Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond

The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer’s disease.

Preliminary Screening of Polybrominated Diphenyl Ethers (PBDEs); Decabromodiphenyl Ether (BDE-209) and Tetrabromobisphenol-A (TBBPA) Flame Retardants in Municipal Dumpsite in Delta State, Nigeria

Aims: This study is aimed at determining the concentration of two widely used BFRs; Decabromodiphenyl Ether (BDE-209) and Tetrabromo Bisphenol-A (TBBPA) in sediment and leachate samples. Place and Duration of Study: Field sampling were carried out from five major dumpsites around Warri Municipality, Delta State, Nigeria. Analyte extraction was done in 2017 at the Science laboratory, Federal University of Petroleum Resources, Effurun Delta State, Nigeria and quantification done in Switzerland by Bachema Analytical Laboratories in 2017. Methods: Three soil samples were collected from each site 15cm from the soil surface. Also, three leachate samples from three different trial pits done for each site. Collected soil samples were stored in glass bottles and labelled. While the leachate samples are stored using glass containers and labelled. The BFRs were extracted using Aceton and cyclohexane for each soil matrix and cyclohexane for the leachate samples, then the extract was analysed using GC coupled with an ECD supplied by Thermo Trace GC Ultra, Italy. Results: The results showed the average concentration for TBBPA in the sediments was 0.0234 g/kg and that of the BDE-209 was recorded as 0.1828 g/kg. Results from the leachate sample were below the detectable range of the analytical equipment, TBBPA (0.02 g/kg) and BDE (0.1 g/kg). There is no statistical difference between the mean concentration of TBBPA for the sediment in each of the locations (P>.05) and no difference (P>.05) for BDE-209 for the sediment in each of the locations (P>.05). Conclusion: Findings from this study holds that the concentration of TBBPA and BDE-209 in sediment is higher when compared with concentrations presented in other literatures studied in this report and this calls for immediate action due to the health risk associated with exposure in these municipalities.

What Is the Effect of Body Mass Index on Subjective Outcome Following Vaginal Hysterectomy for Prolapse? / 대한배뇨장애요실금학회지

PURPOSE: Obesity is a significant risk factor for pelvic organ prolapse (POP), but the effects of obesity on outcomes of surgery for POP are poorly understood. The aim of this study was to assess the relationship between POP symptomatology, subjective outcomes of surgery and body mass index (BMI) in women undergoing vaginal hysterectomy for POP. METHODS: Pre- and postoperative data from a validated pelvic floor questionnaire (electronic Personal Assessment Questionnaire-Pelvic Floor) were collected prospectively from 60 women undergoing vaginal hysterectomy for POP. Of these, 20 were normal weight (BMI 18.5–24.9 kg/m²), 20 were overweight (BMI 25–29.9 kg/m²), and 20 were women with obesity (BMI 30–34.9 kg/m²). The relationship between BMI and symptom scores for prolapse, impact on vaginal symptoms on quality of life (VS-QoL) and ‘overall change in condition’ was assessed. Pre- and postoperative symptom scores were compared using repeated mixed analysis of variance test for BMI as a categorical variable (normal, overweight, and obese). Spearman rank order correlation test was carried out to evaluate BMI as a continuous variable. All women underwent vaginal hysterectomy using a standardized technique. RESULTS: Overall, 93% of women reported improvement in their condition. The main finding was that ‘overall change in condition’ was negatively correlated with increasing BMI (r(s)=-0.324, P=0.028). Irrespective of BMI, significant improvements were observed in symptoms of prolapse and VS-QoL at 3-month postoperation. CONCLUSIONS: With increasing BMI, women are likely to report lower levels of satisfaction following prolapse surgery, despite reporting equivalent improvements in symptoms. BMI is known to affect how individuals perceive their general health and well-being with obese individuals reporting poorer levels of subjective health status. Women with obesity may perceive change in their condition after prolapse surgery differently to women of normal weight. Reduction of weight prior to prolapse surgery could be considered in obese women to improve subjective outcomes of surgery.

FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction?

Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) antivenin is commonly recommended after pit viper snakebites. Because copperhead envenomations are usually self-limited, some physicians are reluctant to use this costly treatment routinely, while others follow a more liberal approach. We hypothesized that, in practice, only patients with evidence of significant (moderate or severe) copperhead envenomation [those with snakebite severity score (SSS) > 3] receive FabAV and examined a large cohort to determine the relationship between clinical findings and FabAV administration. Methods All data from patients evaluated for copperhead snakebite at a rural tertiary referral center from 5/2002 to 10/2013 were compiled. Demographics, transfer status, antivenin use, and clinical findings were collected; SSS was calculated. The relationships among FabAV use, clinical findings, and SSS were analyzed using t-test, chi-square, and Pearsons coefficient (p 0.05 was significant). Results During the study period, 318 patients were treated for copperhead snakebite; 44 (13.8 %) received antivenin. Median dose was four vials (range: 110; IQR: 4,6). There were no deaths. Most patients receiving FabAV (63.6 %) were admitted. With regard to demographics and symptoms, only the degree of swelling (moderate vs. none/mild; p 0.01) and bite location (hand/arm vs. leg: p 0.0001) were associated with FabAV use. A SSS > 3, indicating moderate or severe envenomation, was only very weakly correlated with antivenin use (r = 0.217;p 0.0001). The majority of patients with SSS > 3 (65.8 %) did not receive antivenin while most patients who did receive antivenin (70.5 %) had SSS 3 (indicating mild envenomation). Conclusions Considerable variation occurs in antivenin administration after copperhead snakebite. Use of FabAV appears poorly correlated with patients symptoms. This practice may expose patients to the risks of antivenin and increasing costs of medical care without improving outcomes. Guidelines used for treating other pit viper strikes, such as rattlesnake or cottonmouth snakebite may be too liberal for copperhead envenomations. Our data suggests that most patients with mild or moderate envenomation appear to do well independent of FabAV use. We suggest, for patients with copperhead snakebite, that consideration be given to withholding FabAV for those without clinical evidence of severe envenomation until prospective randomized data are available.

FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction?

Abstract Background Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) antivenin is commonly recommended after pit viper snakebites. Because copperhead envenomations are usually self-limited, some physicians are reluctant to use this costly treatment routinely, while others follow a more liberal approach. We hypothesized that, in practice, only patients with evidence of significant (moderate or severe) copperhead envenomation [those with snakebite severity score (SSS) > 3] receive FabAV and examined a large cohort to determine the relationship between clinical findings and FabAV administration. Methods All data from patients evaluated for copperhead snakebite at a rural tertiary referral center from 5/2002 to 10/2013 were compiled. Demographics, transfer status, antivenin use, and clinical findings were collected; SSS was calculated. The relationships among FabAV use, clinical findings, and SSS were analyzed using t-test, chi-square, and Pearson’s coefficient (p < 0.05 was significant). Results During the study period, 318 patients were treated for copperhead snakebite; 44 (13.8 %) received antivenin. Median dose was four vials (range: 1–10; IQR: 4,6). There were no deaths. Most patients receiving FabAV (63.6 %) were admitted. With regard to demographics and symptoms, only the degree of swelling (moderate vs. none/mild; p < 0.01) and bite location (hand/arm vs. leg: p < 0.0001) were associated with FabAV use. A SSS > 3, indicating moderate or severe envenomation, was only very weakly correlated with antivenin use (r = 0.217;p < 0.0001). The majority of patients with SSS > 3 (65.8 %) did not receive antivenin while most patients who did receive antivenin (70.5 %) had SSS ≤ 3 (indicating mild envenomation). Conclusions Considerable variation occurs in antivenin administration after copperhead snakebite. Use of FabAV appears poorly correlated with patients’ symptoms. This practice may expose patients to the risks of antivenin and increasing costs of medical care without improving outcomes. Guidelines used for treating other pit viper strikes, such as rattlesnake or cottonmouth snakebite may be too liberal for copperhead envenomations. Our data suggests that most patients with mild or moderate envenomation appear to do well independent of FabAV use. We suggest, for patients with copperhead snakebite, that consideration be given to withholding FabAV for those without clinical evidence of severe envenomation until prospective randomized data are available.

Unusual cause of hypoxemia after automatic implantable cardioverter‑defibrillatorleads extraction.

The indication of pacemaker/AICD removal are numerous. Serious complication can occur during their removal, severe tricuspid regurgitation is one of the complication. The occurrence of PFO is not uncommon among adult population. Shunting across PFO in most circumstance is negligible, but in some necessitates closure due to hypoxemia. We report a case of 62 year old man, while undergoing AICD removal, had an emergency sternotomy for cardiac tamponade. Postoperatively, he experienced profound hypoxemia refractory to oxygen therapy. Transthoracic Echocardiogram was performed to rule out intracardiac shunts at an early stage, but it was difficult to obtain an good imaging windows poststernotomy. A small pulmonary emboli was noted on CTPA, but was not sufficient to account for the level of hypoxemia and did not resolve with anticoagulation. Transesophageal echocardiogram showed flail septal tricuspid valve with severe TR and bidirectional shunt through large PFO. Patient was posted for surgery, tricuspid valve was replaced and PFO surgically closed. Subsequently, patient recovered well ad was discharged to home. Cause of hypoxemia might be due to respiratory or cardiac dysfunction. But for hypoxemia refractory to oxygen therapy, transoesophageal echocardiogram should be always considered and performed early as an diagnostic tool in post cardiac surgical patients.

Fluorescence In Situ Hybridization on Enriched CD138-Positive Cells in Plasma Cell Myeloma.

To validate plasma cell enrichment technique for improving the detection of cytogenetic abnormalities in the Plasma cell myeloma (PCM)/multiple myeloma (MM). We compared the abnormality detection rate for overnight unstimulated bone marrow cultures to that for the plasma cell enriched fractions obtained with the use of CD138-coated immunomagnetic beads. Average enrichment factor (EF) was 11. One or more abnormalities were detected in 90% of enriched samples vs. 65% of non-enriched samples, thus resulting in a significantly higher detection rate of total cytogenetic abnormalities in enriched plasma cells (p=0.0038). Additional findings of RB1 deletion, TP53-, 1p-, 1q+ and IGH@ rearrangement seen in the 25% of enriched samples could contribute to the altered risk in the patient. One of the three cases with plasma cells as low as 1% by morphology was positive for a residual disease marker in the enriched sample and negative in the non-enriched sample. The plasma cell enrichment technique increased the detection rate of diagnostic and prognostic markers and is a very sensitive method for detecting minimal residual disease.

Juicios de valor implícitos en la medición de las desigualdades en salud / Implicit value judgments in the measurement of health inequalities

CONTEXTO: Los estimados cuantitativos de magnitud, dirección e índice de cambio de las desigualdades en salud juegan un papel crucial en la creación y evaluación de las políticas destinadas a eliminar la desproporcionada carga de enfermedad en las poblaciones carenciadas. En general se asume que la medición de las desigualdades en salud es un proceso con un valor neutral que brinda datos objetivos que luego se interpretan usando juicios normativos sobre si una particular distribución de la salud es justa, ecuánime o socialmente aceptable. MÉTODOS: Se discuten cinco ejemplos en los cuales los juicios normativos juegan un papel en la medición del proceso en sí, sea mediante la selección de una estrategia de medición sobre la exclusión de otras como mediante la selección del tipo, importancia o peso asignados a las variables que se están midiendo. HALLAZGOS: En términos generales, encontramos que muchas medidas de desigualdad comúnmente usadas son subjetivas y que los juicios normativos implícitos en estas medidas tienen importantes consecuencias de interpretación y respuesta a las desigualdades en salud. CONCLUSIONES: Debido a que los valores implícitos en la generación de las medidas de desigualdad en salud pueden llevar a interpretaciones radicalmente diferentes de los mismos datos subyacentes, instamos a los investigadores a considerar en forma explícita y discutir con transparencia los juicios normativos subyacentes en sus medidas. También instamos a los responsables de las políticas y a otros consumidores de datos sobre desigualdades en salud a prestar mucha atención a las medidas sobre las cuales basan su evaluación sobre las políticas de salud actuales y futuras.

CONTEXT: Quantitative estimates of the magnitude, direction, and rate of change of health inequalities play a crucial role in creating and assessing policies aimed at eliminating the disproportionate burden of disease in disadvantaged populations. It is generally assumed that the measurement of health inequalities is a value-neutral process, providing objective data that are then interpreted using normative judgments about whether a particular distribution of health is just, fair, or socially acceptable. METHODS: We discuss five examples in which normative judgments play a role in the measurement process itself, through either the selection of one measurement strategy to the exclusion of others or the selection of the type, significance, or weight assigned to the variables being measured. FINDINGS: Overall, we find that many commonly used measures of inequality are value laden and that the normative judgments implicit in these measures have important consequences for interpreting and responding to health inequalities. CONCLUSIONS: Because values implicit in the generation of health inequality measures may lead to radically different interpretations of the same underlying data,we urge researchers to explicitly consider and transparently discuss the normative judgments underlying their measures. We also urge policymakers and other consumers of health inequalities data to pay close attention to the measures on which they base their assessments of current and future health policies.

Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.

Molecular genetics of ependymoma / 癌症

Brain tumors are the leading cause of cancer death in children, with ependymoma being the third most common and posing a significant clinical burden. Its mechanism of pathogenesis, reliable prognostic indicators, and effective treatments other than surgical resection have all remained elusive. Until recently, ependymoma research was hindered by the small number of tumors available for study, low resolution of cytogenetic techniques, and lack of cell lines and animal models. Ependymoma heterogeneity, which manifests as variations in tumor location, patient age, histological grade, and clinical behavior, together with the observation of a balanced genomic profile in up to 50% of cases, presents additional challenges in understanding the development and progression of this disease. Despite these difficulties, we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic (copy number) and transcriptome profiling platforms. Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin. This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.

Angioplasty on an infarct-related anomalous right coronary artery arising from posterior coronary sinus

<p><b>INTRODUCTION</b>The objective of this case report was to illustrate the diagnostic and intervention approach of anomalous right coronary artery (RCA).</p><p><b>CLINICAL PICTURE</b>A 60-year-old man presented with acute inferior myocardial infarction. Cardiac catheterisation revealed an anomalous RCA arising from the posterior coronary sinus as the infarct-related artery.</p><p><b>TREATMENT</b>Ad hoc percutaneous coronary intervention with stent implantation was performed using a few technical modifications.</p><p><b>OUTCOME</b>Good angiographic result was achieved within 90 minutes, with 260 mL of contrast used.</p><p><b>CONCLUSION</b>A high index of suspicion and logical diagnostic and intervention approach are required for the proper management of anomalous RCA.</p>

Long-term, tumor-free survival after radiotherapy combining hepatectomy-Whipple en bloc and orthotopic liver transplantation for early-stage hilar cholangiocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To report the experience in surveillance and early detection of cholangiocarcinoma (CC) and in using en bloc total hepatectomy-pancreaticoduodenectomy-orthotopic liver transplantation (OLT-Whipple) to achieve complete eradication of early-stage CC complicating primary sclerosing cholangitis (PSC).</p><p><b>METHODS</b>Asymptomatic PSC patients underwent surveillance using endoscopic ultrasound and endoscopic retrograde cholangiopancreatography (ERCP) with multilevel brushings for cytological evaluation. Patients diagnosed with CC were treated with combined extra-beam radiotherapy, lesion-focused brachytherapy, and OLT-Whipple.</p><p><b>RESULTS</b>Between January 1988 and February 2001, 42 of 119 PSC patients were followed according to the surveillance protocol. CC was detected in 8 patients, 6 of whom underwent OLT-Whipple. Of those 6 patients, 4 had stage I CC, and 2 had stage II CC. All 6 OLT-Whipple patients received combined external-beam and brachytherapy radiotherapy. The median time from diagnosis to OLT-Whipple was 144 days. One patient died 55 months post-transplant of an unrelated cause, without tumor recurrence. The other 5 were well without recurrence at 79, 82, 108, 128, 129 and 145 months.</p><p><b>CONCLUSIONS</b>For patients with PSC, ERCP surveillance cytology and intralumenal endoscopic ultrasound examination allow for early detection of CC. Broad and lesion-focused radiotherapy combined with OLT-Whipple to remove the biliary epithelium en bloc offers promising long-term, tumor-free survival. All patients tolerated this extensive surgery well with good quality of life following surgery and recovery. These findings support consideration of the complete excision of an intact biliary tree via OLT-Whipple in patients with early-stage hilar CC complicating PSC.</p>

Unusual retinal manifestations of PORN combined complications of central retinal artery and vein occlusions / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM:To describe an unusual combination of retinal manifestations in an AIDS patient with progressive outer retinal necrosis (PORN),complicated by combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO).·METHODS:A case report.·RESULTS:The patient presented with PORN with primary optic nerve involvement complicated by combined central retinal artery occlusion(CRAO) and central retinal vein occlusion(CRVO) as a primary manifestation of Varicella Zoster Virus (VZV).Aggressive treatment with intravitreal and specific systemic anti-VZV therapy,in addition to systemic highly active antiretroviral therapy (HAART) achieved retinal quiescence with sparing of the fellow eye.Visual outcome of the affected eye was poor.·CONCLUSION:We present the first report of PORN associated with the unusual combined complications of CRAO and CRVO. Aggressive local treatment was combined with systemic therapy,which achieved local control and empirical prophylaxis for the fellow eye.

Primary malnutrition. Can we always tell?

Patterns of disease in the English-speaking Caribbean have changed considerably over the past two decades. There has been a decrease in the incidence of common infectious diseases, an increase in the prevalence of chronic non-communicable disorders and an increase in the incidence and prevalence of HIV/AIDS. However, published estimates suggest that malnutrition continues to be a serious public health problem. It is possible that changing patterns of disease within the epidemiological transition may affect patterns of presentation of severe forms of childhood malnutrition. We have examined records of 435 children admitted to the clinical research ward of the Tropical Metabolism Research Unit (TMRU) from January 1, 1990, to December 31, 1999; among these were 25 children who were subsequently found to have severe childhood malnutrition (SCM) due to a defined medical or surgical disorder (i.e. secondary SCM). Among children with secondary SCM, the HIV/AIDS group was the largest and comprised 60 of these admissions. Regression analyses show that, over the ten-year period, there was a small, non-significant decline in the number of cases of primary SCM (incidence rate ratio, IRR = 0.99, 95 confidence interval = 0.96, 1.02, p = 0.98), while the number of cases of secondary SCM increased (IRR = 1.18, 95 CI = 1.03, 1.35, p = 0.02). These data are indicative of the need for continued vigilance in the evaluation of children who have clinical features of the syndromes of severe malnutrition and draw attention to the potential impact of HIV/AIDS in yet another area of healthcare delivery.

The appropriateness of the current antibiotic empiric therapy based on the bacteria isolated from severely malnourished Jamaican children

We performed a retrospective audit of antimicrobial sensitivities of bacteria isolated from children admitted with a diagnosis of malnutrition to the Tropical Metabolism Research Unit (TMRU), University of the West Indies, between January 1995 and December 1999. There were 150 admissions for severe malnutrition to the TMRU during this period, which was approximately 50 fewer than in a previous TMRU study done ten years ago, between 1984 and 1989. In the present study, bacteraemia was documented in 10 of 150 severely malnourished children between 1 and 31 months of age. The most common organisms isolated were coagulase-negative Staphylococci, which represented 40 of the total isolates. The micro-organisms grown were most likely to be sensitive to amoxycillin/clavulanic acid. The current TMRU treatment protocol for severe malnutrition recommends use of crystalline penicillin plus gentamicin as empirical antibiotic therapy. This study has provided valuable information suggesting that the current empiric antibiotic therapy may be inappropriate.

Effects of immigration on the prevalence of malaria in rural areas of the Amazon basin of Brazil

Epidemiological studies were conducted on malaria in three rural areas of the Amazon basin in the State of Rondônia: the town of Costa Marques, Forte Príncipe da Beira (Fort), and an immigrant settlement in the nearby forest. These studies were instituted to document the malaria problem and to describe the role of immigration on its distribution and prevalence. Hospital records in the town show that the number of malaria cases increased five fold from 1983 to 1987 and that the predominant malaria parasite changel from Plasmodium vivax to P. falciparum. Increased malaria followed increased immigration and colonization of the forest. A series of epidemiologic studies suggested the linkage between malaria and immigration as the prevalence of malaria was 1-2% at the Fort, a stable community, 8-9% at Costa Marques, a growing community, and 14-26% in the new settlements in the forest

Rizotomia sacra para dor perineal / Sacral rhizotomy for perineal pain

Dor crônica no períneo, é um problema neurocirúrgico difícil. Este artigo avalia a efetividade da Rizotomia Sacra. Estudaram-se vinte e oito pacientes que tinham dor relacionada a câncer ou coccidínia, que foram submetidos a Rizotomia Sacra, e foram seguidos por um período médio de três anos. Bom alívio da dor foi obtido em 53% (10/19) dos pacientes com dor maligna como o oposto de 22% (2/9) dos pacientes com dor näo maligna. Rizotomia Sacra é um tratamento razoável para dor perineal relacionada com câncer, mas inefetiva para coccidínia e outros problemas de dor benigna perineal

Bloqueo del plexo braquial por vía axilar: probable lesión del nervio axilar / Block of brachial plexus by axilla pathway: probable lesion of axillary nervus

Un joven de 26 años de edad, recibió un bloqueo axilar. Un mes después del bloqueo se evidenció pérdida de fuerza en el brazo cuya severidad fue progresando en los meses siguientes llegando a la pérdida de masa muscular del deltoides; 14 meses después del bloqueo la fuerza musculr se ha recuperado. Existe la posibilidad, de un hematoma en un espacio confinado donde la comprensión ha producido la lesión del nervio, como así también que la injuria sea producida por un factor desconocido y por pura coincidencia