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.     

Experimental axonopathy induced by immunization with campylobacter jejuni lipopolysaccharide from a patient with guillain‐barré syndrome

Campylobacter jejuni (C. jejunj) infection is the most common antecedent in the axonal variant of Guillain‐Barré syndrome (GBS). Antibodies against nerve gangliosides found in GBS patients recognize cross‐reactive epitopes in the lipopolysaccharide (LPS) of C. jejuni. This led to the molecular mimicry hypothesis of GBS. We immunized eleven rabbits with a LPS extracted from HS:19 C. jejuni strain isolated from a patient with GBS and complete Freund's adjuvant (CFA)(group I). In a second experiment we immunized seven rabbits with LPS, CFA and keyhole limpet hemocyanin (KLH)(group II). All group I rabbits developed high titers of anti‐LPS, anti‐GM1, anti‐GD1b antibodies and lower titers of anti‐GD1a. One rabbit, 50 days after initial inoculation, showed tremor and weakness. All rabbits of group II developed high titres of antiganglioside antibodies and six animals showed weakness 59–113 days after initial inoculation. Two rabbits died. Pathology showed mild to moderate, tendentially grouped, axonal degeneration in sciatic nerves of four out of five animals. Control rabbits of group I (immunized with CFA only) did not develop antibodies, controls of group II (immunized with CFA + KLH) developed low titers of IgG anti‐GM1. None developed neurological signs or showed axonal degeneration. C. jejuni LPS is a potent B‐cell stimulator capable to induce a strong antiganglioside response in rabbits. However, to induce the neuropathy is crucial to employ KLH, a glycoprotein known to stimulate both humoral and cellular responses. This animal model reproduces the pathogenetic process hypothesized in axonal GBS with antiganglioside antibodies post C. jejuni infection.     

Disorders of perfusion of the anterior segment of the eye

Background: We have investigated the vascular perfusion of a wide variety of conditions of the anterior segment using fluorescein angiography.
Methods: The conditions were classified and findings reported according to the system set out below. Patients underwent full ocular examination. Fluorescein angiography of the anterior segment was carried out when indicated to investigate iris atrophy and neovascularisation. Specular microscopy of the corneal endothelium was used to detect changes in this tissue.
Results: The hypoperfusion was variable in degree and accompanied by varying degrees of iris hypoplasia and atrophy with neovascularisation. The degree of neovascularisation depended upon its rapidity of development, the pre-existing state of vascular perfusion and the underlying pathological condition.
Conclusions: Hypoperfusion with resultant ischaemia and neovascularisation is common in conditions of the anterior segment. An understanding of the changes is valuable in treating many conditions affecting the anterior segment. The changes observed may also occur elsewhere in the physical system and may be a significant part of the ageing process, either as scattered, disparate processes or as part of a general disease process.     

Postoperative radiation therapy in the management of lung cancer

Postoperative radiation therapy for lung cancer is still controversial. In a 9-year period, 69 patients with non-oat-cell carcinoma of the lung (16% stage I, 26% stage II, and 58% stage III) received such therapy. The radiation dose was less than 5,000 cGy in 42 patients, 5,000-5,900 cGy in 16, and 6,000 cGy or more in 11; follow-up ranged from 24 to 64 months. Actuarial survival at 2 and 4 years was 50% and 16%, respectively, for squamous cell carcinoma, and 40% and 26% for adenocarcinoma. The 5-year survival for stages I, II, and III cancer was 29%, 17%, and 19%, respectively. Histologic findings and type of surgery did not affect survival, but the radiation dose apparently did. The 3-year survival for patients who received less than 6,000 cGy was 35%, compared with 73% for patients who received higher doses. In eight patients, treatment failed within the irradiated volume: all had received doses of less than 6,000 cGy, and the volume in three was judged to be inadequate.     

A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor.

PURPOSE: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. EXPERIMENTAL DESIGN: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received > or =3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m(2)/day. RESULTS: Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting > or =7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a > or =50% reduction in CA125 levels. CONCLUSIONS: The maximum tolerated dose of this schedule was 130 mg/m(2). The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.     

Readily releasable pool of synaptic vesicles measured at single synaptic contacts

To distinguish between different models of vesicular release in brain synapses, it is necessary to know the number of vesicles of transmitter that can be released immediately at individual synapses by a high-calcium stimulus, the readily releasable pool (RRP). We used direct stimulation by calcium uncaging at identified, single-site inhibitory synapses to investigate the statistics of vesicular release and the size of the RRP. Vesicular release, detected as quantal responses in the postsynaptic neuron, showed an unexpected stochastic variation in the number of quanta from stimulus to stimulus at high intracellular calcium, with a mean of 1.9 per stimulus and a maximum of three or four. The results provide direct measurement of the RRP at single synaptic sites. They are consistent with models in which release proceeds from a small number of vesicle docking sites with an average occupancy around 0.7.