Diagnosis and treatment of primary thyroid lymphoma from a surgical perspective: a multi-institutional study.

PURPOSE: Surgery of primary thyroid lymphoma (PTL) has been mostly limited to diagnostic work-up. This study aimed to further study its potential role. METHODS: This was a retrospective study from a multi-institutional registry of PTL patients. Clinical, diagnostic work-up (fine needle aspiration, FNA; core needle biopsy, CoreNB), contribution of surgery (open surgical biopsy, OpenSB; thyroidectomy), histology subtype, and outcome data were evaluated. RESULTS: Some 54 patients were studied. Diagnostic work-up included FNA in 47 patients, CoreNB in 11, and OpenSB in 21. CoreNB yielded the best sensitivity (90.9%). Thyroidectomy was performed in 14 patients with other diagnosis (incidental PTL), in 4 for diagnosis and in 4 for elective treatment of PTL. Incidental PTL was associated with not performed FNA nor CoreNB (OR 52.5; P = 0.008), mucosa-associated lymphoid tissue (MALT) subtype (OR 24.3; P = 0.012), and Hashimoto's thyroiditis (OR 11.1; P = 0.032). Lymphoma-related death (10 cases) mostly occurred within the first year after diagnosis and was associated with diffuse large B-cell (DLBC) subtype (OR 10.3; P = 0.018) and older patients (OR 1.08 for every 1-year increase; P = 0.010). There was a trend towards lower mortality rate in patients receiving thyroidectomy (2/22 versus 8/32, P = 0.172). CONCLUSION: Incidental PTL accounts for most of thyroid surgery cases and are associated with incomplete diagnostic work-up, Hashimoto's thyroiditis and MALT subtype. CoreNB appears to be the best tool for diagnosis. Most of PTL deaths occurred during the first year after diagnosis and mostly related to systemic treatment. Age and DLBC subtype are poor prognostic factors.

Structural and histological differences between connective tissue grafts harvested from the lateral palatal mucosa or from the tuberosity area.

Tuberosity grafts had a greater percentage of lamina propria and lower percentage of submucosa when compared to lateral palate grafts. OBJECTIVE: The study aims to understand the differences in the structural composition of soft tissue autografts harvested from the lateral palate or the tuberosity. MATERIAL AND METHODS: Patients were randomly allocated to receive autografts harvested either from palatal or tuberosity sites to augment horizontal volume deficiencies around single-tooth implants. Tissue biopsies were analyzed for histological and histo-morphometric analysis. Picro-sirius red stain was used to evaluate collagen 1 and 3. Also, immuno-histochemical analysis was performed against MMP1, MMP2, cytokeratin-10, cytokeratin-13, and lysine hydroxylase-2. RESULTS: Twenty specimens were harvested from 9 subjects in the lateral palate group (PG) and 11 subjects in the tuberosity group (TG). The percentage of lamina propria represented 51.08% in the PG group and 72.79% in the TG group, while the area of submucosa was minimal in the TG group representing 4.89% of the total sample vs 25.75% in the PG. The total area of COL-1 and 3 in the TG was 1.19 ± 0.57 and 0.72 ± 0.44 mm2, respectively, while in the PG, the corresponding values were 1.4 ± 0.7 and 1.04 ± 0.5 mm2. The immuno-histochemical analysis generally showed a higher expression of LLH-2, MMP2, CYT-10, and CYT-13 in the TG when compared with the PG. CONCLUSION: Tuberosity grafts had a greater percentage of lamina propria and lower percentage of submucosa. The collagen content in the lamina propria was similar for both groups while the immuno-histochemical profile showed differences in the antibody expression of the epithelial cells. CLINICAL RELEVANCE: Tuberosity grafts had more lamina propria and less submocusa, which may be beneficial for volume augmentation.

Optical coherence tomography applied to tests of skin care products in humans--a case study.

BACKGROUND/PURPOSE: When evaluating skin care products for human skin, quantitative test methods need to be simple, precise and reliable. Optical coherence tomography (OCT), provides high-resolution sectional images of translucent materials to a depth of a few millimeters, a technique usually applied to medical measurements in ophthalmology and dermatology. This study aimed to demonstrate the application of OCT as the main technique for monitoring changes in skin topography during tests of a wrinkle-reduction product in humans. METHODS: We used a commercial OCT apparatus to perform clinical examinations of skin roughness in treated and non-treated sites in the periorbital region of thirty human voluntaries who were using an anti-aging product commercially available: Natura Chronos® Flavonóides de Passiflora 45+ FPS15, from Natura Cosméticos, Brazil. Measurements were performed days 0, 7, 14 and 28 of treatment. Equipment and software allowed real-time recording of skin roughness parameters and wrinkle depths. RESULTS: The OCT measurements have allowed the monitoring of changes in skin roughness, which have shown reduction in treated sites around 10%. The obtained depth distributions also indicate reduction in the occurrence of wrinkles deeper than 170 µm. The verified results are consistent with those typically obtained after successful treatment with modern anti-aging products. CONCLUSION: By using the OCT technique, it was possible to quantify changes in skin roughness and in the distribution of depths of skin wrinkles, with adequate sensitivity. OCT imaging allows the direct visualization of the skin topography with resolution of micrometers, a reliable and interactive tool for clinical use. Therefore, for the first time, we demonstrated the use of OCT technique to verify the efficacy of cosmetic products in real time.

Detection of hotspots and rapid determination of methane emissions from landfills via a ground-surface method.

We present a method for the rapid determination of methane emissions from landfills based on atmospheric dispersion theory, which suggests that the methane concentration, at a small distance from the soil/atmosphere interface, is proportional to its flux. Thus, after suitable calibration, the determination of methane concentrations close to the ground allows for flux determination in a shorter time than with standard enclosure techniques. This concept was tested using a surface probe in direct contact with the ground. The probe extracts a continuous sample of the air at the probe/ground interface and transports it to a portable methane analyzer. It was observed that stable methane concentrations were measured 30 s after the probe was positioned at the measurement point. These concentrations correlated well with the fluxes measured by standard static chambers. The method was used to determine the fluxes at 217 points within a 90,000 m(2) landfill. These measurements facilitated mapping of the CH4 emissions and the localization of hotspots. We conclude that the method is simple, effective, and relatively quick, compared to existing standard methods.

Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival.

Voltage dependent anion channels (VDAC) in the outer mitochondrial membrane regulate the influx of metabolites that sustain mitochondrial metabolism and the efflux of ATP to the cytosol. Free tubulin and NADH close VDAC. The VDAC-binding small molecules X1 and SC18 modulate mitochondrial metabolism. X1 antagonizes the inhibitory effect of tubulin on VDAC. SC18 occupies an NADH-binding pocket in the inner wall of all VDAC isoforms. Here, we hypothesized that X1 and SC18 have a synergistic effect with sorafenib, regorafenib or lenvatinib to arrest proliferation and induce death in hepatocarcinoma cells. We used colony formation assays to determine cell proliferation, and a combination of calcein/propidium iodide, and trypan blue exclusion to assess cell death in the well differentiated Huh7 and the poorly differentiated SNU-449 cells. Synergism was assessed using the Chou-Talalay method. The inhibitory effect of X1, SC18, sorafenib, regorafenib and lenvatinib was concentration and time dependent. IC50s calculated from the inhibition of clonogenic capacity were lower than those determined from cell survival. At IC50s that inhibited cell proliferation, SC18 arrested cells in G0/G1. SC18 at 0.25-2 IC50s had a synergistic effect with sorafenib on clonogenic inhibition in Huh7 and SNU-449 cells, and with regorafenib or lenvatinib in SNU-449 cells. X1 or SC18 also had synergistic effects with sorafenib on promoting cell death at 0.5-2 IC50s for SC18 in Huh7 and SNU-449 cells. These results suggest that small molecules targeting VDAC represent a potential new class of drugs to treat liver cancer.

C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies.

BACKGROUND: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6(-/-)) mice. METHODS: C6(-/-) mice or the wild-type C3H/HeJ (C6(+/+)) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. RESULTS: Thrombus sizes were significantly larger in C6(+/+) treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6(+/+) mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6(-/-) mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6(+/+) counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6(-/-) mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6(+/+)) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-ß(2)glycoprotein I (aß(2)GPI) antibodies. CONCLUSIONS: These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.

Bilateral facial palsy with paresthesias, variant of Guillain-Barré syndrome following COVID-19 vaccine: A case series of 9 patients.

Several cases of Guillain-Barré Syndrome (GBS) associated with COVID-19 vaccination have been reported, including the rare subtype known as Bilateral Facial Palsy with paresthesias (BFP). To date, it is not known whether a causal relationship may exist between the two. We report 9 cases of BFP in patients vaccinated against COVID-19 in the previous month. Nerve conduction studies revealed demyelinating polyneuropathy in 4 patients, and 5 presented bilateral, focal facial nerve involvement, exclusively. Ganglioside antibody panel was positive in 4 patients (anti-GM1=2, anti-GD1a=1 and anti-sulfatide=1). Seven patients received intravenous immunoglobulin treatment, one plasma exchange, and one patient died from sudden cardiac arrest following arrhythmia before treatment could be administered. Rates of BFP following COVID-19 vaccination, did not differ from those reported in previous series. Epidemiological studies are essential to determine whether a causal relationship may exist between this rare form of GBS and COVID-19 vaccination.

News on initiation and elongation of transcription by RNA polymerase II.

Transcription by RNA polymerase II is a complex process that requires additional factors to initiate transcription at the promoters. New developments in the past year have furthered our understanding of the functions of the transcription factors and provided more insights into the mechanisms involved in the regulation of initiation and elongation of transcription. One of the most significant advances of the past year was the discovery of the involvement of the general transcription factor TFIIH in DNA excision repair. Surprisingly, studies aimed at identifying the kinase activity within TFIIH responsible for phosphorylating the carboxy-terminal domain of RNA polymerase II revealed it to be the MO15/Cdk7 kinase and its partner, cyclin H. These exciting observations suggest a paradigm for linking transcription, DNA excision repair and cell cycle progression through one pivotal factor.

Analysis of the presence of cell proliferation-related molecules in the Tgf-ß3 null mutant mouse palate reveals misexpression of EGF and Msx-1.

The Tgf-ß(3) null mutant mouse palate presents several cellular anomalies that lead to the appearance of cleft palate. One of them concerns the cell proliferation of both the palatal medial edge epithelium and mesenchyme. In this work, our aim was to determine whether there was any variation in the presence/distribution of several cell proliferation-related molecules that could be responsible for the cell proliferation defects observed in these palates. Our results showed no difference in the presence of EGF-R, PDGF-A, TGF-ß(2), Bmp-2, and Bmp-4, and differences were minimal for FGF-10 and Shh. However, the expression of EGF and Msx-1 changed substantially. The shift of the EGF protein expression was the one that most correlated with that of cell proliferation. This molecule is regulated by TGF-ß(3), and experiments blocking its activity in culture suggest that EGF misexpression in the Tgf-ß(3) null mutant mouse palate plays a role in the cell proliferation defect observed.

Time-dependent analysis of extra length of stay and mortality due to ventilator-associated pneumonia in intensive-care units of ten limited-resources countries: findings of the International Nosocomial Infection Control Consortium (INICC).

Ventilator-associated pneumonias (VAPs) are a worldwide problem that significantly increases patient morbidity, mortality, and length of stay (LoS), and their effects should be estimated to account for the timing of infection. The purpose of the study was to estimate extra LoS and mortality in an intensive-care unit (ICU) due to a VAP in a cohort of 69,248 admissions followed for 283,069 days in ICUs from 10 countries. Data were arranged according to the multi-state format. Extra LoS and increased risk of death were estimated independently in each country, and their results were combined using a random-effects meta-analysis. VAP prolonged LoS by an average of 2·03 days (95% CI 1·52-2·54 days), and increased the risk of death by 14% (95% CI 2-27). The increased risk of death due to VAP was explained by confounding with patient morbidity.

Fast acetone tissue processing of human organs provides tissue characteristics equal to conventional processing.

Routine preparation of paraffin embedded tissue for histopathological diagnosis, here termed conventional histological technique (CT), whether performed manually or using an automated system, requires approximately 12 h. We developed earlier a rapid acetone dehydration technique (AT) for processing biopsies of nervous tissue that meets requirements for preserving tissue morphology and staining properties, and reduces processing time to 3.3 h. We compared the morphology and staining properties of human organ biopsies including adrenal gland, liver, ovary, pancreas, prostate, testis and thyroid prepared using both AT and CT. Following fixation with 10% formaldehyde and processing by either AT or CT, sections were stained using routine and special staining, and immunohistochemical methods. We evaluated nuclear and cytoplasmic staining, staining intensity, sharpness of images and presence of artifacts such as cracking and folding. AT preserved the morphology and staining properties of the tissues as well as CT. Consequently, the rapid AT procedure is a promising alternative technique for tissue processing.

JNK activation and translocation to mitochondria mediates mitochondrial dysfunction and cell death induced by VDAC opening and sorafenib in hepatocarcinoma cells.

The multikinase inhibitor sorafenib, and opening of voltage dependent anion channels (VDAC) by the erastin-like compound X1 promotes oxidative stress and mitochondrial dysfunction in hepatocarcinoma cells. Here, we hypothesized that X1 and sorafenib induce mitochondrial dysfunction by increasing reactive oxygen species (ROS) formation and activating c-Jun N-terminal kinases (JNKs), leading to translocation of activated JNK to mitochondria. Both X1 and sorafenib increased production of ROS and activated JNK. X1 and sorafenib caused a drop in mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, after 60 min. Mitochondrial depolarization after X1 and sorafenib occurred in parallel with JNK activation, increased superoxide (O2•-) production, decreased basal and oligomycin sensitive respiration, and decreased maximal respiratory capacity. Increased production of O2•- after X1 or sorafenib was abrogated by JNK inhibition and antioxidants. S3QEL 2, a specific inhibitor of site IIIQo, at Complex III, prevented depolarization induced by X1. JNK inhibition by JNK inhibitors VIII and SP600125 also prevented mitochondrial depolarization. After X1, activated JNK translocated to mitochondria as assessed by proximity ligation assays. Tat-Sab KIM1, a peptide selectively preventing the binding of JNK to the outer mitochondrial membrane protein Sab, blocked the depolarization induced by X1 and sorafenib. X1 promoted cell death mostly by necroptosis that was partially prevented by JNK inhibition. These results indicate that JNK activation and translocation to mitochondria is a common mechanism of mitochondrial dysfunction induced by both VDAC opening and sorafenib.

Multiple myeloma-associated amyloidosis is an independent high-risk prognostic factor.

Several prognostic factors have been recognized in patients with multiple myeloma (MM). Among the most important are: the serum levels of beta2-microglobulin, albumin, and LDH; the labeling index; and an abnormal karyotype. Patients with amyloidosis (AL) have poor prognosis; however, little is known concerning the prognostic significance of AL associated to MM. In 201 consecutive patients with de novo MM, we performed a fat-pad biopsy needle aspiration (FPBNA) that was stained with Congo red. Sixty eight (34%) patients had AL and a poorer prognosis disease: lower performance status, presence of B symptoms, higher LDH and calcium values, and worse response to chemotherapy. Cox regression model for overall survival detected three variables having independent prognostic significance: the presence of AL (RR = 3.4, P < 0.004), serum albumin levels <3.5 g/dl (RR 3.2, p < 0.005), and patients not achieving complete remission or very good partial remission (RR 2.9, p < 0.02). In 28% of patients with de novo MM, FPBNA was useful to detect incidental amyloidosis. During follow-up, 69% of these patients had symptoms of AL. Excluding 16 patients with obvious symptoms of AL at diagnosis, overall survival was worse in patients who developed later symptoms of AL. MM-associated AL represents a poorer prognosis disease even in the absence of symptoms at diagnosis, and this specific association may be considered as an independent high-risk prognostic factor. The routine study of periumbilical fat-pad tissue should be mandatory in all patients with MM.

Morphology-diet relationships in four killifishes (Teleostei, Cyprinodontidae, Orestias) from Lake Titicaca.

This study explores the relationship between morphology and diet in four Andean killifishes (Orestias) from Lake Titicaca that are known to differ in habitat use. Species that fed preferentially on amphipods (Orestias albus) or molluscs (Orestias luteus) separated in multivariate space from other species that feed on cladocera and algae (Orestias agassii and Orestias jussiei). Generally, specimens feeding on cladocera were characterized by a short, blunt nose with a small mouth; whereas, specimens feeding on amphipods exhibited a long snout with a large mouth. Specimens including molluscs in their diet tended to have a larger posterior part of the head and the larger opercles than others; while the occurrence of substratum in gut content was generally related to a short but deep head. The present analysis suggests that the littoral O. jussiei has an intermediate phenotype and diet between the pelagic (O. agassii) and benthic (O. albus and O. luteus) species. Results suggest that resource partitioning was occurring and that several morphological traits relate to characteristics of the diet, and it is inferred that the benthic, the pelagic and the littoral zones in the lake host different prey communities constituting distinct adaptive landscapes.

Performance of butanol separation from ABE mixtures by pervaporation using silicone-coated ionic liquid gel membranes.

This work aims at the separation of n-butanol from aqueous solutions by means of pervaporation using membranes based on gelled ionic liquids (IL). These membranes were mechanically stabilized with a double silicone coating using two polydimethylsiloxane (PDMS) films. The first step of the membrane preparation considered the formation of a gelled ionic liquid layer, which was formed using two different imidazolium-based ionic liquids: [omim][Tf2N] and [bmim][Tf2N], and two different phosphonium-based ionic liquids: [P6,6,6,14][Tf2N] and [P6,6,6,14][DCA]. The gelation procedure was carried out on a porous paper support using a low molecular weight gelator. The membranes obtained from this method were tested in pervaporation assays to separate butanol from model ABE (Acetone-Butanol-Ethanol) fermentation solutions. These assays were done in an experimental setup especially built for this purpose. The pervaporation performance of these ionic liquid-based membranes was compared to that obtained with a single PDMS layer membrane. From these experimental results, butanol/water selectivity for [P6,6,6,14][Tf2N]-based membranes reached a value equal to 892, which is 150 times higher than the value obtained for a single PDMS layer membrane. Simultaneously, for the same IL, the transmembrane fluxes (kg h-1 m-2) of butanol and water were 37% and 99.6% lower than the values obtained using a single PDMS layer membrane, respectively. The hydrophobic character of the selected ionic liquid and its relatively high values for the transport parameters can explain this experimental response.

mTORC1 Prevents Epithelial Damage During Inflammation and Inhibits Colitis-Associated Colorectal Cancer Development.

Epithelial cells lining the intestinal mucosa constitute a selective-semipermeable barrier acting as first line of defense in the organism. The number of those cells remains constant during physiological conditions, but disruption of epithelial cell homeostasis has been observed in several pathologies. During colitis, epithelial cell proliferation decreases and cell death augments. The mechanism responsible for these changes remains unknown. Here, we show that the pro-inflammatory cytokine IFNγ contributes to the inhibition of epithelial cell proliferation in intestinal epithelial cells (IECs) by inducing the activation of mTORC1. Activation of mTORC1 in response to IFNγ was detected in IECs present along the crypt axis and in colonic macrophages. mTORC1 inhibition enhances cell proliferation, increases DNA damage in IEC. In macrophages, mTORC1 inhibition strongly reduces the expression of pro-inflammatory markers. As a consequence, mTORC1 inhibition exacerbated disease activity, increased mucosal damage, enhanced ulceration, augmented cell infiltration, decreased survival and stimulated tumor formation in a model of colorectal cancer CRC associated to colitis. Thus, our findings suggest that mTORC1 signaling downstream of IFNγ prevents epithelial DNA damage and cancer development during colitis.

Effect of butyl benzyl phthalate on early postnatal mortality in rats.

ABSTRACT The present study was undertaken to examine early postnatal mortality in rat pups following exposure to butyl benzyl phthalate (BBP) during pregnancy. Seventeen pregnant rats were given 750 mg/kg bw/day of BBP by oral gavage on gestation days 13, 14, and 15, and the volume of each dose was adjusted to 5 ml/kg body weight. Four rats were given olive oil only and served as control. Natural birth was allowed to take place. One hundred and eighty-three pups were born to the experimental rats and 46 pups to the control group. Close observation of the newborn pups during the first 3 h of life revealed that all the pups in both the control and experimental groups were born alive. Only six pups from the experimental group (3.2%) died within this time period. These and four control pups were fixed and decalcified. Histological examination of the thoracic cavity of the newborn rats in both groups revealed no differences in the position or size of any of the heart chambers, ductus arteriosus, or great vessels. However, the lungs of the six experimental pups that died showed athelectasia and bronchi dilatation. The results therefore suggest that exposure to BBP of rats during pregnancy does not produce significant postnatal mortality in their offspring.

[Prognostic factors in localised and regionally advanced renal cell carcinoma]. / Factores pronósticos en cácer renal localizado y localmente avanzado.

In the last 10 years, several factors have been identified to confer a prognostic effect on renal cancer outcome. Pathologic stage, nuclear and histologic grade are the most frecuent studied and the most important at this moment. We evaluated those factors and introduced some others, looking for new parameters that could be useful. 96 cases of non methastatic renal cell cancer were included in our study. We found that as was mentioned by other authors pathologic and Furhman stage are the stronger prognostic factors but the presence of palpable tumor, pain and weight lost had significance too.

Stress-induced germ cell apoptosis by a p53 independent pathway in Caenorhabditis elegans.

In Caenorhabditis elegans, several distinct apoptosis pathways have been characterized in the germline. The physiological pathway is though to eliminate excess germ cells during oogenesis to maintain gonad homeostasis and it is activated by unknown mechanisms. The DNA damage-induced germ cell apoptosis occurs in response to genotoxic agents and involves the proteins EGL-1 and CED-13, and the DNA damage response protein p53. Germ cell apoptosis can also be induced in response to pathogen infection through an EGL-1 dependent pathway. To gain insight into the mechanism and functions of germ cell apoptosis, we investigated whether and how other forms of stress induce this cell death. We found that oxidative, osmotic, heat shock and starvation stresses induce germ cell apoptosis through a p53 and EGL-1 independent pathway. We also learned that the MAPK kinases MEK-1 and SEK-1, and the p53 antagonist protein ABL-1, are essential for stress-induced germ cell apoptosis. We conclude that in C. elegans responses to various stresses that do not involve genotoxicity include an increase in germ cell apoptosis through the physiological pathway.