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Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3’UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, −148a or −152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3’UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

Chronic inflammatory demyelinating polyradiculoneuropathy is a clinically heterogeneous group of immune- mediated peripheral neuropathies that share neurophysiological manifesta-tions of demyelination and albuminocytologic dissociation. There are typical and atypical variants of this disease, some associated with antibodies against proteins of the node of Ranvier, such as neurofascin- 155. We present the case of a 38- year- old male who presented with an eight- month history of par-esthesia and progressive weakness of four limbs associated with diplopia and dysphagia. The patient was conscious, with symmetric flaccid quadriparesis of distal predominance, hyp-otrophy in the dorsum and palm of both hands, generalized areflexia, postural low frequency, and high amplitude tremor in upper limbs of left predominance, appendicular dysmetria, dys-diadochokinesia, ophthalmoparesis to dextroversion in the right eye, absent gag reflex, ataxic gait with an increased base of support and positive Romberg's sign. Cerebrospinal fluid showed albuminocytologic dissociation, and electromyography was com-patible with primarily demyelinating sensory- motor polyneuropathy. Due to clinical suspicion, we requested anti- neurofascin- 155 antibodies, which tested positive. The patient was treated with methylprednisolone at a dose of one gram per day for five days, followed by one milligram per kilogram for three months of prednisone, with progressive de-crease, which improved diplopia and dysphagia, with no effect on limb strength and even worsening of function. For this reason, treatment with rituximab was started in doses of two grams, presenting a substantial improvement in distal muscle strength, tremor, gait stability, coordination, and functionality measured with the modified Rankin scale.

ABSTRACT Amnestic mild cognitive impairment (aMCI) is a subtle alteration in cognitive function that does not affect day-to-day activities and can precede Alzheimer's dementia. An increase in the prevalence of both these conditions is expected given the growing elderly population and recognizing risk factors can help reduce the burden. Objective: the aim of this study was to determine the frequency and associated factors of aMCI in senior citizen clubs (SCC) at four districts with different socioeconomic status in Lima, Peru. Methods: we applied Petersen's criteria to determine the presence of the condition in an interview which included the use of the Memory Alteration Test (M@T) and the Pfeffer Functional Activity Questionnaire (PFAQ). Results: sixty-three out of 352 (17.9%) participants had aMCI. Factors associated with this condition were older age, fewer years of education at marriage whereas being from the SCC La Molina (district with highest socioeconomic status and resources for activities for the elderly) were associated with not having aMCI. There was no difference for sex, body mass index or history of hypertension. Conclusion: this predementia stage is frequent and usually undetected in urban Lima. Tools such as the M@T could help general practitioners detect this condition before its progression to dementia.

Summary: The RNA N6-methyladenosine (m6A) methylation is installed by the METTL3-METTL14 methyltransferase complex. This modification has critical regulatory roles in various biological processes. Here, we report that deletion of Mettl14 dramatically reduces mRNA m6A methylation in developing B cells and severely blocks B cell development in mice. Deletion of Mettl14 impairs interleukin-7 (IL-7)-induced pro-B cell proliferation and the large-pre-B-to-small-pre-B transition and causes dramatic abnormalities in gene expression programs important for B cell development. Suppression of a group of transcripts by cytoplasmic m6A reader YTHDF2 is critical to the IL-7-induced pro-B cell proliferation. In contrast, the block in the large-pre-B-to-small-pre-B transition is independent of YTHDF1 or YTHDF2 but is associated with a failure to properly upregulate key transcription factors regulating this transition. Our data highlight the important regulatory roles of the RNA m6A methylation and its reader proteins in early B cell development.

Morphea is an inflammatory, sclerosing skin condition of unknown cause that generally does not present systemic manifestations. A 66-year-old Caucasian Peruvian female patient, who was previously a nurse, presented with a prior history of 4 years of indurated dermal plaque lesions with constant progression. Diagnosis of morphea was made by clinical examination and skin biopsy. The patient started topical treatment with methoxsalen and phototherapy. When no improvement was seen, it was switched to methotrexate. However, due to changes in liver profile, phototherapy was restarted with progressive clinical improvement. It is essential to differentiate all morphea subtypes for proper management.

Background: The use of the cardiovascular polypill, a fixed-dose combination treatment, is conceived to improve adherence. However, randomized controlled trials (RCTs) may overestimate it. Studies focusing on cerebrovascular disease and real-life efficacy compared with conventional treatment are lacking. Methods: This is a retrospective, hospital-based cohort study of acute ischaemic stroke patients who were prescribed a polypill (aspirin 100 mg, atorvastatin 20/40 mg, ramipril 2.5/5/10 mg) versus conventional treatment (aspirin 100 mg and other blood pressure/lipid-lowering agents) in secondary prevention (2017–2018). Clinical records were reviewed 90 days after discharge for stroke recurrence, vascular risk factor control, and safety. Adherence was assessed using the adapted Morisky-Green scale. Results: A total of 104 patients were included (61% male; mean age 69.7 ± 13.9 years); 54 were treated with the polypill and 50 with conventional treatment. No baseline differences in clinical or demographic variables were detected. No recurrences were registered in the polypill group, compared to 1 recurrence in the conventional treatment group. A significant reduction of systolic blood pressure (SBP) was achieved in the polypill group (12.1 mm Hg) compared to the conventional treatment group (6.8 mm Hg) (p = 0.002). No significant differences were detected regarding the goal of LDL cholesterol ≤70 mg/dL (41 vs. 44%). The adverse events were mild and their frequency was similar in the two groups (9 vs. 2%, ns). Adherence was similarly good in the two groups (93 vs. 88%, ns). Polypill group adherence was similar to that reported in a previous meta-analysis of RCTs (93 vs. 84%, ns). Conclusion: In our experience, the cardiovascular polypill achieved a higher reduction in SBP levels and was well tolerated. Adherence was similar to that found in the previous literature, which is remarkable given the real-life setting of our study.

Background: Urinary symptoms are common, disabling and generally unresponsive to treatment in Parkinson´s disease (PD). Safinamide is approved as an add-on therapy to levodopa to improve fluctuations. Methods: Retrospective analysis of electronic records of nondemented PD patients seen consecutively in a Movement Disorders Unit (November 2018–February 2019). All were assessed with Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms-Urinary subscale (SCOPA-AUT-U) by the attending neurologist, and a month afterwards by an independent researcher blinded to treatment and clinical records in a routine clinical practice setting. Clinical variables were compared among patients who were prescribed safinamide (SA+) for the treatment of motor fluctuations and those with different treatment regimes (SA−). Results: From 169 patients screened initially, 54 were excluded due to severe incontinence, absence of urinary symptoms or previous safinamide treatment. Thirty-five patients were included in SA+ and 79 in SA−. Both groups were comparable in terms of clinical variables, except in basal urinary symptoms, with more severity in the SA+ group. In the follow-up assessment, total SCOPA-AUT-U, as well as urgency, incontinence, frequency and nocturia subscales improved significantly in the SA+ group, while the SA− group remained unchanged. Conclusions: Safinamide could be helpful in the improvement of urinary symptoms in PD.