A systematic review of immune checkpoint inhibitor-related neurological adverse events and association with anti-neuronal autoantibodies.

Introduction: Immune checkpoint inhibitors (ICI) therapy has led to a paradigm shift in cancer drug development and in the clinical evaluation of approaches to combination cancer treatment. Dysregulation of the immune system by ICI therapy may also elicit autoimmune phenomena and consequently manifest clinically as immune-related adverse events (irAEs) including neurological irAEs. Areas Covered: The purpose of this review is to explore the role of autoantibodies in the diagnosis and prediction of neurological irAEs and to evaluate their pathogenicity. We searched Pubmed and Embase for neurological irAEs and associated autoantibodies and found 28 patients with central and peripheral neurological irAEs. Of these patients, up to 40% had encephalitis, 34.4% with myasthenia gravis and 22% of patients with peripheral neuropathy and Guillain-Barre Syndrome had autoantibodies. Expert Opinion: Overall, our survey suggested a causal relationship between neurological irAEs and autoantibodies. Detection of autoantibodies may help to diagnose neurological irAEs and inform their clinical management.

The safety and efficacy of immune checkpoint inhibitors in patients with advanced cancers and pre-existing chronic viral infections (Hepatitis B/C, HIV): A review of the available evidence.

The treatment paradigm of several cancers has dramatically changed in recent years with the introduction of immunotherapy. Most oncology trials involving immune checkpoint inhibitors (ICIPs) have routinely excluded patients with HIV infection and chronic viral hepatitis B (HBV) and C (HCV) due to concerns about viral reactivation, fears of increased toxicity, and the potential lack of efficacy in these patient subgroups. However, with current antiviral therapies, HIV and HBV infections have become chronic diseases and HCV infections can even be cured. Broadening cancer trial eligibility criteria in order to include cancer patients with chronic viral infections can maximize the ecological validity of study results and the ability to understand the ICPIs' benefit-risk profile in patients with these comorbidities. In this review, we examined the evidence on the efficacy and safety of using ICPIs in cancer patients with concurrent chronic viral infections.

Diastereoselective synthesis of novel heterocyclic scaffolds through tandem Petasis 3-component/intramolecular Diels-Alder and ROM-RCM reactions.

A high-yielding, stereoselective and extraordinarily complexity-generating Petasis 3-component/intramolecular Diels-Alder reaction has been developed. In combination with ROM-RCM, rapid access to complex sp3-rich heterocyclic scaffolds amenable to subsequent functionalization and library synthesis is provided.

Solvent-Controlled Chemoselectivity in the Photolytic Release of Hydroxamic Acids and Carboxamides from Solid Support.

The synthetic utility and theoretical basis of a photolabile hydroxylamine-linker are presented. The developed protocols enable the efficient synthesis and chemoselective photolytic release of either hydroxamates or carboxamides from solid support. The bidetachable mode of the linker unit is uniquely dependent on the solvent. Hydroxamic acids are obtained by performing photolysis in protic solvents, whereas photolysis in aprotic solvents enables the selective release of carboxamides.

Neuro-ophthalmologic manifestations of cholangiocarcinoma: a case series.

PurposeTo describe the neuro-ophthalmologic findings of cholangiocarcinoma.MethodsWe report a retrospective chart review of cholangiocarcinoma patients presenting at two tertiary care centers in the Texas Medical Center.ResultsFive patients with neuro-ophthalmologic symptoms related to cholangiocarcinoma were identified. One patient presented with diplopia due to metastasis to the left medial rectus muscle, two patients had metastasis to the occipital lobe resulting in homonymous hemianopsia, one patient had involvement of the clivus resulting in sixth nerve palsy, and one presented with a hypercoagulable state-related stroke causing a homonymous hemianopsia and visual hallucinations.ConclusionsNeuro-ophthalmic manifestations of cholangiocarcinoma depend upon both mechanism and localization. We report five cases of cholangiocarcinoma with neuro-ophthalmologic findings. To our knowledge, this is the largest such series reported in the English language ophthalmic literature.

Osteocalcin, under-carboxylated osteocalcin and osteopontin are not associated with gestational diabetes mellitus but are inversely associated with leptin in non-diabetic women.

OBJECTIVE: To measure serum osteocalcin (OC), under-carboxylated osteocalcin (ucOC), osteopontin (OPN), and leptin in pregnant women with gestational diabetes mellitus (GDM) and in healthy pregnant women during pregnancy and after birth and relate these markers to glucose metabolism. METHODS: This was a prospective study including 60 women with GDM and 60 subjects with normal gestation who were evaluated at gestational week 30 and 6 weeks postpartum. Serum OC, ucOC, OPN, leptin, insulin and insulin resistance were evaluated during the study. RESULTS: Bone biomarkers and leptin were similar between GDM and normal pregnancy. After delivery, OC, ucOC and OPN increased in both groups, while leptin decreased only in healthy controls. Bone markers did not correlate with insulin and insulin resistance in the two groups, but leptin was positively correlated with insulin and insulin resistance and negatively correlated with bone biomarkers only in healthy women. Furthermore, the women who developed diabetes postpartum had lower levels of OC than women with normal glucose tolerance. CONCLUSION: GDM is not associated with OC, ucOC, OPN, and leptin and does not correlate with insulin resistance. At postpartum, women who develop diabetes have lower osteocalcin concentrations. Leptin correlates with insulin resistance and bone biomarkers in non-diabetic women.

Inhibición in vitro del veneno de Bothrops asper con extractos etanólicos de Brownea ariza B. (Caesalpiniaceae) / In vitro inhibition of Bothrops asper venom by ethanol extracts from Brownea ariza B. (Caesalpiniaceae)

En Colombia, cerca del 90% de los accidentes ofídicos son ocasionados por serpientes del género Bothrops, cuyos venenos provocan alteraciones locales y sistémicas, como edema, anticoagulación, hemorragia y mionecrosis. El suero antiofídico es el único tratamiento efectivo, pero su limitada acción local y escasa disponibilidad en zonas geográficas aisladas hace necesaria la búsqueda y validación de alternativas terapéuticas que actúen como recurso y disminuyan el porcentaje de secuelas de estos accidentes. Recientes estudios han reportado acción inhibitoria del extracto etanólico de Brownea rosademonte (Caesalpiniaceae) sobre algunos efectos locales de estos venenos. Así, en el presente estudio in vitro se evaluó la capacidad inhibitoria de extractos etanólicos de hojas y corteza de Brownea ariza sobre las actividades proteolítica, fosfolipasa A2 y coagulante del veneno de B. asper; esta última según el efecto de coagulación in vitro, se relaciona con anticoagulación observada in vivo. Los resultados mostraron que los extractos de corteza inhiben la acción de fosfolipasas A2 (93,2 ± 0,4%), prolongan el tiempo de coagulación (más de 10 min), e inhiben la actividad proteolítica, aunque ésta última con menores efectos que el extracto foliar (77 ± 0,6% y 93,8 ± 0,6% respectivamente).

In Colombia, about 90% of snakebites are caused by Bothrops snakes, whose venoms cause in vivo, local andsystemic disturbances, such as edema, myonecrosis, blood-clotting disorders and hemorrhage. Antivenom is the only effective treatment to manage these poisonings, but its limited action at local level and little availability in geographically isolated areas makes necessary the validation and search for therapeutic alternatives acting as an immediate resource to reduce the percent of sequels caused in these snakebites. Recent studies have reported the inhibitory action of the Brownea rosademonte (Caesalpiniaceae) extract against some local effects produced by these snakes. Therefore, in this in vitro research the inhibitory ability of the ethanol extract of leaves and bark from Brownea ariza was evaluated on proteolytic, phospholipaseA2 and coagulant activities of B. asper venom, which is related with anticoagulation observed in vivo. The results showed that bark extracts inhibit phospholipase A2 activity (93,2 ± 0,4%), extend the clotting time of plasma (more than 10 minutes) and inhibit the proteolytic activity, although the latter showed lesser effects than those observed with leaves extract (77 ± 0,6% and 93,8 ± 0,6%, respectively).

Differential mobility separation of ions using a rectangular asymmetric waveform.

The performance of a planar differential mobility spectrometer (DMS) is investigated when operated in air at ambient pressure and driven by a rectangular asymmetric waveform, limited to frequencies of <1.2 MHz and voltage pulse amplitudes of <1 kV with steep rise times of the order of approximately 15 ns. Independent control of frequency, voltage pulse amplitude, and duty cycle allow for characterizing the DMS in terms of transmission, resolution and separation. The tradeoff between sensitivity and resolution and the effect of duty cycle on instrument performance are demonstrated experimentally. The dependence of ion mobility on the magnitude of the electric field determines the displacement of ions measured by the DC compensation voltage as a function of the duty cycle. Optimum values for the duty cycle exist for the separation of A- and C-type ions, while, B-type ions exhibit a more complex behavior. An analytical expression for describing the effect of duty cycle on the separation of the ions, determined by variations in the compensation voltage, is developed and compared to experimental results obtained in air below 75 Td using estimated alpha parameters for a set of ketones. In this context, errors associated with the calculation of alpha parameters using polynomials of even powers are highlighted.

[Inflammatory markers associated with asthma and body mass index]. / Marcadores inflamatorios relacionados con asma e índice de masa corporal.

BACKGROUND: Obesity can be considered as a chronic inflammatory process, which is associated with many different diseases. Its relationship with asthma has been poorly evaluated. Obesity induces the production of leptin and cytokines in asthmatic patients, and it is associated with worse disease severity. OBJECTIVE: To determine the relationship between obesity (according to body mass index, BMI), asthma severity and leptin, IL-1 beta, and IL-4 concentrations in blood. PATIENTS AND METHOD: 37 adult allergic asthmatic patients where involved in the study, each of them with different clinical disease stages, evaluated by GINA international diagnosis and treatment criteria 2004. BMI was determined and peripheral blood samples were taken to determine IL-1 beta, IL-4, and leptin concentrations. RESULTS: BMI and asthma severity shown a moderate correlation (r = 0.528), according to Colton's criteria. BMI and leptin correlation levels were r = 0.425 with p < 0.025. Plasma leptin levels and asthma severity shown a significant difference in the groups composed of intermittent mild asthma and persistent severe asthma (p < 0.02). There was a non significant correlation between BMI and asthma severity with IL-4, and finally there was no correlation with IL-1 beta. This results suggest that asthmatic patients with a BMI3 30 have higher plasma leptin concentrations and worse disease severity, mainly in women.

Could the homologous sequence of anti-inflammatory pentapeptide (MLIF) produced by Entamoeba histolytica in the N protein of rabies virus affect the inflammatory process?

Amebiasis and rabies are public health problems, and they have in common a poor inflammatory effect in the target organs that they affect. In the GenBank, it was found that the anti-inflammatory peptide monocyte locomotion inhibitory factor (MLIF) produced by Entamoeba histolytica homologates 80%, with a fragment of the N protein of the rabies virus. We speculated if the N protein could contribute to the scant inflammatory reaction produced by rabies virus in central nervous system. The N protein was obtained and studied in vitro and in vivo. The N protein, as MLIF, inhibited the respiratory burst in human mononuclear phagocytes (43%, p<0.05), but in contrast to MLIF, it increased chemotaxis and it did not significantly inhibit delayed hypersensitivity skin reaction to 1-chloro-2-4-dinitrobenzene in guinea pigs. Therefore, the full peptide sequence has to be present or it has to be cleaved-free from the large recombinant N protein molecule (55 kDa) to become active.

Diversidad de arañas (Arachnida: Araneae) en el Parque Nacional Natural Isla Gorgona, pacífico colombiano / x

Para poder establecer una aproximación a la araneofauna de la Isla Gorgona, ubicada en el Océano Pacifico a 60 km de la costa SO de Colombia, tomamos muestras durante el mes de julio del 2003, empleando métodos de captura directa (manual), barridos con red entomológica (sweeping), agitación de follaje (beating) y trampas de caída (pitfall). Los muestreos se realizaron en jornadas diurnas y nocturnas en cuatro niveles de estratificación vertical, los cuales fueron llevados a cabo en seis tipos de habitat contrastantes de acuerdo con su grado de intervención. Fueron tomadas 65 muestras, colectados 1398 individuos agrupados en 247 morfoespecies, pertenecientes a 34 familias. Los datos fueron analizados con 7 estimadores de riqueza: ACE, ICE, Chao 1, Chao 2, Jack-knife de primer orden, Jack-knife de segundo orden y Bootstrap. Los índices de riqueza variaron entre sí, con Bootstrap obteniendo el valor más bajo (302) e ICE obteniendo el más alto (504). La curva de acumulación de especies nunca llegó a una asíntota, demostrando que el muestreo fue insuficiente. El método de captura más efectivo fue la colecta manual, ya que con este método se registraron 33 de las 34 familias encontradas. El índice de Bray-Curtis indicó que la similitud entre los hábitat es muy pequeña. A pesar de comprender un área relativamente pequeña, la Isla Gorgona aloja una significativa diversidad de arañas, lo cual se refleja por que en cuanto a familias se pudo detectar el equivalente al 71 por ciento de las reportadas para el país.

In order to establish an approximation to the araneofauna in the Isla Gorgona, located in the Pacific Ocean at approximately 60 km from the SW coast of Colombia, we took samples in July 2003, using various methods such as capturing the spiders manually, pitfall traps, sweeping with an entomological net, and beating foliage. The samples were taken during the day and night, at four different levels of vertical stratification, in six different habitat which had different states of succession. Sixty-five samples were taken; 1398 spiders were collected and placed in 247 morphospecies, which belong to 34 families. The data were analyzed with 7 species richness estimators: ACE, ICE, Chao 1, Chao 2, first order Jack-knife, second-order Jack-knife, and Bootstrap. The richness estimators varied between each other, with bootstrap having the lowest value (302) and ICE having the highest (504). The failure of the observed species accumulation curve to find an asymptote, showed that more sampling is needed. The most effective method applied was manual collection, with which 33 of the 34 families were collected. The Bray-Curtis similarity index showed that similarity between habitat is very small. Even though Gorgona has a small extension, it presents a high diversity of spiders, which is reflected in the number of families, that is equivalent to 71 percent of those found in the whole country.

[A comparison of moxifloxacin and amoxicillin in the treatment of community-acquired pneumonia in Latin America: results of a multicenter clinical trial]. / Moxifloxacino frente a amoxicilina en el tratamiento de la neumonía adquirida en la comunidad en América Latina. Resultados de un ensayo clínico multicéntrico.

Since community-acquired pneumonia (CAP) is a common disease with a high morbidity rate, it is important to obtain information concerning its etiology and susceptibility to antibiotics across different geographic areas. This study presents data obtained in 5 Latin American counties in the course of an international clinical trial that evaluated the efficacy and safety of treatment with either moxifloxacin or amoxicillin administered for 10 days to patients suspected of having CAP caused by a pneumococcal infection. Details are given of the pathogens identified, the patterns of sensitivity to antibiotics observed, and the clinical and microbiological results obtained.A total of 84 patients were studied, of whom 70 (83.3%) were evaluated at the end of the trial to determine the efficacy and safety of the treatment received. Gram-positive bacteria were found in samples from 29 patients (80.5%). The pathogen was Streptococcus pneumoniae in 28 of those cases (77.7%). Gram-negative bacteria were found in 7 patients (19.4%), the most common being Haemophilus influenzae in 3 patients (8.3%). The presence of atypical microorganisms was detected in 18 of the 70 patients (25%), mainly Mycobacterium pneumoniae (n=11), and in 6 cases (8.5%) the infection was mixed. Ten strains of S. pneumoniae (35.7%) were shown to be susceptible to penicillin, 2 (7.1%) were highly resistant, and 16 (57.1%) showed moderate resistance. The clinical success rate at the final visit after treatment was 94.1% for moxifloxacin and 91.7% for amoxicillin. The results of this trial demonstrate a high prevalence of S. pneumoniae with reduced susceptibility to penicillin in patients with CAP in Latin America. It also revealed a high incidence of atypical pathogens and mixed infection in 8.6% of patients. This information should be taken into account when establishing protocols for empirical treatment of CAP in Latin America.

The monocyte locomotion inhibitory factor produced by Entamoeba histolytica inhibits induced nitric oxide production in human leukocytes.

The monocyte locomotion inhibitory factor, an anti-inflammatory pentapeptide produced by Entamoeba histolytica, inhibits the in vitro production of nitric oxide induced by cytokines (INF-gamma, TNF-alpha) or PMA in human leukocytes. This can be added to the other previously reported functional effects of this factor, such as the inhibition of monocyte locomotion and the synthesis of reactive oxygen intermediates in both monocytes and neutrophils. The decreased nitric oxide production may interfere with the killing of amebas by neutrophils in the early invasive stages of amebiasis, when oxidative mechanisms are used [reactive oxygen and nitrogen intermediates either individually or synergistically via peroxynitrite (ONOO(-))], and in the advanced stages, when both non-oxidative and oxidative (including nitric oxide) mechanisms are employed by macrophages. Diminished nitric oxide production by leukocytes may also contribute to the paucity of late inflammatory components in amebic abscess of the liver and other amebic lesions.

Influence of admixed carboxymethylcellulose on release of 4-aminopyridine from hydroxypropyl methylcellulose matrix tablets.

Among different technological variables that influence drug release from hydrophilic matrices, the use of mixtures of polymers represents a potential way of achieving a variety of release properties. Tablets of the model drug 4-aminopyridine with hydroxypropyl methylcellulose were prepared with different proportions of polymer content as well as with different proportions of admixed carboxymethylcellulose (CMC) in the range up to 35% (based on the total polymer content). The matrices release behavior was examined by absorption of samples at 261 nm (USP 23 apparatus 2, paddle, at 50 rpm) using 0.1 N HCl and 0.2 M phosphate buffer as dissolution media. Increasing proportions of CMC in the polymer mixture lead to decreasing dissolution rates, in a range of k=0.094-0.036 for HCl and k=0.044--0.009 for phosphate buffer. The release mechanism in HCl is predominantly controlled by diffusion (n=0.46--0.62), while in phosphate buffer it is controlled, as reported previously, by diffusion/relaxation (n=0.58--0.85) and near zero order release at high CMC concentrations. Approximately doubling the total polymer content gives lower release rates for HCl in the range k=0.038--0.015 and for phosphate buffer k=0.0099--0.0034. Near zero order release is observed only at pH 7.4 (n=0.79--0.96). Decreasing release constant values show a logarithmic relationship with increasing values of the exponent n. This indicates that zero-order release occurs with sufficiently reduced release rate.

A novel anti-inflammatory oligopeptide produced by Entamoeba histolytica.

The monocyte locomotion inhibitory factor (MLIF), a heat-stable oligopeptide found in the supernatant fluid of Entamoeba histolytica axenic cultures was isolated by ultra-filtration, gel-sieve chromatography and high powered liquid chromatography (HPLC), and its primary structure (Met-Gln-Cys-Asn-Ser) established by Edman sequencing and mass-spectrometry (MS). A synthetic peptide had the same selective anti-inflammatory features as the native material in comparable concentrations: in vitro inhibition of the locomotion in human peripheral blood monocytes, and of the respiratory burst in the same cells and in human neutrophil polymorphonuclear leucocytes; and in vivo depression of delayed hypersensitivity skin reactions to dinitrochlorobenzene in guinea pigs. This oligopeptide is apparently synthesized by the ameba as suggested by [(35)S]-Cys and Met incorporation, probably as part of a larger molecule, from which it is cleaved by proteolysis. The full sequence was not found in the 431 available E. histolytica protein sequences. The factor may contribute to the unexpected paucity of the late inflammatory reaction found in advanced invasive amebiasis and, perhaps in consequence, to the regeneration without scarring (restitutio ad integrum) of the affected organs that is observed following successful treatment of this disease