Ivermectin is a nonselective inhibitor of mammalian P-type ATPases

Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na⁺ , K⁺-ATPase and H⁺/K⁺-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na⁺, K⁺-ATPase in order to appreciate its putative selectivity towards the α₁ isoform (kidney) and the α₂/α₃ isoforms (brain), and in an H⁺/K⁺-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC₅₀ values (6–17 µM). With respect to the inhibition of the Na⁺, K⁺-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K⁺ and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.     

The Relationship Between Body Composition and Response to Neoadjuvant Chemotherapy in Women with Operable Breast Cancer

Introduction.

Overweight women diagnosed with breast cancer have greater recurrence and mortality risks. Recent studies in advanced cancer showed that the combination of sarcopenia and an overweight or obese body mass index (BMI) is associated with poor clinical outcomes.

Objectives.

To compare pathological complete response (pCR) cases with controls and evaluate associations among a pCR, survival outcome, and sarcopenia as well as the combination of both sarcopenia and a BMI ≥25 kg/m².

Methods.

Sixty-seven breast cancer patients with a pCR to neoadjuvant chemotherapy (NC) were matched with controls who did not have a pCR to NC. Patients were matched by age, Black''s nuclear grading system, clinical cancer stage, and estrogen receptor and progesterone receptor status. Body composition was analyzed using computed tomography images taken prior to NC.

Results.

BMI was associated with pCR. Among normal weight patients, the pCR rate was higher in sarcopenic patients and the progression-free survival (PFS) interval was significantly longer than in overweight or obese BMI patients. The death hazard was 2% higher for each unit higher skeletal muscle index and 0.6% higher for each unit higher visceral adipose tissue.

Conclusions.

Overweight patients treated with NC had a lower pCR rate and shorter PFS time. Among patients with a normal BMI, the pCR rate was better in sarcopenic patients. More research is required to evaluate the negative impact of sarcopenic obesity on prognosis and the contributors to better response rates in operable, normal weight breast cancer patients with sarcopenia.     

Amyloid-<Emphasis Type="Italic">like</Emphasis> fibrils are not detected in non-small cell lung cancer tissue samples

Some proteins, canonically not associated with amyloid diseases, can aggregate into amyloid-like fibrils under special conditions. Our group hypothesized that stressful cancer microenvironment might induce the formation of insoluble deposits of p53 mutant protein. A cohort of 28 non-small cell lung cancer (NSCLC) patients was used to test the aforementioned hypothesis. Tumor specimens were assessed for TP53 mutations using DNA sequencing and for amyloid formation by Congo red staining. TP53 mutations were present in 57% of patients, whereas no amyloid deposits were detected in tissue sections under polarized light microscopy. Mutant p53 proteins are not associated with the appearance of amyloid-like fibrils in NSCLC samples, and DNA sequencing remains the standard method to detect such abnormality.     

High voltage electrical stimulation as an alternative treatment for chronic ulcers of the lower limbs

High voltage electrical stimulation has been recommended as a means of accelerating the wound healing process. The effects of high voltage electrical stimulation were evaluated in the treatment of three volunteers with chronic ulcers of the lower limbs. After fifteen weeks of treatment, a reduction was found in the area of all the ulcers, suggesting that high voltage electric stimulation is an effective therapeutic option for chronic ulcers.     

Polysaccharide fractions of Caesalpinia ferrea pods: potential anti-inflammatory usage

Ethnopharmacological relevance

Caesalpinia ferrea (Caesalpinioideae), known as pau-ferro or juca, has been used in the traditional medicine in North and Northeast of Brazil in inflammatory disorder, among others. Thus, experimental evaluation of the anti-inflammatory activity of extracts and fraction polysaccharides of Caesalpinia ferrea pods, and correlation with its anti-inflammatory activity and popular use is important.

Materials and methods

Total polysaccharides (TPL) were applied to ion exchange chromatography and eluted stepwise. Paw edema was induced s.c. by λ-carrageenan, dextran, histamine, serotonin, compound 48/80, bradykinin, prostaglandin E₂ (PGE₂) or l-arginine and analyzed by plethysmometry and protein leakage by spectrophotometry. Peritonitis was induced i.p. by carrageenan or N-formyl-methionyl-leucyl-phenylalanine (fMLP) and analyzed 4 h later for leukocyte migration and protein leakage. Animals were treated i.v. with TPL or polysaccharide fractions (0.01, 0.1, 1 mg/kg) 30 min before stimuli in both models. Toxicity (variation of body/organ mass and hematological/biochemical parameters) was evaluated after the seven-day treatment with the most active polysaccharide fraction (1 mg/kg; i.v.).

Results

Chromatography of TPL (2.8% yield) provided three major polysaccharide fractions (FI, FII, FIII). At 1 mg/kg, TPL inhibited the paw edema induced by carrageenan (60%) and FIII (fraction presenting high carbohydrate and low protein content) inhibited the inflammatory parameters in the paw edema induced by the following stimuli: carrageenan (70%), dextran (53%), histamine (65%), serotonin (62%), bradykinin (60%), PGE₂ (63%), nitric oxide (61%) and compound 48/80 (36%). Additionally, FIII at 1 mg/kg inhibited the carrageenan-induced edema in animals with intact mast cells, but only the late phase of those with degranulated mast cells elicited by compound 48/80. Moreover, FIII inhibited cell migration and protein leakage in the model of peritonitis elicited by carrageenan (88%) and fMLP (64%), being well tolerated by animals.

Conclusions

Extracts and polysaccharide fractions of Caesalpinia ferrea pods exhibit potent anti-inflammatory activity via negative modulation of histamine, serotonin, bradykinin, PGE₂ and NO released in the carrageenan-induced edema, showing involvement of mast cells. FIII could be interfering not only in the vascular, but also in cellular inflammatory events, revealing to be an important active component of traditionally prepared remedies used to treat inflammatory states.     

Cognitive evoked potentials and central auditory processing in children with reading and writing disorders

Learning disorders are often magnified by auditory processing disorders (APD).ObjectiveThis paper aims to verify whether individuals with reading and writing disorders and P300 latencies above the average also present altered Staggered Spondaic Word (SSW) and speech-in-noise test results suggestive of APD.Materials and MethodsThis is a cross-sectional cohort study. Twenty-one individuals with reading and writing disorders aged between 7 and 14 years were enrolled.ResultsAll subjects had normal findings on ENT examination, audiological tests, and brainstem auditory evoked potentials. The average P300 latency (334,25 ms) of all patients was picked as a cutoff point to divide the subjects into two groups: group A with latencies above 335 ms, and group B with latencies below 335 ms. Individuals in group A underwent SSW and speech-in-noise testing.ConclusionAltered results in the SSW and speech-in-noise tests suggestive of APD were found in the group of individuals with reading and writing disorders with P300 latencies above 335 ms.     

Preliminary evaluation of the endovascular treatment of intracranial aneurysms with detachable coils in vigil patients

Endovascular treatment of intracranial aneurysms with coil embolization became the most important therapeutic option with better morbidity and mortality rates and quality of life. Following immobility, patients are treated with general anaesthesia. OBJECTIVE: To test viability of endovascular treatment on wake patients. METHOD: Considering clinical symptoms, psychological characteristics and aneurysmal morphology, four patients with five intracranial aneurysms were selected. RESULTS: Four among five cases were completed with this technique. Patient 1 was partially treated after 75 minutes presenting vesical stress. Patient 2 presented subarachnoid hemorrhage after aneurysmal re-rupture, and the procedure was completed under general anaesthesia. The other three patients presented no intercurrences during the treatment. CONCLUSION: Endovascular treatment on wake patients with intracranial aneurysm can be an alternative to a selected group of patients.     

Mutation in filamin A causes periventricular heterotopia, developmental regression, and West syndrome in males

PURPOSE: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome. METHODS: The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing. RESULTS: Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrhythmia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene. CONCLUSIONS: The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.