Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Abnormal spinal interactions from hand afferents to forearm muscles in writer's cramp.

OBJECTIVE: Spinal reflexes from hand to wrist muscles were investigated in writer's cramp. METHODS: Stimulus-triggered rectified EMG averages after ulnar nerve and cutaneous stimulation, in wrist flexors and extensors during tonic contraction, were compared in 18 controls and 19 patients. RESULTS: On the patient dystonic side, ulnar-induced EMG suppression was decreased in wrist extensors, and facilitation in wrist flexors modified dependent on the dystonic wrist posture during writing. No change was found on the patient non-dystonic side. Cutaneous stimulation increased wrist flexor EMG on both sides of the patients with normal wrist posture during writing, but had no effect in controls and patients with abnormal wrist posture. CONCLUSIONS: Comparison between cutaneous and mixed nerve stimuli suggests that spindle afferents from intrinsic hand muscles may mediate patients' ulnar-induced EMG modulations. Abnormal proprioceptive control was only observed on dystonic side, while bilateral unusual cutaneous control was found in patients. Changes in spinal transmission were partly related to the dystonic wrist posture, suggesting that systems involved in sensory processing can be differentially altered in writer's cramp. SIGNIFICANCE: Changes in spinal transmission, probably related to peripheral and/or cortical inputs, might either take part in primary or adaptive mechanisms underlying writer's cramp.     

Systematic review of methods to diagnose infection in foot ulcers in diabetes.

AIM: To undertake a systematic review of the diagnostic performance of clinical examination, sample acquisition and sample analysis in infected foot ulcers in diabetes. METHODS: Nineteen electronic databases plus other sources were searched. To be included, studies had to fulfil the following criteria: (i) compare a method of clinical assessment, sample collection or sample analysis with a reference standard; (ii) recruit diabetic individuals with foot ulcers; (ii) present 2 x 2 diagnostic data. Studies were critically appraised using a 12-item checklist. RESULTS: Three eligible studies were identified, one each on clinical examination, sample collection and sample analysis. For all three, study groups were heterogeneous with respect to wound type and a small proportion of participants had foot ulcers due to diabetes. No studies identified an optimum reference standard. Other methodological problems included non-blind interpretation of tests and the time lag between index and reference tests. Individual signs or symptoms of infection did not prove to be useful tests when assessed against punch biopsy as the reference standard. The wound swab did not perform well when assessed against tissue biopsy. Semiquantitative analysis of wound swab might be a useful alternative to quantitative analysis. The limitations of these findings and their impact on recommendations from relevant clinical guidelines are discussed. CONCLUSION: Given the importance of this topic, it is surprising that only three eligible studies were identified. It was not possible to describe the optimal methods of diagnosing infection in diabetic patients with foot ulceration from the evidence identified in this systematic review.     

Contribution of hypoxia-measuring molecular imaging techniques to radiotherapy planning and treatment

Hypoxia is related to poor prognosis because it is associated to chemo-and radioresistance. During recent years the evolution of imaging methods like PET/CT and MRI has meant the appearance of new perspectives with direct implications in radiation therapy. We discuss previous experiences in staging, planning and in the follow-up process with these techniques for measuring tumour hypoxia.     

Assay of cytomegalovirus susceptibility to ganciclovir in renal and heart transplant recipients

Ganciclovir (GCV) prophylaxis or pre-emptive therapy significantly reduce the rate of cytomegalovirus (CMV) disease and viremia, but increase the potential for emergence of ganciclovir-resistant CMV strains. The inhibitor concentration at 50% (IC(50)) of GCV from 156 CMV isolates from 59 renal or heart transplant recipients was calculated by means of a rapid phenotypic susceptibility assay. Twenty-seven strains were from 14 patients undergoing GCV therapy. The IC(50) was higher in patients under the prophylaxis regimen. One CMV strain, from a heart transplant recipient, became GCV-resistant after 1 month of therapy (IC(50)=13.7 micromol/l). These data, together with clinical and virological markers, suggested that a switch to foscarnet was necessary, and good evolution was observed. Thus, assay of CMV susceptibility to GCV could be helpful in clinical management.     

Characteristics of pollinosis caused by Betula in patients from Ourense (Galicia, Spain).

A retrospective study was performed to describe the features of the pollinosis caused by Betula in the area of Ourense, Spain. The pollen count was carried out with a Lanzoni volumetric Hirts spore trap (1993-2000). The Betula pollen represented 5% over the annual total (annual mean quantity: 965 grains). It was present in the air from March to mid-May. The highest peaks took place in April (maximum values mean: 131 grains/m3). The medical records of 222 patients (mean age 25.66 years) diagnosed with pollinosis (1998-2000), who lived at less than 30 km. from the spore trap, were reviewed. In all of them, the skin-prick test (SPT) was carried out with pollen allergens. The percentages of positive SPT were: Lolium perenne, 91.89% (16.6% monosensitized); Plantago lanceolata, 71.17% (1.26% monosensitized); Betula alba, 41.89% (10.75% monosensitized); Platanus hybrida, 34.95%; Olea europea, 10.36%; and Parietaria judaica, 6.3%. The mean age of Betula monosensitized patients was 44.7 years. The majority of them had symptoms in March-April, 40% had asthma symptoms, 80% had lived in Central Europe, and 30% of them presented an oral allergy syndrome to fruits. There were 41.93% of the patients with positive SPT to Betula pollen who had asthma symptoms, in comparison with 23.25% of the patients with negative SPT to Betula (p = 0.0034). There were 20.28% of the patients with positive SPT to Betula pollen, who had lived in Central Europe, in comparison with 4.27% of the patients with negative SPT to Betula, p: 0.00049. The relative risk of sensitization was 2.05. CONCLUSIONS: Betula pollen was the second cause of clinical pollinosis in our patients, after grass, being responsible of the symptoms in the early spring, in a small number of the patients in their forties. The presence of asthma was higher in Betula sensitized patients, and the residence in Central Europe was a sensitization risk factor.     

First radiological description of Morgagni's hydatid. Laparoscopic confirmation

The authors explain the clinical case of a female patient suffering from secondary sterility; she was submitted, among other test, to the H.S.G. in order to study the possibility of a among other tests, to the H.S.G. in order to study the possibility of a cervical failure. The radiological findings obtained of Morgagni's Hydatis, not described previously in literature and their laparoscopic confirmation justify, we believe, its publication.     

Epirubicin: clinical toxicity during the phase II program in endometrial and cervical cancer.

We have evaluated the clinical toxicity of Epirubicin 80 mg/m2 i.v., every 3 weeks in 58 patients with FIGO III-IV endometrial adenocarcinoma or squamous uterine cervix carcinoma. The median age of the whole group was 59 years (37-77); 37 patients were previously treated with radiotherapy and two with cisplatin based chemotherapy. The median KI at entry was 80. A total of 308 courses of chemotherapy were administered with a median of 5 per patient. Overall toxicity data shows that this dose level is associated with mild haematological toxicity with only two cases having grade 3 (WHO) leukopenia. Nine patients suffered emesis in spite of prophylactic therapy and were classified as grade 3. One case presented grade four diarrhoea but the relation with the antineoplastic treatment was uncertain. One woman with hepatic dysfunction at entry had grade 3 leukopenia, developed pneumonia and died. The median total cumulative dose of EPI was 360 mg/m2 (160-880) with 19 cases exposed to cumulative doses higher than 550 mg/m2. Congestive heart failure was not observed. Our data confirm the safety of EPI at these dose levels and suggest the possibility of developing new trials with higher doses of this anthracycline analog.