Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis Patients with Very Mild Clinical Disability.

Cognitive dysfunction affects 40-65% of multiple sclerosis (MS) patients and can occur in the early stages of the disease. This study aimed to explore cognitive functions by means of the Italian version of the minimal assessment of cognitive function in MS (MACFIMS) in relapsing-remitting MS (RRMS) patients with very mild clinical disability to identify the primarily involved cognitive functions. Ninety-two consecutive RRMS patients with Expanded Disability Status Scale (EDSS) scores ≤ 2.5 and forty-two healthy controls (HC) were investigated. Our results show that 51.1% of MS patients have cognitive dysfunction compared to HC. An impairment of verbal and visual memory, working memory, and executive functions was found in the RRMS group. After subgrouping RRMS by EDSS, group 1 (EDSS ≤ 1.5) showed involvement of verbal memory and executive functions; moreover, group 2 (2 ≤ EDSS ≤ 2.5) patients were also impaired in information processing speed and visual memory. Our results show that utilizing a comprehensive neuropsychological assessment, approximately half of MS patients with very mild physical disability exhibit cognitive impairment with a primary involvement of prefrontal cognitive functions. Detecting impairment of executive functions at an early clinical stage of disease could be useful to promptly enroll MS patients in targeted rehabilitation.

Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis.

STUDY QUESTION: Do the benefits of ovarian tissue cryopreservation outweigh the risks for patients seeking to preserve fertility before gonadotoxic treatment in various indications? SUMMARY ANSWER: In >90% of the patients undergoing cryopreservation of ovarian tissue, oncological treatment was associated with a reduced ovarian reserve and in 30% of patients, premature ovarian failure (POF) occurred within 5 years. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation is an effective fertility preservation option, especially for pre-pubertal patients and patients who have a short time between diagnosis of a disease and gonadotoxic treatment. STUDY DESIGN, SETTING, DURATION: This study retrospectively analysed ovarian function and fertility recovery rates, as well as ovarian tissue characteristics, of patients who underwent ovarian tissue cryopreservation at Erasme Hospital between 1999 and 2011. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: A total of 225 patients referred from 15 Belgian oncological units underwent cryopreservation of ovarian tissue before gonadotoxic therapy for malignant or benign diseases. There were 28 patients (12.4%) who died during follow-up due to recurrence of disease. One severe adverse event occurred during anaesthesia for ovarian tissue collection, leading to the death of the patient. Ovarian function and fertility outcomes were available for 114 patients including 13 girls who were pre-pubertal at the time of the procedure. Eight patients had undergone ovarian tissue transplantation in order to restore their fertility after remission of the disease. MAIN RESULTS AND THE ROLE OF CHANCE: Breast cancer and haematological disease were the most frequent indications for ovarian tissue cryopreservation. Overall, 90% of post-pubertal patients were diagnosed with poor ovarian reserve (AMH < 0.5 ng/ml) after a mean of 50 months of follow-up (11-125 months), including 30% with POF (FSH > 40 IU/ml). Breast cancer patients had a lower rate of POF than did post-pubertal patients with haematological diseases (11 versus 34.5%, respectively), despite the older age (mean 31 versus 23.5 years old, respectively) of the breast cancer patients. Ovarian function returned in 71 post-pubertal patients without the need for grafts of cryopreserved tissue. Spontaneous pregnancies were reported for 33 of them, leading to 34 live births. Among the 13 pre-pubertal patients who reached pubertal age during the follow-up, 10 had POF. Eight patients received cryopreserved ovarian grafts to reverse POF and three of them have already become pregnant. LIMITATIONS, REASONS FOR CAUTION: This study is a retrospective analysis. The cohort was not compared with a control group of patients who did not undergo the procedure. WIDER IMPLICATIONS OF THE FINDINGS: After careful evaluation of the surgical risks, ovarian tissue cryopreservation can be proposed as an efficient option to preserve the fertility of children and young adults facing gonadotoxic therapies. However, alternative procedures such as oocyte or embryo cryopreservation should be considered as first options especially for older patients or if there is high risk of neoplastic cells within the ovaries. STUDY FUNDING/COMPETING INTEREST: This study was supported by the Télévie, FNRS-FRSM and Fondation Belge contre le cancer. There are no competing interests to report.

Sensorimotor Cortex Reorganization in Alzheimer's Disease and Metal Dysfunction: A MEG Study.

Objective. To verify whether systemic biometals dysfunctions affect neurotransmission in living Alzheimer's disease (AD) patients. Methods. We performed a case-control study using magnetoencephalography to detect sensorimotor fields of AD patients, at rest and during median nerve stimulation. We analyzed position and amount of neurons synchronously activated by the stimulation in both hemispheres to investigate the capability of the primary somatosensory cortex to reorganize its circuitry disrupted by the disease. We also assessed systemic levels of copper, ceruloplasmin, non-Cp copper (i.e., copper not bound to ceruloplasmin), peroxides, transferrin, and total antioxidant capacity. Results. Patients' sensorimotor generators appeared spatially shifted, despite no change of latency and strength, while spontaneous activity sources appeared unchanged. Neuronal reorganization was greater in moderately ill patients, while delta activity increased in severe patients. Non-Cp copper was the only biological variable appearing to be associated with patient sensorimotor transmission. Conclusions. Our data strengthen the notion that non-Cp copper, not copper in general, affects neuronal activity in AD. Significance. High plasticity in the disease early stages in regions controlling more commonly used body parts strengthens the notion that physical and cognitive activities are protective factors against progression of dementia.

Multiple approaches for individualized fertility protective therapy in cancer patients.

In the last decade, fertility preservation has risen as a major field of interest, creating new interactions between oncologists and gynecologists. Various options, such as cryopreservation of ovarian tissue, have been developed and are currently routinely proposed in many centers. However, many of the options remain experimental and should be offered to patients only after adequate counseling. This paper addresses the efficiency and the potential of the different fertility preservation approaches.

Longitudinal prognostic value of serum "free" copper in patients with Alzheimer disease.

BACKGROUND: Serum copper not bound to ceruloplasmin ("free") appears slightly elevated in patients with Alzheimer disease (AD). We explored whether a deregulation of the free copper pool can predict AD clinical worsening. METHODS: We assessed levels of copper, iron, zinc, transferrin, ceruloplasmin, peroxides, total antioxidant capacity, free copper, and apolipoprotein E genotype in 81 patients with mild or moderate AD, mean age 74.4, SD = 7.4 years, clinically followed up after 1 year. The association among biologic variables under study and Mini-Mental State Examination (MMSE) (primary outcome), activities of daily living (ADL), and instrumental activities of daily living (IADL) (secondary outcomes) performed at study entry and after 1 year were analyzed by multiple regression. RESULTS: Free copper predicted the annual change in MMSE, adjusted for the baseline MMSE by means of a linear regression model: it raised the explained variance from 2.4% (with only sex, age, and education) to 8.5% (p = 0.026). When the annual change in MMSE was divided into < 3 or > or = 3 points, free copper was the only predictor of a more severe decline (predicted probability of MMSE worsening 23%: odds ratio = 1.23; 95% confidence interval = 1.03-1.47; p = 0.022). Hyperlipidemic patients with higher levels of free copper seemed more prone to worse cognitive impairment. Free copper at baseline correlated with the ADL and IADL clinical scales scores at 1 year. CONCLUSIONS: These results show an association between copper deregulation and unfavorable evolution of cognitive function in Alzheimer disease. Further research is needed to establish whether copper is an independent risk factor for cognitive decline.

Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau.

OBJECTIVE: To assess whether serum copper in Alzheimer disease (AD) correlates with cognitive scores, beta-amyloid, and other CSF markers of neurodegeneration. METHODS: The authors studied copper, ceruloplasmin, total peroxide, and antioxidants levels (TRAP) in serum; beta-amyloid in plasma; and copper, beta-amyloid, h-tau, and P-tau in the CSF of 28 patients with AD and 25 healthy controls, in relation to clinical status. RESULTS: Serum copper (p < 0.0001), peroxides (p = 0.002), a copper fraction unexplained by ceruloplasmin (p < 0.0001), and CSF h-tau (p = 0.001) were increased in AD, whereas serum TRAP (p = 0.03) and CSF beta-amyloid were decreased (p < 0.0001). Plasma beta-amyloid increased with age in healthy controls (r = 0.6; p = 0.05). CSF markers of AD correlated with serum copper variables. CSF copper was partially dependent on the serum copper fraction unexplained by ceruloplasmin (t = 2.2, p = 0.04). CSF beta-amyloid seemed to be related to serum copper (r = -0.46; p = 0.002). Mini-Mental Status Examination scores correlated positively with beta-amyloid (r = 0.46, p = 0.002) and inversely with copper unexplained by ceruloplasmin (r = -0.45, p = 0.003). CONCLUSIONS: The authors' results confirm the existence of changes in copper component distribution, particularly the copper fraction unexplained by ceruloplasmin and support the hypothesis of a beta-amyloid and copper connection in Alzheimer disease.

[Exposure to traffic noise and effects on attention]. / Effetti sull'attenzione per esposizione a rumore da traffico urbano.

This study was aimed to evaluate if workers exposed to environmental stressors, including the urban traffic noise, might show significant differences compared to a control group in neuro-psychological and emotional profile as well as neurophysiological functions. In particular if these differences could be evidenced by the application of the "oddball paradigm" for event related potential P300 component. The study consisted of the following examinations: (1) exposed workers vs. controls under the odd-ball paradigm and the Stroop test in baseline condition; (2) amplitude and latency ofP300 (in baseline condition and after administration of acute urban traffic noise and Stroop test). The research was carried on a sample of 81 volunteers: 39 workers exposed to environmental stressors and 42 controls. The phonometric measurements showed mean levels of noise due urban traffic like 74 dBAeq. In baseline condition significative differences in exposed workers vs. control were found in Raven's Matrices PM 38 (p = 0.002) and Arithmetic reasoning from WAIS-R (p = 0.0024). Attention capacities as measured by Digit Span Forward and Visual Search, emotional functioning as measured by state- and trait-anxiety test and mood profile were not different in the two groups. Either in baseline condition or after acute stimuli no significant changes were found in two groups concerning the odd-ball paradigm. Exposed workers showed a higher execution time at Stroop test compared to controls (p = 0.047). No differences were found in the number of errors at the Stroop test. Before the acute stimulus, P300 amplitude was significant higher in the exposed workers than in controls (p = 0.002) while the latency was not different between two groups. Both noise (p = 0.001) and Stroop test (p = 0.002) stimulation increased the P300 latency of the whole sample, without significant differences between exposed workers and controls. A significative decrease of P300 amplitude due noise both in the exposed workers (p = 0.001) and in controls (p = 0.012) was found, without significant difference between the two groups. These results are interpreted as follows: (1) there are chronic effects on cognitive functioning in the exposed group vs. controls in baseline condition, like showed by significant differences in Raven PM38 and WAIS-R; (2) the exposed workers have a smaller cognitive flexibility, as shown by the Stroop test results; (3) in baseline condition the greater P300 amplitude in exposed workers reflect a greater division of attentive resources vs. controls, probably linked to the chronic stimulation by environmental stressors, especially noise, to which these workers are exposed; (4) the effects on P300 latency and amplitude can document the physiological response both in the exposed and not exposed to the acute stimulus and that the lack of significative differences in P300 latency and amplitude may be due to adaptative response to acute stimuli in exposed too. Our results allow us to consider that in workers exposed to urban stressor, such as noise, there are effects on cognitive functioning, especially on attention, without auditory damages. The valuation of P300 might represent a valid diagnostic instrument to evaluate the effects on cognitive functions especially on attention, in workers chronically and acutely exposed to urban stressors.

Excess of serum copper not related to ceruloplasmin in Alzheimer disease.

OBJECTIVE: To assess the role of serum copper in relation to ceruloplasmin and other peripheral markers of inflammation in Alzheimer disease (AD). METHODS: The authors studied serum levels of copper, ceruloplasmin, and transferrin, as well as total peroxides, antioxidants, and other peripheral markers of inflammation in 47 patients with AD, 24 patients with vascular dementia (VaD), and 44 healthy controls. Biochemical variables were related to the patients' and controls' clinical status. RESULTS: The authors found that copper (p < 0.001), peroxides (p = 0.026), and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in patients with AD, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in the serum of AD patients, but not of VaD or normal controls, of a large pool of non-ceruloplasmin-bound copper. CONCLUSIONS: Changes in the distribution of the serum copper components, consisting of an increase of a copper fraction not explained by ceruloplasmin, seem to be characteristic of Alzheimer disease and may be implicated in the pathogenesis of the disease.

d-penicillamine reduces serum oxidative stress in Alzheimer's disease patients.

BACKGROUND: Several lines of evidence address the emerging role for copper in Alzheimer's disease (AD) for sustaining oxidative mechanisms. Studies indicate that peripheral markers of oxidative stress in AD patients could be informative about the pathophysiology of this brain condition. Here, we present a pilot study examining the efficacy of the copper-chelating agent d-penicillamine in reducing oxidative stress in AD patients. DESIGN: Serum levels of copper sampled in AD patients and healthy controls indicate a copper homeostasis imbalance in AD. On this basis, 34 AD patients were enrolled in a 6-month, double-blind, placebo-controlled trial with the copper d-penicillamine-chelating agent. Nine patients for each group completed the trial. Oxidative stress, trace metals and clinical parameters were evaluated. RESULTS: At the start of the study (t0) total peroxides and copper serum content of AD patients were higher (P < 0.0001, P < 0.0001, respectively) and antioxidants were lower (P < 0.05) than in healthy controls. Copper and peroxides were correlated in the AD population (Pearson's r = 0.61, P < 0.001). After treatment with d-penicillamine, the extent of oxidative stress (P < 0.05) was decreased, but no difference was observed in the rate of cognitive decline. CONCLUSION: Data from this pilot study suggest that copper could play a role in the production of peroxides in AD, and that d-penicillamine has an effect in reducing oxidative damage, however, results are still inconclusive in terms of drug efficacy on the clinical progression of AD. Studies with larger cohorts are needed to elucidate the real effectiveness of d-penicillamine treatment in AD.

Signaling pathway of nitric oxide-induced acrosome reaction in human spermatozoa.

Nitric oxide (NO) has been recently shown to modulate in vitro motility, viability, the acrosome reaction (AR), and metabolism of spermatozoa in various mammalian species, but the mechanism or mechanisms through which it influences sperm functions has not been clarified. In human capacitated spermatozoa, both the intracellular cGMP level and the percentage of AR-positive cells were significantly increased after 4 h of incubation with the NO donor, sodium nitroprusside (SNP). SNP-induced AR was significantly reduced in the presence of the soluble guanylate cyclase (sGC) inhibitors, LY83583 and ODQ; this block was bypassed by adding 8-bromo-cGMP, a cell-permeating cGMP analogue, to the incubation medium. Finally, Rp-8-Br-cGMPS and Rp-8-pCPT-cGMPS, two inhibitors of the cGMP-dependent protein kinases (PKGs), inhibited the SNP-induced AR. Furthermore, SNP-induced AR did not occur in Ca2+ -free medium or in the presence of the protein kinase C (PKC) inhibitor, calphostin C. This study suggests that the AR-inducing effect of exogenous NO on capacitated human spermatozoa is accomplished via stimulation of an NO-sensitive sGC, cGMP synthesis, and PKG activation. In this effect the activation of PKC is also involved, and the presence of extracellular Ca2+ is required.

Viagra for temporary erectile dysfunction during treatments with assisted reproductive technologies.

During treatments with assisted reproductive technologies (ART), some men may have difficulties in producing spermatozoa on demand at the time of insemination, either for intrauterine insemination (IUI) or for in-vitro fertilization (IVF). This situation imposes tremendous stress on the couple and may cause cancellation of the treatment. Here we describe, for the first time, the use of sildenafil citrate (ViagraTM) for temporary erectile dysfunction in couples undergoing ART. The first case was a man who could not produce spermatozoa for the first IVF treatment after an exhausting trial for 12 h, despite the fact that he never had problems in providing sperm samples during previous IUI cycles. Using Viagra enabled him to provide spermatozoa, but the delay in oocyte insemination resulted in no embryonic development. This prompted us to be more alert to this option and to suggest the use of Viagra to men who had a history of erectile dysfunction during previous ART cycles. In these cases, the use of Viagra was planned in advance and it successfully solved any unpredictable erectile dysfunction on the day of insemination. Such cases emphasize the need to think in advance of this potential use of Viagra during ART.

Observations on surgical anatomy for rectal cancer surgery.

BACKGROUND/AIMS: The investigators studied the surgical anatomy of the main structures involved in the mobilization of the rectum (Denonvilliers' fascia, mesorectum, middle rectal artery, superior and inferior hypogastric plexuses). METHODOLOGY: The study was carried out on 20 cadavers (17 unembalmed and 3 embalmed). To study Denonvilliers' fascia, ten embryos and fetuses (11 mm to 80 mm CRL) were also examined. RESULTS: Denonvilliers' fascia originates from the fusion of the primary pouch of Douglas. The two leaves making up this structure are easily separated. The mesorectum surrounds the rectum on three sides; it is easily separated from the presacral fascia and its connective tissue is bordered by a thin membrane. The middle rectal artery varies in appearance rate, origin, size, distribution and anastomosis. It runs under the lateral ligament and also sends branches to the genital apparatus. Of the two hypogastric plexuses, the inferior is the most difficult one to identify. Its superior branches extend to the rectum, and the inferior ones to the genital apparatus. Because the anterior part contains the parasympathetic nerves and the middle rectal artery, this region is at major risk during surgical dissection. CONCLUSIONS: A sound understanding of the surgical anatomy of the rectum enables the surgeon to perform a more correct and reasonable procedure in terms of both the extent of surgical treatment and the preservation of important anatomical structures.

[Venous ulcers of the lower limbs in the aged. Indications for bandages]. / Le ulcere venose degli arti inferiori negli anziani. Indicazioni al bendaggio.

BACKGROUND: There are many causes of ulcer of the lower limb. In the elderly, venous ulcers and arteriosclerosis often coexist; for this reason pressure bandages might be contraindicated for the risk of precipitating a potentially critical arterial flow. In this work, the conditions which allow a safely treatment with pressure bandage in the elderly are evaluated. MATERIAL AND METHOD: Eleven self-sufficient elderly, with venous ulcerations to one leg only, and ankle pressure/omeral pressure between 0.92 and 0.86 were treated with elastic bandaging of the leg. RESULTS: All patients completed the treatment, with healing of the ulcer obtained in 3-8 months time. So far none of them relapsed. CONCLUSIONS: In the elderly, in selected cases, when Pc/Po > 0.86, pressure bandages can be safely applied to heal the ulcer, without running the risk of endangering arterial circulation.

[Cervical mechanical anastomosis by transhiatal approach with a new circular stapler, Ehicon ECS 21]. / Anastomosi meccanica cervicale per via transiatale con una nuova suturatrice circolare, Ethicon ECS 21.

Authors describe a new technique of mechanical cervical anastomosis using a new, particularly long, stapler, the ECS Ethicon. Mechanical anastomosis at neck level is difficult to perform with stapler now in use, so manual anastomosis is usually preferred. However the percentage of leakage is relatively high. The possibility of doing a mechanical anastomosis introducing the stapler through the pylorus is described. At the moment cases are too few to give a full evaluation of this new technique, but certainly it could be a valid alternative, safer and quicker, to manual anastomosis.

[Acute suppurative thyroiditis. Report of a case and review of the literature]. / La tiroidite acuta suppurativa. Presentazione di un caso e revisione della letteratura.

The authors present a case of acute suppurative thyroiditis complicated by acute dyspnoea with asphyxia in a patient of geriatric age. In this patient there were present possible infectious focuses like multiple dental abscesses and contamination of the urinary tract. Histological examination highlighted a focus of papillifer carcinoma in the context of the gland. We have a review of the literature on this observation and description. Acute suppurative thyroiditis is currently a pathology of rare observation. This rarity is due, apart from the availability of antibiotic therapy, to an intrinsic resistance of the thyroid gland to contamination. In most cases we are talking of bacterial infections, but in immunodepressed subjects fungal etiology is noteworthy. The infection could arise from primitive focuses present in any bodily district with propagation to the thyroid across different ways. Expressive is the anamnestic observation of preexisting thyroid dysfunction. After an attentive evaluation of the clinical findings, usually characteristic, it is important to complete the diagnostic course with some instrumental investigations. In particular cervical sonography, possibly associated with agobiopsy is fundamental. Initially therapy is medical (basically antibiotic). The surgical resolution foresees the drainage of the purulent abscess or the thyroidectomy if it is associated with a struma.