth, not even in women who were continent during pregnancy.

Conclusions

Slight or moderate SUI was common after the first vaginal delivery and the impact on quality of life was low. Urinary incontinence during pregnancy was the only risk factor independently associated with the presence of SUI six months after the first vaginal delivery.     

Asparaginase-like protein 1 is an independent prognostic marker in primary endometrial cancer,and is frequently lost in metastatic lesions

Objective

Loss of Asparaginase-like protein 1 (ASRGL1) has been suggested as a prognostic biomarker in endometrial carcinoma. Our objective was to validate this in a prospectively collected, independent patient cohort, and evaluate ASRGL1 expression in endometrial carcinoma precursor lesion and metastases.

Self-sampled and air-dried cervicovaginal secretions can be used for analyses of mucosal antibodies

Cervicovaginal secretions were collected from 26 women (13 premenopausal and 13 postmenopausal) using a new sampling device (MucoSafe™) with an absorbent which was introduced into the vagina and retrieved by the women themselves, after which it was air-dried and stored for months at room temperature until extraction of immunoglobulins. Cervical secretions were also collected by absorbent cylindrical wicks (Polyfiltronics) which were introduced into the cervical canal during speculum examination and thereafter kept frozen until extraction. The concentrations of specific IgA and IgG antibodies (to group B streptococci) in extracts from both methods were corrected by reference to total immunoglobulin levels. Three pairs of samples, all from postmenopausal women, were excluded from analysis due to undetectable levels of antibodies in the MucoSafe™ specimen. In the remaining 23 pairs, corrected concentrations of IgA and IgG antibodies in samples obtained by MucoSafe™ correlated well with the corresponding concentrations in wick samples, R=0.84 (p<0.0001) and R=0.69 (p=0.0002), respectively. Thus, cervicovaginal secretions for antibody measurements can be obtained by this novel method for self-sampling, obviating the need for speculum examination and storage of frozen samples.