Subsarcolemmal expression of utrophin in neuromuscular disorders: an immunohistochemical study of 80 cases

The immunohistochemical expression of utrophin in 80 muscle biopsies from patients with dystrophinopathies and other neuromuscular disorders is reported. All biopsy specimens were routinely studied by a battery of 12 histoenzymatic techniques, and immunohistochemistry was performed for spectrin, three domains of dystrophin and two domains of utrophin. Abnormal utrophin expression was observed in all dystrophinopathic muscles compared with normal controls or biopsy samples from several other muscular diseases. Inflammatory myopathies presented abnormal overexpression of utrophin and an abnormal dystrophin immunolabeling pattern. This overexpression of utrophin appears to be directly related to the decrease in dystrophin. We conclude that the study of utrophin is important for the histological interpretation and differential diagnosis of dystrophin-related muscular disorders. Received: 13 November 1997 / Revised: 6 February 1998, 20 May 1998 / Accepted: 22 May 1998     

Indexed effective orifice area after mechanical aortic valve replacement does not affect left ventricular mass regression in elderly.

OBJECTIVE: After aortic valve replacement, the effects of a small functional prosthesis on the extent and pattern of regression of left ventricular hypertrophy and on clinical outcomes may be less significant in older patients with low cardiac output requirements. The objective of this study was therefore to determine whether patient-prosthesis mismatch affects left ventricular mass regression in the elderly. METHODS: The population studied was made up of 88 patients over 65 years of age with pure aortic stenosis who underwent mechanical aortic valve replacement. The effective orifice area index was calculated for each patient on the basis of the projected prosthesis in vivo effective orifice area. It was considered a continuous variable and influence of its entire range of values on the extent of left ventricular mass regression was analyzed in a multivariate prediction model. RESULTS: Even though, in the group with prosthesis-patient mismatch there was a trend for lower postoperative left ventricular mass index (115+/-24 g/m(2) vs 102+/-27 g/m(2), p=0.24) and postoperative peak trans-prosthetic gradients (32+/-9.8 mmHg vs 28.9+/-7.79 mmHg, p=0.35) these differences were not statistically significant. The prevalence of residual left ventricular hypertrophy at follow-up was 50% in the group with patient-prosthesis mismatch and 50% in the group without patient-prosthesis mismatch (p=0.83). In multivariate analysis the only factors associated with indexed left ventricular mass were the follow-up time (p=0.015, r(2)=0.22) and preoperative indexed left ventricular mass (p=0.0012, r(2)=0.11). CONCLUSIONS: The major finding of our study is that patient-prosthesis mismatch does not affect left ventricular mass regression in patients older than 65 with pure aortic stenosis who underwent mechanical aortic valve replacement. In older patients with low cardiac output requirements, even a small change in the valve effective orifice area after aortic valve replacement with modern efficient mechanical prosthesis, will result in a marked reduction of pressure gradient and this will be associated with a significant regression of left ventricular mass.     

Differences among Clinical Classification Schemes for Predicting Stroke in Atrial Fibrillation: Implications for Therapy in Daily Practice

Background: Several clinical classification schemes (CCSs) for predicting stroke in nonvalvular atrial fibrillation (NVAF) have been developed to help identify patients eligible for anticoagulation. Objectives: To estimate the agreement in predicting the risk of stroke among four widespread CCSs, and to determine their implications for thromboprophylaxis in clinical practice. Methods: The authors conducted a prospective, multicenter, observational study of adults with NVAF in 12 emergency departments (EDs) in July 2000 and February 2001. The proportions of patients classified as having high, moderate, and low risk of stroke among the following CCSs were compared: the Atrial Fibrillation Investigators (AFI), the Stroke Prevention in Atrial Fibrillation (SPAF), the CHADS₂ (an acronym for congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or transient ischemic attack), and the American College of Chest Physicians (ACCP). Results: One thousand two hundred twenty patients were included. The proportions of patients stratified as having high/moderate/low risk of stroke according to each CCS were: 70%/22%/8% (AFI), 38%/41%/21% (SPAF), 13%/45%/42% (CHADS₂), and 86%/7%/7% (ACCP). The agreement was medium between AFI and ACCP (κ= 0.52) and poor among the rest of them (AFI/SPAF, κ= 0.01; AFI/CHADS₂, κ= 0.02; SPAF/CHADS₂, κ= 0.18; SPAF/ACCP, κ= 0.11; CHADS₂/ACCP, κ= 0.03). The agreements in selecting patients as eligible for antiplatelet therapy or anticoagulation were: AFI/SPAF, κ= 0.45; AFI/CHADS₂, κ= 0.22; AFI/ACCP, κ= 0.91; SPAF/CHADS₂, κ= 0.47; SPAF/ACCP, κ= 0.11; CHADS₂/ACCP, κ= 0.03. Conclusions: In the ED population studied, these CCSs showed relevant differences in the risk of stroke stratification and, therefore, in the identification of patients with NVAF eligible for anticoagulation.     

Glutamate‐dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons

The idea that astrocytes merely provide structural and trophic support for neurons has been challenged by the demonstration that astrocytes can regulate neuronal calcium levels. However, the physiological consequences of astrocyte–neuron signalling are unknown. Using mixed cultures of rat hippocampal astrocytes and neurons we have determined functional consequences of elevating astrocyte calcium levels on co-cultured neurons. Electrical or mechanical stimulation of astrocytes to increase their calcium level caused a glutamate-dependent slow inward current (SIC) in associated neurons. Microinjection of 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) into astrocytes to prevent the stimulus-dependent increase in astrocyte calcium level, blocks the appearance of the neuronal SIC. Pharmacological manipulations indicate that this astrocyte-dependent SIC is mediated by extracellular glutamate acting on N-methyl-d -aspartate (NMDA) and non-NMDA glutamate receptors. Additionally, stimulation of astrocytes reduced the magnitude of action potential-evoked excitatory and inhibitory postsynaptic currents through the activation of metabotropic glutamate receptors. The demonstration that astrocytes modulate neuronal currents and synaptic transmission raises the possibility that astrocytes play a neuromodulatory role by controlling the extracellular level of glutamate.     

Age-related differences in breast cancer stage at diagnosis between black and white patients in an urban community hospital

Background: Breast cancer mortality is significantly higher among black patients compared to white patients. Black women are reportedly at increased risk for early-onset breast cancer. Our goal was to evaluate stage distribution relative to age among black and white breast cancer patients in an institution with a relatively high minority patient population. Methods: We evaluated 425 patients diagnosed with breast cancer between 1990 and 1994: 56% white, 34% black, the remainder were other ethnicities. Patients were stratified by age: under 50 years versus 50 and older. Socioeconomic status was estimated by utilization of medical care in the private-practice setting versus the public clinic. Results: Significantly more black patients were younger at diagnosis compared to white patients (32% vs. 20%; p=0.008). There was a significantly more advanced stage distribution among the younger black patients, but not among the older black patients. Most of the black and white patients received private-practice care. Conclusions: These age-related differences in breast cancer stage distribution between black and white patients (which appeared independent of socioeconomic status) indicate that more aggressive screening and public education progams directed toward younger black women is warranted, and they lend support to the possibility of ethnicity-related variation in primary tumor biology.     

Pure cervical radiculopathy due to spontaneous spinal epidural haematoma (SSEH): report of a case solved conservatively

Introduction: Spontaneous spinal epidural haematoma (SSEH) is widely recognised throughout the literature as a cause of myelopathy, radicular compression being very rarely reported. Surgical management is almost always recommended, especially in the cases of spinal cord compression. Conservative treatment is reported as a curiosity and only in the case of spontaneous improvement. This report presents the particular case of a 64-year-old patient undergoing anticoagulant therapy that had a cervical radiculopathy due to a SSEH confirmed by MRI. The patient improved spontaneously and symptoms were solved with unconventional conservative treatment and without stopping the anticoagulant therapy. Conclusions: Spontaneous epidural haematoma must be kept in mind when patients undergoing anticoagulant therapy have a sudden onset of cervicobrachialgia. Even though most spinal surgeons advocate surgical treatment, a conservative approach may lead to a complete recovery and may be considered as a good option in the case of radicular involvement. Discontinuation of the anticoagulant therapy may not always be needed, especially when the clinical syndrome improves spontaneously.

     

A genetic selection for Caenorhabditis elegans synaptic transmission mutants.

We have isolated 165 Caenorhabditis elegans mutants, representing 21 genes, that are resistant to inhibitors of cholinesterase (Ric mutants). Since mutations in 20 of the genes appear not to affect acetylcholine reception, we suggest that reduced acetylcholine release contributes to the Ric phenotype of most Ric mutants. Mutations in 15 of the genes lead to defects in a gamma-aminobutyric acid-dependent behavior; these genes are likely to encode proteins with general, rather than cholinergic-specific, roles in synaptic transmission. Ten of the genes have been cloned. Seven encode homologs of proteins that function in the synaptic vesicle cycle: two encode cholinergic-specific proteins, while five encode general presynaptic proteins. Two other Ric genes encode homologs of G-protein signaling molecules. Our assessment of synaptic function in Ric mutants, combined with the homologies of some Ric mutants to presynaptic proteins, suggests that the analysis of Ric genes will continue to yield insights into the regulation and functioning of synapses.     

Regulators of sperm function: Single cell analysis of tyrosine kinase dependent and independent Ca2+ fluxes in progesterone induced acrosome reaction

In this study we developed a single cell analysis protocol withwhich protein tyrosine kinase (PTK)-dependent and independentCa²⁺ fluxes occurring in human spermatozoa in response to progesteronewere evaluated. By recording the fluorescence emitted by fluo-3-loadedspermatozoa using a confocal laser scanning microscopy systemit was possible not only to monitor relative changes in theintracellular free Ca²⁺ concentration ([Ca²⁺]i) but also todetermine the time at which the acrosomal exocytosis began.The addition of progesterone produced a rapid transient [Ca²⁺]iincrease in 35% of spermatozoa. In     

Small-diameter invasive melanomas: clinical and pathologic characteristics

Background: Most melanomas when first diagnosed clinically are larger than common benign melanocytic nevi (> 6 mm). Smaller melanomas, however, may occasionally occur. Yet, very little is known about them.
Objective: To determine the incidence and delineate the clinical and histologic characteristics of small-diameter invasive melanomas.
Methods: Slides of all melanomas diagnosed between 1984–1993 were reviewed and measured. All invasive lesions less than 6 mm were further scrutinized clinically and morphologically. Results: Among 357 invasive melanomas, 16 (4.4%) were less than 6 mm. Most lesions lacked some of the histologic features usually seen in large melanomas. One half of them were over 0.75 mm deep. Patients with small melanomas were on average 15 years younger than those with large lesions. In females, sites on the upper extremities predominate. In females, small melanomas had clinical signs of melanoma, while in males they resembled nevi.
Conclusion: Melanomas smaller than 6 mm are not rare. Clinicians and pathologists must learn their features in order to diagnose them properly.     

Pregnancy: Antiphospholipid antibodies and human reproductive failure

Routine screening for circulating antiphospholipid antibodies(aPL), namely the lupus anticoagulant (LA) and anticardiolipinantibodies (aCL), was carried out in a total of 1273 women aged<45 years. Of them, 822 were experimental subjects and 451were controls. The former comprised the following three studygroups: 498 infertile patients (group 1), 284 spontaneous recurrentaborters (group 2), and 40 patients with repeated failure ofembryo transfer (group 3). Controls included five groups ofwomen: 125 normal healthy women who had never been pregnant(group 4), 125 normal healthy parous women with no previousabortion (group 5), 52 women in labour after normal pregnanciesat term (group 6), 49 infertile patients achieving a livebirthwith their first in-vitro fertilization (IVF) and embryo transfer(group 7), and 100 female patients with systemic lupus erythematosus(positive controls, group 8). aPL positivity in the eight groupsstudied was as follows: 2.4, 9.2, 10, 0.8, 0, 0, 0 and 42% respectivelyfor groups 1 to 8. There were no differences within groups 1and 3 regarding incidence of aPL when patients were groupedaccording to infertility aetiological factors and indicationsfor IVF respectively. Twenty-six out of 284 recurrent aborters(9.2%) tested positive for aPL, and the LA and/or aCL were identifiedas the aetiological factor in 12% of patients (24/199) withsupposedly unexplained recurrent abortion. Incidence of positivesera for aPL in group 1 was similar to that observed in controlgroups 4, 5 and 6. On the contrary, incidence of aPL positivityin groups 2 and 3 was significantly higher than in control groups4, 5 and 6 and among infertile women (group 1). The differencebetween groups 3 and 7 almost reached statistical significance.Interestingly, there was no difference between groups 2 and3, but groups 2 and 7 resulted probably different regardingincidence of aPL positive sera. As expected, the highest incidenceof patients testing positive for aPL was found in group 8. Seveninfertile patients having circulating aPL and becoming pregnantspontaneously or after specific infertility treatment, successfullycarried to term in spite of the fact that they did not receiveimmunotherapy. Among recurrent aborters, the live-born babyrate was significantly higher after treatment with low-doseaspirin than prior therapy. It is concluded that the presenceof circulating aPL may be associated with recurrent abortionbut not with infertility. In addition, our results favour apossible role of aPL hi failure of implantation after IVF andembryo transfer.