Neurofilament light chain levels in pregnant multiple sclerosis patients: a prospective cohort study.

BACKGROUND AND PURPOSE: Neurofilament light chain is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum neurofilament light chain (sNfL) levels in multiple sclerosis (MS) patients and healthy controls during pregnancy and puerperium. METHODS: This was a prospective, longitudinal, single-center study. sNfL concentration was assessed using a highly sensitive single-molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P-MS). Twenty-one healthy pregnant women (HPW) served as a control group. Eight P-MS suffered relapses during pregnancy (P-MS-R) in the first or second trimesters. RESULTS: No differences in pregnancy and delivery data were observed between P-MS and HPW. P-MS showed higher sNfL values than HPW in the first trimester, independently of the presence (P = 0.002) or not (P = 0.02) of relapses during pregnancy. However, in the third trimester, only P-MS-R showed higher sNfL values than HPW (P = 0.001). These differences extended to the puerperium, where P-MS-R showed higher sNfL values than those with no relapses during gestation (P = 0.02). CONCLUSION: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium.

Serum neurofilament light chain in patients with acute cerebrovascular events.

BACKGROUND AND PURPOSE: Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months. RESULTS: We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score < 7, 13.1 pg/mL [interquartile range (IQR), 5.3-27.8]; NIHSS score 7-15, 16.7 pg/mL (IQR, 7.4-34.9); and NIHSS score > 15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P < 0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors. CONCLUSIONS: In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months.

Transient liver injury and severe neonatal cholestasis in infant with glucose-6-phosphate dehydrogenase deficiency due to a new mutation.

We report the case of a neonate with a new, previously undescribed, glucose-6-phosphate dehydrogenase (G6PD) gene mutation, which was revealed by severe cholestasis, hyperbilirubinemia, and transient liver dysfunction. The severity of the clinical phenotype with ongoing chronic hemolytic anemia suggests that this mutation belongs to class 1 G6PD deficiency. The hemizygous mutation «c.675G>c; p.Trp225Cys¼ was detected by genomic sequencing. Since severe G6PD deficiency can be revealed by cholestasis, it is important to check G6PD enzyme activity when faced with a case of liver dysfunction in the neonatal period.

The paradoxical association between inherited factor VII deficiency and venous thrombosis.

Inherited factor VII (FVII) deficiency is considered to be a haemorrhagic disease. Nonetheless, some patients paradoxically present with venous thrombosis. We assessed whether there was a link between phenotype and genotype in seven patients with inherited FVII deficiency and thrombosis (eleven venous thrombotic events). For each patient (FVII:C < 50%), clinical data were collected, aetiological assessment of risk factors for thrombosis was investigated, and direct sequencing of the nine exons and promoter of the FVII gene (F7) was performed. We present the second series ever published on FVII patients with thrombosis. In nine of the eleven thrombotic events, there was at least one classical triggering risk factor; clinical (n = 4), familial antecedent (n = 2), or biological, defined by phospholipid-binding antibodies or elevated FVIII:C levels (n = 7). In contrast to a previous series, only two events occurred after surgery, performed both with and without replacement therapy. The thrombotic event remained unexplained in one young patient, highlighting the lack of 'protection' against venous thrombosis by low FVII:C levels. Genetic mutations were found to be heterogeneous. Among the seven F7 sequence alterations identified in the present study, only two (p.Ala354Val and p.Arg364Gln) have previously been reported in FVII-deficient patients presenting with venous thrombosis. Our genetic analyses of the F7 mutations in these patients show the complexity of FVII deficiency associated with thrombosis. These data justify a holistic, clinical and biological approach for patients with these specific symptoms. This series also strongly suggest that mild FVII deficiency should not prevent physicians from using antithrombotic prophylaxis in FVII-deficient patients.

[Management of thrombotic thrombocytopenic purpura in two French centers: A series of 27 patients]. / Prise en charge du purpura thrombotique thrombopénique dans deux centres français : à partir de 27 patients.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to platelet microthrombosis involved in multiple systems associated with multiple organ dysfunctions and often severe disease course. METHODS: In order to enhance the understanding of TTP, the clinical features, laboratory characteristics, treatment and outcome of 27 patients with TTP were retrospectively analyzed and investigated in two centres (Annecy and Grenoble). RESULTS: All the 27 patients presented with haemolytic anemia and decreased platelet counts. Eight patients had fever. Thirteen patients had kidney involvement including proteinuria and renal function abnormalities. Eighteen patients had neurological manifestations. Association of the 5 characteristic features of TTP was rarely found (11%) which could lead to diagnosis delay. The von Willebrand factor-cleaving protease (ADAMTS13) activity was less than 10% in all patients. At the same time, plasma ADAMTS13 inhibitors were detected in 20 patients out of the 27. After treatment with plasma exchange, glucocorticoid and rituximab, 23 patients (85%) achieved complete remission. Four patients died, in which two cases were secondary to late diagnosis. CONCLUSION: TTP is a thrombotic microangiopathy often associated with multiple organ dysfunctions. Salvage therapy, based on some studies experiences and discussed with the Reference Center, could help getting answers in most severe cases. Awareness of physicians is an important step to further limit any delay in medical care, and to further improve the prognosis of patients with TTP.

Differential expression and secretion of gelatinases and tissue inhibitor of metalloproteinase-1 during neutrophil adhesion.

Transmigrating neutrophils secrete a 92 kDa gelatinase (MMP-9) in order to degrade type IV endothelial basement membrane collagen. A model system for neutrophil adhesion combining a short pre-adhesion time (30 min) in plastic or endothelium-coated wells, medium removal and addition of soluble stimuli (fMLP, TNF alpha), enabled us to induce the release of a basal level of gelatinase activity (> 12% total cell content) from tertiary granules, while the release of vitamin B12 binding protein from specific granules was limited to 4% total cell content. Neutrophil gelatinase activity in unfractionated supernatants from endothelium-coated wells was significantly reduced (P < 0.01) compared to levels obtained on plastic supports, even after TNF alpha treatment or when cell populations were physically separated by trans-well inserts. In contrast, gelatin zymograms of supernatants from plastic and endothelium-coated wells remained similar. These findings suggest that MMP-9 is equally secreted but differentially inhibited by the tissue inhibitor of metalloproteinase-1 originating from the neutrophils. MMP-9 RT-PCR from neutrophils, assessed after up to one hour adhesion on plastic, yielded a single 270 bp fragment which was almost undetectable in the endothelial RT-PCR counterpart, whereas the TIMP-1 PCR product was apparent in both cell types. Furthermore, neutrophil adhesion on endothelial cells and TNF alpha activation for one hour induced the disappearance of MMP-9 cDNA without changes in TIMP-1 and beta-actin PCR products. These results suggest the existence of a dual down-regulation during neutrophil-endothelial interaction, both at the level of secreted MMP-9 activity and of MMP-9 gene transcription.

Quantitative high D-dimer value is predictive of pulmonary embolism occurrence independently of clinical score in a well-defined low risk factor population.

We performed a prospective study to assess whether positive quantitative D-dimer (DD) levels could be integrated for a selected population in a defined strategy to accurately diagnose pulmonary embolism (PE). For this purpose, 1528 in- or outpatients with clinically suspected PE were investigated according to our prescription rules. Clinical probability was defined as low, intermediate or high. Patients in whom DD levels were measured met criteria defined by our previously described decision-making algorithm: in- and outpatients, < 80 years, without surgery in the previous 30 days or active cancer. Nine hundred and twenty-three patients (60.4%) had quantitative DD measurement using automated latex DD assay (STA-Liatest D-Di). According to our decision-making algorithm, DD measurement was applied to 70.5% of out-, and 55.7% of inpatients, and PE diagnosis was ruled out in 49.5% of the 923 patients. This allowed us to confirm prospectively that our specific rules greatly improve the DD testing efficiency. PE was diagnosed in 115 (12.5%) patients. For a 0.5 mg L(-1) cut-off, the test sensitivity was 97.4%, but its specificity was only 56.7%. However, PE prevalence increased gradually with DD levels. The true observed PE prevalence, according to the quantitative assessment of DD levels, differed from that predicted with pretest clinical probability only. Moreover, in this well-defined patient group, a quantitative DD level > 2 mg L(-1) was predictive of PE occurrence independently of the clinical score (odds ratio 6.9, 95% confidence interval 3.7, 12.8). As part of a defined strategy, knowledge of positive DD quantitative value, together with the clinical probability score, improves the PE predictive model. A clinical validation of these results in a follow-up study would now be necessary before considering the implementation of this strategy into clinical practice.

Covalent binding of non-proteolysed C3 to Jurkat T cells.

Purified C3 binds covalently to Jurkat T cells upon incubation at neutral pH. This binding does not appear to involve proteolysis of C3; it leads to high-molecular-weight associations, preferentially through ester linkages, which are disrupted upon incubation with hydroxylamine at alkaline pH. Part of the association also appears to involve disulfide links between C3 and Jurkat cells. Similarly, plasma membranes purified from these cells bind C3 with no evidence for proteolysis of C3. Binding of C3 appears to be "catalysed" by Jurkat cells, and is not due to the well-known spontaneous hydrolysis of C3. Binding of C3 involves hydrolysis of its thioester bond, as titratable--SH groups are available in soluble C3 after incubation of purified C3 with Jurkat plasma membranes; loss of C3 haemolytic activity confirms this finding. These observations give evidence for the binding of C3b-like C3 to Jurkat cells, conferring on these cells the potential to interact with other complement receptor-bearing cells such as B cells.

Proteolytic potential of human neutrophil membranes.

A synergistic role for proteases in the degradation of extracellular matrix proteins has been proposed. Plasma membrane was isolated from a neutrophil homogenate, on a sucrose gradient, and shown to activate gelatinolysis when purified 92 kDa gelatinase was added to the medium. This stimulatory activity was enhanced by the addition of phorbol 12-myristate 13-acetate (PMA), in a dose-dependent manner, and was partially sensitive to phenylmethylsulfonyl fluoride treatment. The effect was abolished by the addition of 1 M KCl or 0.05% Brij 35 extraction. Both elastase and urinary type plasminogen activator were shown to be involved in the process. Moreover, upon neutrophil stimulation by PMA, 92 kDa gelatinase, as elastase, became associated with the plasma membrane, as shown by a subcellular fractionation experiment. These in vitro observations suggest that human neutrophils may be able, in vivo, to recruit endogenous or exogenous proteinases to mediate proteolysis associated with diapedesis and chemotactism during the inflammation process.

Matrix metalloproteinase expression in rat pancreatic islets.

Matrix metalloproteinases (MMPs) are involved in the regulation of extracellular matrix turnover and tissue remodeling, through which they can influence the infiltration of a graft by immune-competent cells. Little is known about their role in islet allograft rejection. Therefore we investigated the expression of several MMPs and of two of their tissue inhibitors (TIMPs) in rat pancreatic islets. MMP and TIMP expression in isolated rat pancreatic islets was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) from total RNA. Several MMPs of different substrate specificities were found to be expressed in rat pancreatic islets, either shortly after islet isolation and in all conditions tested (MMP-9, TIMP-1) or after a lag time (MMP-2, MMP-3, MMP-14, TIMP-2). Fetal calf serum induced MMP-7 expression. The inflammatory cytokine interleukin-1 beta (IL-1 beta) did not induce MMP or TIMP expression. We showed that rat pancreatic islets are well equipped with MMPs and TIMPs, but the functional meaning of this expression remains to be elucidated. On the basis of the known effects on tissue remodeling and cytokine processing, we anticipate that they can influence islet engraftment and viability and participate to islet graft rejection.

Gelatinase concentration in tears of corneal-grafted patients.

PURPOSE: Gelatinolytic enzymes, which degrade type IV basement membrane collagen, have been shown to be expressed by corneal cells, either constitutively (gelatinase A or MMP-2) or after induction (gelatinase B or MMP-9). Our aim was to determine whether an enhanced MMP-9 and eventually MMP-2 concentration in tears could be evidenced in the case of corneal-graft failure. METHODS: The amount of MMP-2 and MMP-9 gelatinolytic enzymes was measured by quantitative zymography in tears of twenty-one controls (84 samplings) and in tears of twenty-three corneal-grafted patients in a one-year post-graft follow-up study. RESULTS: The mean MMP-2 values in controls were of 8.4 (+/-7.3) pg/10 micrograms protein and the mean MMP-9 values in controls were of 73 (+/-76) pg/10 micrograms protein. No active gelatinase form was detected in any of controls, but in all cases of corneal graft failure, the active forms of both enzymes were present, and enzyme concentrations were higher than control values. All patients had significantly higher MMP-9 values than controls at each sampling time (p < 0.0001). The "corneal-graft failure" patient group had statistically significant higher MMP-9 concentrations in tears than the "successful-graft" patient group at one month (p = 0.0312), four months (p = 0.0158) and one year (p < 0.01) after the graft. The presence of active MMP-9 was highly significant of graft failure four months and one year after the graft (p < 0.0001). In contrast, MMP-2 increase was delayed, with significantly higher MMP-2 values than controls in all patients at four months (p = 0.0231) and one year (p = 0.0001) after the graft, but MMP-2 values could not discriminate between patient groups. CONCLUSIONS: In our study, all cases of graft failure showed abnormally high levels of the active forms of metalloproteinase enzymes, and these values far exceeded the maximum control concentration. MMP-9 measurements in tears made between one and four months after corneal transplantation, and while local corticotherapy is steadily established, should help in predicting corneal graft rejection.

Complications after total laryngectomy in nonradiated laryngeal and hypopharyngeal carcinomas.

To study the complications of total laryngectomy, we evaluated 471 previously untreated patients who underwent total laryngectomy between 1980 and 1997. This series consisted of 358 patients with primary carcinoma of the larynx and 113 with carcinoma of the hypopharynx. Concurrent neck dissection was performed in 85% of patients. Complications were studied in relation to age, T and N stage, previous tracheostomy, neck dissection, margins, reconstruction, tracheoesophageal puncture, and surgeon. Complication treatment and hospitalization were also evaluated. The overall complication rate was 30.7%, with 29.2% major and 6.5% minor complications. The mortality rate was 0.6% (3/471). Pharyngocutaneous fistula was the most frequent wound complication (21%), followed by wound infection (4.2%) and hemorrhage (2.3%). Pneumonia (1.4%) and embolism (0.4%) were the most frequent medical complications. Hypopharyngeal tumors, neck dissection, and extended procedures had a significantly higher rate of complications. Complication causes, prevention, and treatment are discussed.

Esophageal foreign bodies in adults.

The main point in managing suspected impaction of esophageal foreign bodies is to decide whether the patient needs an esophageal endoscopy. Decision-making is based on clinical history, physical examination, and radiographic studies. We review 100 cases of adults having esophagoscopy for removal of esophageal foreign bodies. Fish bones were the most frequently responsible foreign body and the cervical esophagus was the most frequent level of impaction. Decision-making based on clinical history and patient-referred symptoms revealed a positive esophagoscopy in 72% of the suspected cases. Radiographic studies gave falsely positive and falsely negative information in 30% of the cases. Rigid esophagoscopy was used successfully for foreign body removal in 99% of the cases. Average hospital stay was 3.2 days. No complications associated with the use of a rigid esophagoscope were found.

[Focalized matrix proteolysis and inflammation]. / Protéolyse matricielle, protéolyse focalisée et inflammation.

The zinc metalloproteinases (MMPs or matrixins) are capable of damaging most of the constituents of the extra-cellular matrix and the basement membrane. The matrix proteolysis is the result of an imbalance both in the turnover of these constituants and in the ratio of the tissue inhibitors of metalloproteinases (TIMPs) versus metalloproteinases. After a brief description of the nature and structure of MMPs and TIMPs, this article reports on recent progress concerning the intra and extra-cellular activation mechanisms of proenzymes (proMMPs) which bring into play a series of proteolytic activations involving different proteinase families. Two points are stressed: 1) the main sites of focalized matrix proteolysis regulation, illustrated in the cellular interaction of inflammation, and 2) the wide phenotypic variety of MMPs and TIMPs.

[Postoperative enteral nutrition in patients with cancer of the neck and head]. / Nutrición enteral postoperatoria en pacientes con cáncer de cabeza y cuello.

Nutritional management of patients with head and neck cancer have received little attention in the literature, but its role in the management of patients undergoing surgical, chemotherapeutic, or radiotherapeutic treatment is gaining more importance. We present the nutritional results obtained in 69 patients who underwent oncological surgery for head and neck malignant tumours. Nutritional requirements were administered by enteral via, through a nasogastric tube. The results show no deterioration of the nutritional status during the postoperative period, with a positive nitrogenun balance from the beginning of the nutritional program. Results were measured using two anthropological measures (PCT and CMB) and two laboratory datas (Albuminum and transferrin).

[Post-surgical results of 48 septal perforations]. / Resultado postquirúrgico de 48 perforaciones septales.

We have studied the post-surgical results of 48 perforations of the nasal septum, regarding their etiology, location and size, which must be taken into account when deciding which closure technique to use.

[Factors affecting local and regional control and survival of carcinomas of the tongue and floor of mouth]. / Factores que afectan el control local, regional y supervivencia en carcinomas de lengua móvil y suelo de boca.

A retrospective study of 142 patients that had previous surgery for carcinoma of the tongue or floor of mouth looking into the factors that affect significantly the evolution of our patients and in which circumstances we could benefit from new therapeutic techniques. Cause specific survival at 3 and 5 years was 63.4% and 56.9% respectively. Recurrences were found locally in 32 patients (22.5%), regional in 32 (22.5%) and metastasis in 11 (7.4%). T staging had no did impact on local recurrence, but the presence of positive margins (p = 0.0323). Regional control for N0/N1 was 85% (90/106) versus 55.5% (20/36) for N2/N3 (p = 0.001). Regional control by N staging was 84.5% (73/86) for N0, 85% (17/20) for N1, 57% (30/35) for N2 and 0% for N3 (0/1). Both, N staging and number of positive nodes had a significant impact in specific survival. Positive margins and the presence of positive nodes have the greatest impact on survival and regional control. Adjuvant postoperative radiotherapy did not increase survival, but not prospective random selection was performed. To evaluate this.

[Recurrence of peritracheostoma and emergency tracheotomy]. / Recidiva peritraqueostoma y traqueotomía de urgencia.

The relationship between emergency tracheotomy (ET) and stomal recurrence (SR) was evaluated in 369 patients who underwent surgery for laryngeal cancer. Emergency tracheostomy was performed in 31 patients. Age, sex, primary location, T stage, pN stage, histological grading, and time from emergency tracheotomy to definitive treatment were examined. Stomal recurrence occurred in 2.1% overall; in 1.2% of the tracheotomy-free group, and in 13% (4/31) of the emergency tracheotomy group (p < 0.0001). Recurrences were significantly more frequent in subglottic (p = 0.00007) and T3 lesions (p < 0.0001). Emergency tracheostomy often is needed in patients who have primary subglottic tumors or tumors than invade the subglottis. The relationship between ET and SR appears to be more circumstantial than causal. Aggressive local treatment is recommended in patients with subglottic lesions or subglottic tumor extension to prevent SR.

[Second primary tumors in patients with carcinoma of the head and neck]. / Segundos tumores primarios en pacientes con carcinoma de cabeza y cuello.

With improved loco-regional control of cancer of the head and neck, second primary tumors (SPT) have an increasingly negative impact on survival. The appearance of SPT depends on the location and extension of the primary and is associated with lower survival. SPT were studied in a series of 1493 previously untreated patients with carcinoma of the head and neck and a minimum follow-up of 2 years. SPT occurred in 6.3% (96/1493). SPT were associated with the following primary tumor sites: 10.8% (57/727) larynx, 4% (6/153) hypopharynx, 4% (16/404) oral cavity, and 4% (6/153) oropharynx. Forty-three percent (42.7%) of SPT were carcinomas of the head and neck, 27% bronchogenic carcinomas, and 17.7% esophageal carcinomas. Survival at 6 months, 1 year, 3 years, and 5 years of patients diagnosed as SPT was 62%, 43%, 21%, and 16%, respectively.