GABAergic/Glycinergic and Glutamatergic Neurons Mediate Distinct Neurodevelopmental Phenotypes of STXBP1 Encephalopathy.

An increasing number of pathogenic variants in presynaptic proteins involved in the synaptic vesicle cycle are being discovered in neurodevelopmental disorders. The clinical features of these synaptic vesicle cycle disorders are diverse, but the most prevalent phenotypes include intellectual disability, epilepsy, movement disorders, cerebral visual impairment, and psychiatric symptoms ( Verhage and Sørensen, 2020; Bonnycastle et al., 2021; John et al., 2021; Melland et al., 2021). Among this growing list of synaptic vesicle cycle disorders, the most frequent is STXBP1 encephalopathy caused by de novo heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1; Verhage and Sørensen, 2020; John et al., 2021). STXBP1 is an essential protein for presynaptic neurotransmitter release. Its haploinsufficiency is the main disease mechanism and impairs both excitatory and inhibitory neurotransmitter release. However, the disease pathogenesis and cellular origins of the broad spectrum of neurological phenotypes are poorly understood. Here we generate cell type-specific Stxbp1 haploinsufficient male and female mice and show that Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons causes developmental delay, epilepsy, and motor, cognitive, and psychiatric deficits, recapitulating majority of the phenotypes observed in the constitutive Stxbp1 haploinsufficient mice and STXBP1 encephalopathy. In contrast, Stxbp1 haploinsufficiency in glutamatergic neurons results in a small subset of cognitive and seizure phenotypes distinct from those caused by Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons. Thus, the contrasting roles of excitatory and inhibitory signaling reveal GABAergic/glycinergic dysfunction as a key disease mechanism of STXBP1 encephalopathy and suggest the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.

Loss of WNT4 in the gubernaculum causes unilateral cryptorchidism and fertility defects.

Undescended testis (UDT) affects 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. To improve our understanding of the etiology of infertility in UDT, we generated a novel murine model of left unilateral UDT. Gubernaculum-specific Wnt4 knockout (KO) mice (Wnt4-cKO) were generated using retinoic acid receptor ß2-cre mice and were found to have a smaller left-unilateral UDT. Wnt4-cKO mice with abdominal UDT had an increase in serum follicle-stimulating hormone and luteinizing hormone and an absence of germ cells in the undescended testicle. Wnt4-cKO mice with inguinal UDT had normal hormonal profiles, and 50% of these mice had no sperm in the left epididymis. Wnt4-cKO mice had fertility defects and produced 52% fewer litters and 78% fewer pups than control mice. Wnt4-cKO testes demonstrated increased expression of estrogen receptor α and SOX9, upregulation of female gonadal genes, and a decrease in male gonadal genes in both CDT and UDT. Several WNT4 variants were identified in boys with UDT. The presence of UDT and fertility defects in Wnt4-cKO mice highlights the crucial role of WNT4 in testicular development.

PRSS50 is a testis protease responsible for proper sperm tail formation and function.

Multiple morphological abnormalities of the sperm flagella (MMAF) are a major cause of asthenoteratozoospermia. We have identified protease serine 50 (PRSS50) as having a crucial role in sperm development, because Prss50-null mice presented with impaired fertility and sperm tail abnormalities. PRSS50 could also be involved in centrosome function because these mice showed a threefold increase in acephalic sperm (head-tail junction defect), sperm with multiple heads (spermatid division defect) and sperm with multiple tails, including novel two conjoined sperm (complete or partial parts of several flagellum on the same plasma membrane). Our data support that, in the testis, as in tumorigenesis, PRSS50 activates NFκB target genes, such as the centromere protein leucine-rich repeats and WD repeat domain-containing protein 1 (LRWD1), which is required for heterochromatin maintenance. Prss50-null testes have increased IκκB, and reduced LRWD1 and histone expression. Low levels of de-repressed histone markers, such as H3K9me3, in the Prss50-null mouse testis may cause increases in post-meiosis proteins, such as AKAP4, affecting sperm formation. We provide important insights into the complex mechanisms of sperm development, the importance of testis proteases in fertility and a novel mechanism for MMAF.

Gene dosage changes in KCTD13 result in penile and testicular anomalies via diminished androgen receptor function.

Despite the high prevalence of hypospadias and cryptorchidism, the genetic basis for these conditions is only beginning to be understood. Using array-comparative-genomic-hybridization (aCGH), potassium-channel-tetramerization-domain-containing-13 (KCTD13) encoded at 16p11.2 was identified as a candidate gene involved in hypospadias, cryptorchidism and other genitourinary (GU) tract anomalies. Copy number variants (CNVs) at 16p11.2 are among the most common syndromic genomic variants identified to date. Many patients with CNVs at this locus exhibit GU and/or neurodevelopmental phenotypes. KCTD13 encodes a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3-ubiquitin-protein-ligase complex (BCR (BTB-CUL3-RBX1) E3-ubiquitin-protein-ligase complex (B-cell receptor (BCR) [BTB (the BTB domain is a conserved motif involved in protein-protein interactions) Cullin3 complex RING protein Rbx1] E3-ubiqutin-protein-ligase complex), which has essential roles in the regulation of cellular cytoskeleton, migration, proliferation, and neurodevelopment; yet its role in GU development is unknown. The prevalence of KCTD13 CNVs in patients with GU anomalies (2.58%) is significantly elevated when compared with patients without GU anomalies or in the general population (0.10%). KCTD13 is robustly expressed in the developing GU tract. Loss of KCTD13 in cell lines results in significantly decreased levels of nuclear androgen receptor (AR), suggesting that loss of KCTD13 affects AR sub-cellular localization. Kctd13 haploinsufficiency and homozygous deletion in mice cause a significant increase in the incidence of cryptorchidism and micropenis. KCTD13-deficient mice exhibit testicular and penile abnormalities together with significantly reduced levels of nuclear AR and SOX9. In conclusion, gene-dosage changes of murine Kctd13 diminish nuclear AR sub-cellular localization, as well as decrease SOX9 expression levels which likely contribute in part to the abnormal GU tract development in Kctd13 mouse models and in patients with CNVs in KCTD13.

[Guidelines on atopic dermatitis for Mexico (GUIDAMEX): using the ADAPTE methodology]. / Guía de dermatitis atópica para México (GUIDAMEX): lineamientos usando metodología ADAPTE.

With the advancement of knowledge in relation to the physiopathogenesis of atopic dermatitis (AD), several new therapeutic forms have been developed. There are also new guidelines for self-care. On the other hand, there is still an underdiagnosis of AD in Mexico. Thus, the need was seen to develop a national guide, with a broad base among the different medical groups that care for patients with AD. The Atopic Dermatitis Guidelines for Mexico (GUIDAMEX) was developed with the ADAPTE methodology, with the endorsement and participation of ten national medical societies, from physicians in Primary Healthcare to allergists and dermatologists. Throughout the manuscript, key clinical questions are answered that lead to recommendations and suggestions for the diagnosis of AD (including differential diagnosis with immunodeficiency syndromes), the recognition of comorbidities and complications, non-pharmacological treatment including therapeutic education, treatment of flares and maintenance therapy. The latter encompasses general measures to avoid triggering factors, first-line treatment focussed on repair of the skin barrier, second-line treatment (topical proactive therapy), and third-line phototherapy or systemic treatment, including dupilumab and JAK inhibitors.

Con el avance de los conocimientos en relación con la fisiopatogenia de la dermatitis atópica (DA) se han desarrollado varias formas terapéuticas nuevas. Asimismo, existen nuevos lineamientos para el autocuidado. Por otro lado, aún existe un subdiagnóstico de la DA en México. Así, se vio la necesidad de desarrollar una guía nacional, con base amplia entre las diferentes agrupaciones médicos que atienden pacientes con DA. Se desarrolló la Guía de DA para México (GUIDAMEX) con la metodología ADAPTE, con el aval y la participación de diez sociedades médicas nacionales, desde médicos del primer contacto hasta alergólogos y dermatólogos. A lo largo del escrito se contestan preguntas clínicas clave que llevan a recomendaciones y sugerencias para el diagnóstico de la DA (incluyendo diagnóstico diferencial con síndromes de inmunodeficiencia), el reconocer de las comorbilidades y complicaciones, las medidas generales (tratamiento no farmacológico) incluyendo la educación terapéutica, el tratamiento de los brotes y el tratamiento de mantenimiento. Este último abarca las medidas generales de evitar agravantes, el tratamiento de primera línea reparador de la barrera cutánea, de segunda línea (manejo proactivo tópico), hasta la fototerapia y el tratamiento sistémico de la tercera línea, incluyendo dupilumab y los inhibidores de la cinasa de Jano.

Severe Cervicofacial Emphysema and Pneumomediastinum Caused by a Dental Handpiece: A Case Report and Guidelines for Management for the Dental Practitioner.

Cervicofacial emphysema (CE) is a rare but potentially serious condition that can arise iatrogenically from dental or surgical procedures. Dental handpieces with fore-exhaust can inject air into tissues at pressures at or greater than 30 psi. Since 1963, there have been approximately 100 case reports in the literature of iatrogenic CE from routine dental procedures. Prompt recognition and treatment are essential; however, many general practitioners may only be familiar with CE from their dental school curriculum. A case of unusually severe cervicofacial emphysema with concomitant pneumomediastinum is presented, along with a discussion and review of management principles for the general dentist. It is our hope that refamiliarization with this condition will give the general dentist an appreciation for and recognition of signs of CE, thereby being the first. link in a chain of successful treatment.

Expression of mouse CD47 on human cancer cells profoundly increases tumor metastasis in murine models.

BACKGROUND: Many commonly used xenograft tumor models do not spontaneously metastasize to distant organs following subcutaneous or orthotopic implantation, limiting their usefulness in preclinical studies. It is generally believed that natural killer cells are the key component of the innate immune system in determining tumor metastatic potential in xenograft models. However, recent studies suggest that macrophages may play an important role, as resident macrophages can eliminate the invading tumor cells if they do not express adequate levels of the CD47 molecule. METHODS: We investigated the effect of overexpressing murine CD47 (mCD47) in PC-3 cells, a commonly used human prostate cancer line, on the metastatic potential in three mouse strains with different genetic background and varying degrees of immunodeficiency. We implanted the tumor cells either subcutaneously or orthotopically and then examined their local and distant metastases. RESULTS: Our results show that mCD47-expressing PC-3 cells subcutaneously implanted in NSG and CB17. Scid mice metastasized to the sentinel lymph node, lung and liver significantly more efficiently than the control cells. When implanted orthotopically to NOD. Scid mice, these cells spontaneously metastasized to lung and liver. CONCLUSIONS: Our data demonstrate that mCD47 can facilitate human tumor cell metastasis in murine models, and that these mCD47-expressing tumor cells may be useful for in vivo studies where spontaneous metastases are desirable.

Comparison of Direct Laryngoscopy and Video Laryngoscopy in Intubating a Mannequin: Should Video Laryngoscopy Be Available to Manage Airway Emergencies in the Oral and Maxillofacial Surgery Office?

PURPOSE: Video laryngoscopy (VL) is an innovation in tracheal intubation that could be beneficial in an emergency situation. However, the technique could be detrimental if it prolongs intubation performed by an inexperienced physician. The purpose of this study was to compare direct laryngoscopy (DL) with VL skill for oral and maxillofacial surgery (OMS) residents and practitioners to assess the practicality of recommending the inclusion of VL as a component of OMS emergency airway management. MATERIALS AND METHODS: To address the research purpose, the authors designed and implemented a randomized crossover study investigating the performance of OMS residents and practitioners to intubate a mannequin using DL versus VL. The predictor variables were the experience level of the participants and their ability to intubate with DL and with VL. The outcome variables were time to view cords, the Cormack-Lehane glottis view achieved, the time to intubate the mannequin, and the total time for performing laryngoscopy and intubation. Comparisons of laryngoscopy and intubation and resident and practitioner experiences were compared using Cox proportional hazards survival analysis. RESULTS: Data from 22 OMS residents and 26 practitioners were assessed. The comparison outcomes between DL and VL showed that the time to view cords was shorter for VL, the Cormack-Lehane glottis view was better for VL, the time to intubate was shorter for DL, and the total time between techniques was not statistically different. OMS practitioners showed better times than OMS residents and showed adeptness with VL that was comparable to DL. CONCLUSION: The combined findings with OMS residents and practitioners showed comparable total intubating times between DL and VL, which is consistent with what has previously been reported with other medical colleagues.

Medical emergencies in a dental school clinic - A 12-year review and lessons learned.

PURPOSE: The aims of this study were to estimate the type and frequency of different medical emergencies that occurred over the study period (twelve years) and discuss the lessons learned and the modifications made in the curriculum to better equip dental students and faculty in their management. MATERIALS AND METHODS: A retrospective study was conducted to evaluate all medical emergencies that needed activation of the response team at our school from 2008 to 2020. RESULTS: The emergency response system was activated 250 times during the 12-year period. There were 132 medical emergencies in the pre-doctoral clinic and 105 events in the post-doctoral clinic (p 0.0680). Most of the emergencies occurred in patients between 45 and 64 years of age. Syncope occurs most often followed by adverse cardiovascular, respiratory, anxiety, and hypoglycemic events. CONCLUSIONS: Medical emergencies occurring in a dental school provide a unique opportunity for students to gain experience in their management. The key lies in preparing the students and faculty to prevent them from occurring, but should these occur, then they should be able to promptly recognize symptoms and institute prompt intervention.

[Therapeutic effect of vitamin D supplementation in mexican patients with allergic rhinitis]. / Efecto de la suplementación con vitamina D en pacientes mexicanos con rinitis alérgica.

OBJETIVES: To evaluate the impact of cholecalciferol (D3) supplementation using clinical and paraclinical variables in patients with RA and vitamin D insufficiency and deficiency. METHODS: A randomized, double-blind, placebo-controlled study included patients from 5 to 40 years with a diagnosis of RA and vitamin D insufficiency and deficiency. They were supplemented for 8 weeks with 4000 or 5000 IU, depending on age. Total nasal symptoms score (TNSS) was measured monthly and 25(OH)D3 levels at baseline and at the end of the study. RESULTS: A total of 31 patients were included, with a mean age of 18.19 years. In the active group, there was a significant improvement in symptomatology with respect to the TNSS score and an increase in serum vitamin D levels (p < 0.01). There were no adverse reactions with cholecalciferol or placebo. CONCLUSIONS: Supplementing patients with vitamin D3, at the evaluated dose, together with conventional treatent for allergic rhinitis results in symptoms and quality of life improvement in patients with this disease.

OBJETIVOS: Evaluar el impacto de la suplementación con colecalciferol (D3) mediante variables clínicas y paraclínicas en pacientes con RA e insuficiencia y deficiencia de vitamina D. MÉTODOS: Estudio aleatorio, doble ciego, placebo controlado, en el que se incluyeron pacientes de 5 a 40 años, con diagnóstico de RA e insuficiencia y deficiencia de vitamina D. Fueron suplementados con 4000 o 5000 UI, dependiendo de la edad, durante 8 semanas. Mensualmente se midió la puntuación total síntomas nasales (TNSS) y las concentraciones de 25(OH)D3 al inicio y al final del estudio. RESULTADOS: Se incluyeron 31 pacientes, con una edad promedio de 18.19 años. En el grupo activo existió una mejoría significativa en la sintomatología respecto a la puntación de TNSS y un incremento en los niveles séricos de vitamina D (p < 0.01). No se presentaron reacciones adversas con la ingesta de colecalciferol o placebo. CONCLUSIONES: Suplementar a los pacientes con vitamina D3, a la dosis evaluada, junto con el tratamiento convencional para la rinitis alergica resulta en una mejoría sintomática y en la calidad de vida de los pacientes con esta enfermedad.

Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery.

Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a CAR containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvß3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvß3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was codelivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues.

Incorporation of the B18R gene of vaccinia virus into an oncolytic herpes simplex virus improves antitumor activity.

Interferon (IFN) antiviral defense mechanism plays a critical role in controlling virus infection. It thus represents a formidable hurdle for virotherapy. Despite the reported ability of herpes simplex virus (HSV) to counteract this defense, the duration and extent of HSV infection in vivo is still largely dictated by host's IFN activity status. Because the HSV genes that have been reported to block IFN activity mainly act intracellularly, we hypothesized that their inhibitory effect could be enhanced by exploiting a gene whose product acts extracellularly. The B18R gene from vaccinia virus encodes a secreted decoy receptor with a broad antagonizing effect against type I IFNs. We therefore cloned B18R into an HSV-1-based oncolytic virus to generate Synco-B18R. In the presence of increased IFN levels in vitro, Synco-B18R largely retained its oncolytic effect, whereas the tumor-killing ability of the parental virus, Synco-2D, was severely compromised. When injected intratumorally in vivo, Synco-B18R showed significantly greater oncolytic activity than Synco-2D. Our results suggest that incorporation of the vaccinia virus B18R gene can safely potentiate the antitumor effect of an oncolytic HSV, and that similar strategies may be useful with other types of oncolytic viruses.

Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells.

Selective replication in tumor cells is a highly desirable feature for oncolytic viruses. Recent studies have shown that microRNAs (miRNAs) play important roles in controlling gene expression, and that certain tissue-specific miRNAs are frequently downregulated in malignant cells. miR-122 is a liver-specific microRNA. It is abundantly expressed in normal hepatocytes but is absent in many hepatocellular carcinoma (HCC) cells. We hypothesized that expression of an essential viral gene by a liver-specific promoter would initially restrict virus replication to cells of hepatic origin and that adding miR-122 complementary sequences to the viral gene would make the transcripts degradable by miR-122 in normal hepatocytes, thus further confining its replication to HCC. We have constructed such an oncolytic herpes simplex virus by linking the essential viral glycoprotein H gene with the liver-specific apolipoprotein E (apoE)-AAT promoter and by adding the miR-122a complimentary sequence to the 3' untranslated region (3'UTR). To further increase the safety of this virus, complementary sequences from miR-124a and let-7 were also engineered into the same 3'UTR. Designated liver-cancer specific oncolytic virus (LCSOV), it was highly selective in killing HCC cells and in shrinking HCC xenografts. We conclude that LCSOV is a highly specific oncolytic virus that can precisely target HCC.

TGFß signaling regulates lipogenesis in human sebaceous glands cells.

BACKGROUND: Sebaceous glands are components of the skin essential for its normal lubrication by the production of sebum. This contributes to skin health and more importantly is crucial for the skin barrier function. A mechanistic understanding of sebaceous gland cells growth and differentiation has lagged behind that for keratinocytes, partly because of a lack of an in vitro model that can be used for experimental manipulation. METHODS: We have developed an in vitro culture model to isolate and grow primary human sebocytes without transformation that display functional characteristics of sebocytes. We used this novel method to probe the effect of Transforming Growth Factor ß (TGFß) signaling on sebocyte differentiation, by examining the expression of genes involved in lipogenesis upon treatment with TGFß1. We also repressed TGFß signaling through knockdown of the TGFß Receptor II to address if the effect of TGFß activation is mediated via canonical Smad signal transduction. RESULTS: We find that activation of the TGFß signaling pathway is necessary and sufficient for maintaining sebocytes in an undifferentiated state. The presence of TGFß ligand triggered decreased expression in genes required for the production of characteristics sebaceous lipids and for sebocyte differentiation such as FADS2 and PPARγ, thereby decreasing lipid accumulation through the TGFß RII-Smad2 dependent pathway. CONCLUSION: TGFß signaling plays an essential role in sebaceous gland regulation by maintaining sebocytes in an undifferentiated state. This data was generated using a novel method for human sebocyte culture, which is likely to prove generally useful in investigations of sebaceous gland growth and differentiation. These findings open a new paradigm in human skin biology with important implications for skin therapies.

Extended composite temporoparietal fascial flap: clinical implications for tissue engineering in mandibular reconstruction.

BACKGROUND: The authors have expanded upon a well-described and widely used flap in the head and neck region. The purpose of the cadaver study was to determine the feasibility, angiosome, and the potential application of this pedicled flap in bone tissue engineering of the mandible. METHODS: A total of 6 fresh human cadaver heads were dissected for a total of 12 flaps. The extended composite temporoparietal fascial flap, based on the superficial temporal artery (STA) and including cranial periosteum, was dissected and the dimensions were measured. Through a combined submandibular and preauricular incision, the mandible was exposed and the dimensions were measured from the sigmoid notch to the gonion angle and from the gonion angle to the symphysis. CT angiography and silicone injections were performed to identify the vascular anatomy of the flap. RESULTS: The combined distance from the sigmoid notch to the gonion and the gonion to the symphysis, plotted versus the cranial apex to tragus length, demonstrated adequate flap dimensions in all specimens for hemi-mandibular reconstruction. The average flap length was 16.5 ± 1.40 cm and the average flap width was 11.4 ± 0.98 cm, resulting in an average flap surface area of 94.5 ± 13.08 cm. Radiographic images and silicone injections confirmed STA perfusion of the cranial periosteum. CONCLUSIONS: The extended composite temporoparietal fascial flap with periosteum can be a viable option for providing vascularized periosteum in tissue-engineered craniofacial reconstruction.

Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome.

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we report that reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult maternal Ube3a knockout mice rescues the abnormal electroencephalogram (EEG) rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and EEG power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.

[Vitamin D and respiratory allergy: state of the art]. / Vitamina D y alergia respiratoria: estado del arte.

An increasing number of studies are analyzing the relationship between serum vitamin D levels and the development of sensitization and allergic diseases in genetically predisposed individuals, as well as the impact of vitamin D supplementation. This article reviews the literature on this subject. Clinical trials, meta-analyses and systematic reviews consulted in PubMed, EMBASE, Scopus, Ovid, Wiley Online Library, Springer, Cochrane and manual resources were included, with the keywords: vitamin D, 25 hydroxyvitamin D, cholecalciferol, asthma, rhinitis, allergy, 25-OH-D, 1,25 hydroxyvitamin D, supplementation. The results show a positive linear trend, however, differ. We should keep in mind that in the studies there is heterogeneity of population groups and associated factors, which may modify such studies. It is necessary to increase research to clarify this relationship and to have successful interventions from the patient's approach to the strengthening of pharmacological and immunological treatment of allergic patients with these diseases.

Cada vez son más los trabajos que analizan la relación de los niveles séricos de vitamina D y el desarrollo de sensibilizaciones y enfermedades alérgicas en los individuos con predisposición genética, así como el impacto de su suplementación. El presente artículo efectúa una revisión de la literatura acerca de este tema. Se incluyeron ensayos clínicos, metaanálisis y revisiones sistemáticas consultadas en PubMed, EMBASE, Scopus, Ovid, Wiley Online Library, Springer, Cochrane y recursos manuales, con las palabras clave: vitamina D, 25 hidroxivitamina D, colecalciferol, asma, rinitis, alergia, 25-OH-D, 1,25 hidroxivitamina D, suplementación. Los resultados muestran una tendencia lineal positiva; sin embargo, algunos difieren. Debemos tener en mente que en los estudios existe heterogeneidad de los grupos poblacionales y los factores asociados, lo que puede modificarlos. Es necesario incrementar las investigaciones para clarificar esta relación y tener intervenciones exitosas desde el abordaje del paciente hasta el fortalecimiento del tratamiento farmacológico e inmunológico de los pacientes alérgicos con estas enfermedades.

Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication.

Oncolytic herpes simplex virus (HSV) is currently in phase III clinical trials for development as a novel therapeutic agent against a broad range of human tumors. Although results have been promising, clinical outcome is likely to be compromised by intrinsic and acquired resistance to HSV replication, leading us to test agents that may overcome this obstacle. We found that, despite showing no effect on HSV replication in tumor cells fully permissive to the virus growth, the mTOR inhibitor rapamycin markedly increased the yield and dissemination of oncolytic HSVs in semipermissive tumor cells. Similar results were obtained in tumor-bearing mice. Co-administration of rapamycin with an HSV-derived oncolytic virus either blocked or reversed the growth of tumor xenografts established from semipermissive human tumor cells, while use of either agent alone produced only transient inhibitory effect. Together, our results suggest that rapamycin could be used to potentiate the activity of oncolytic HSVs against difficult-to-treat human tumors or perhaps to prevent the emergence of resistant tumor cells during virotherapy.

Preliminary study of the impact of elevated circulating plasma levels of catecholamines on opioid requirements for acute surgical pain.

INTRODUCTION: The objective of this study is to determine whether elevated circulating plasma catecholamine levels significantly impact opioid requirements during the first 24 hours postoperative period in individuals with acute surgical pain. METHODS: We retrospectively reviewed 15 electronic medical records (EMRs) from adults 18 years and older, with confirmed elevated plasma catecholamine levels (experimental) and 15 electronic health records (EHRs) from matched-controls for age, gender, race and type of surgery, with a follow up of 24 hours postoperatively. RESULTS: The total morphine milligram equivalents (MMEs) requirements from the experimental group were not statistically different when compared with controls [44.1 (13 to 163) mg versus 47.5 (13 to 151) mg respectively; p 0.4965]. However, the intraoperative MMEs showed a significant difference, among the two groups; [(experimental) 32.5 (13. to 130) mg, (control) 15 (6.5 to 130) mg; p 0.0734]. The intraoperative dosage of midazolam showed a highly significant positive correlation to the total MMEs (p 0.0005). The subjects with both elevated plasma catecholamines and hypertension used significantly higher intraoperative MMEs compared to controls [34.1 (13 to 130) mg versus 15 (6.5 to 130) mg, respectively; p 0.0292)]. Those 51 years and younger, with elevated circulating levels of catecholamines, required significantly higher levels of both the postoperative MMEs [29.1 (0 to 45) mg versus 12 (0 to 71.5) mg; (p 0.0553)] and total MMEs [544.05 (13 to 81) mg versus 29.42 (13 to 92.5) mg; (p 0.00018), when compared to controls with history of nicotine and alcohol use. CONCLUSION: This preliminary study evaluated a biologic factor, which have promising clinical usefulness for predicting analgesic requirements that can drive clinical decisions on acute surgical pain.