High risk and low prevalence diseases: Metformin toxicities.

INTRODUCTION: Metformin toxicity is a rare but serious condition that carries with it a high rate of morbidity and mortality. OBJECTIVE: This review highlights the pearls and pitfalls of metformin toxicity, including diagnosis, initial resuscitation, and management in the emergency department (ED) based on current evidence. DISCUSSION: Metformin is a common medication used for treatment of diabetes mellitus. Metformin toxicity is a spectrum of conditions that may be differentiated into three subgroups: metformin-associated lactic acidosis (MALA), metformin-induced lactic acidosis (MILA), and metformin-unrelated lactic acidosis (MULA). MILA is a condition found predominantly in patients chronically taking metformin or those with large acute overdoses. Conversely, MULA occurs in patients on metformin but with a critical illness stemming from a separate cause. MALA is rare but the most severe form, with mortality rates that reach 50%. Differentiating these entities is difficult in the ED setting without obtaining metformin levels. Patients with metformin toxicity present with nonspecific gastrointestinal symptoms and vital sign abnormalities. Laboratory analysis will reveal a high lactate with anion gap metabolic acidosis. Patients presenting with elevated lactate levels in the setting of metformin use should be considered at risk for the most severe form, MALA. Patients with MALA require aggressive treatment with intravenous fluids, treatment of any concomitant condition, and early consideration of hemodialysis, along with specialist consultation such as nephrology and toxicology. CONCLUSIONS: An understanding of metformin toxicity can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

A novel phage-displayed MilA ELISA for detection of antibodies against Myc. bovis in bovine milk.

AIMS: The aim of this study was to assess a phage-displayed MilA protein of Myc. bovis in an indirect ELISA for the detection of Myc. bovis antibodies in milk samples. METHODS AND RESULTS: The desired sequence of milA gene was synthesized and cloned into pCANTAB-F12 phagemid vector. The expression of the MilA on the phage surface was confirmed by Western blotting. The recombinant phage was used in the development of an indirect ELISA to detect Myc. bovis antibodies in milk samples. There was a significant agreement between the results of phage-based ELISA and recombinant GST-MilA ELISA for the detection of Myc. bovis antibodies in milk samples. CONCLUSIONS: The inexpensive and convenient phage-based ELISA can be used instead of recombinant protein/peptide ELISA as an initial screening of Myc. bovis-associated mastitis. SIGNIFICANCE AND IMPACT OF STUDY: Mastitis associated with Myc. bovis is a continuous and serious problem in the dairy industry. Sero-monitoring of Myc. bovis infection cases are one of the key factors for surveillance of the infections in dairy farms. Despite the existence of some commercially serological assays for Myc. bovis antibodies, they have some limitations regarding their sensitivity and availability. The development of accurate diagnosis tools could contribute to control programmes of Myc. bovis-associated mastitis in the dairy herds.

Mycoplasma bovis antibody dynamics in naturally exposed dairy calves according to two diagnostic tests.

BACKGROUND: Inexpensive and convenient diagnostic tests for use in clinical work and for the surveillance of infection with Mycoplasma bovis are in demand. The objective of this longitudinal field study was to gain knowledge about the dynamics of antibodies against M. bovis in sera from naturally exposed calves with and without different clinical signs, measured by two different ELISA tests. RESULTS: A total of 83 calves were subject to between one and five blood samples and clinical examinations using a standard protocol during five herd visits to each of four outbreak dairy herds. The blood samples were analysed for the presence of antibodies against M. bovis using the commercial IgG ELISA test BioX K302 (BioX) and an in-house indirect IgG ELISA test (MilA ELISA). Linear mixed models were used to describe and compare the antibody dynamics as measured by the two tests in relation to the disease status and age of the animals. The BioX ELISA response was below the recommended cut-off (37 ODC%) for the entire study period in many of the calves. The estimated mean ODC% increased slowly but did not reach the recommended individual animal cut-off in three of the four herds. The highest estimated ODC% was not reached until the calf was 110-130 days old. The MilA ELISA response rose above the recommended cut-off (135 antibody units (AU)) in almost all calves, and in two herds, the estimated mean was above the individual animal cut-off shortly after the birth of the calf. The highest estimated antibody concentration was reached when the calf was approximately 60 days old. Disease status of the calf was not significantly associated with the results of either test. CONCLUSIONS: We conclude that the BioX ELISA cannot be recommended for use in calves below 3 months of age. The MilA ELISA was able to detect antibodies shortly after birth (i.e. from approximately 3 weeks of age and onwards) and is therefore a more sensitive test for M. bovis exposure in young calves. Neither ELISA seemed able to differentiate between calves with arthritis and/or otitis media, and respiratory disease.

Post-earthquake damage classification and assessment: case study of the residential buildings after the M w = 5 earthquake in Mila city, Northeast Algeria on August 7, 2020.

On August 7th, 2020, a magnitude Mw = 5.0 earthquake shook 5 km north of Mila city center, northeast of Algeria, causing substantial damage directly to structures, and indirectly from induced impacts of landslides and rock falls, ultimately disrupt to everyday civilian life. Given the recent significant seismic occurrences in the region, a detailed and comprehensive examination and assessment of post-earthquake damage is critical to Algeria. This is primarily because masonry, concrete, and colonial-era structures are sensitive to horizontal motions caused by seismic waves, and because masonry and concrete structures constitute a substantial portion of today's Algeria's build environment. We present a post-earthquake investigation of the Mila earthquake, starting from the earthquake source, and a catalogue of buildings type, damage categorization, and failure patterns of residential structures in Mila's historic old town, where colonial-era brick buildings prevail. We find that structures that represent notable architectural achievements were severely damaged as a result of the earthquake. Data acquired during the immediate post-earthquake analysis was also evaluated and discussed. The graphical representations of the damages are detailed and complemented by photos. This seismic event has shown the fragility of Algeria's building stock, which must be addressed properly in future years. This study reports on an overall estimate of residential buildings in Mila's lower city, as well as an evaluation of the seismic vulnerability of three neighborhood towns (El-Kherba, Grareme-Gouga, and Azzeba). A generic database for graphical surveys and geometric research was developed and implemented making it possible to evaluate the shear strength on-site. The broad observations, collated data, and consequences were then loaded into the 3Muri structural verification program. Nonlinear static analysis was conducted to analyze probable failure paths and compare the real damage to the software results.

Sand Flies (Diptera: Psychodidae): Fauna and Ecology in the Northeast of Algeria.

Sand flies (Diptera: Psychodidae) transmit several Leishmania (Kinetoplastida: Trypanosomatidae) species, which cause leishmaniasis, a significant public health concern in Algeria. We compared sand fly species abundance and composition among different biotopes (urban, peri-urban, rural areas), bioclimatic zones (humid, sub-humid, semi-arid), and elevation ranges. We also used the additive partitioning of beta diversity to test whether the variation in sand fly composition among biotopes, bioclimatic zones, and elevation ranges is due to species turnover or community subsetting. In total, 7,478 specimens were captured; of which, 7,162 (51.5% males vs. 48.5% females) belong to eight species: Phlebotomus perniciosus Newstead, 1911 (77.4% of the total captured specimens), Phlebotomus perfiliewi Parrot, 1930 (14.6%), Phlebotomus longicuspis Nitzulescu, 1911 (5.9%), Phlebotomus papatasi Scopoli, 1786 (<1%), Phlebotomus sergenti Parrot, 1917 (<1%) and Phlebotomus chadlii Rioux, Juminer et Gibily 1966 (<1%), Sergentomyia minuta Adler et Theodor, 1927 (1%), and Sergentomyia fallax Parrot, 1921 (<1%). Sand fly total abundance showed negative correlations with altitude and was significantly higher in rural areas. Sandfly community composition was significantly different between rural and urban/peri-urban areas. The additive partitioning of beta diversity showed that 71.4% of the compositional dissimilarity among elevation ranges and bioclimates was due to sand fly species turnover, and 28.6% resulted from nestedness. However, the variation in sand fly composition among different biotopes was mainly due to community nestedness. Findings from this study help define the risk of Leishmania transmission and develop methods for vector control in Mila province and Algeria as a whole.

Bayesian latent class analysis to estimate the optimal cut-off for the MilA ELISA for the detection of Mycoplasma bovis antibodies in sera, accounting for repeated measures.

The MilA ELISA has been identified as a highly effective diagnostic tool for the detection of Mycoplasma bovis specific antibodies and has been validated for serological use in previous studies. This study aimed to estimate the optimal cut-off and corresponding estimates of diagnostic sensitivity (DSe) and diagnostic specificity (DSp) of the MilA ELISA for testing bovine serum. Serum samples from 298 feedlot cattle from 14 feedlots across four Australian states were tested on entry into the feedlot and approximately 42 days later. The paired serum samples were tested with the MilA ELISA, BIO K302 (Bio-X Diagnostics, Belgium) and BIO K260 (Bio-X Diagnostics, Belgium). A cut-off of 135 AU was estimated to be optimal using Bayesian latent class analysis with three tests in multiple populations, accounting for conditional dependence between tests. At this cut-off, the DSe and DSp of the MilA ELISA were estimated to be 92.1 % (95 % highest probability density [HPD] interval: 87.4, 95.8) and 95.5 % (95 % HPD: 92.4, 97.8), respectively. The DSes of the BIO K260 and BIO K302 ELISAs were estimated to be 60.5 % (95 % HPD: 54.0, 66.9) and 44.6 % (95 % HPD: 38.7, 50.7), respectively. DSps were 95.6 % (95 % HPD: 92.9, 97.7) and 97.8 % (95 % HPD: 95.9, 99.0), respectively. Mycoplasma bovis seroprevalence was remarkably high at follow-up after 42 days on the feedlots. Overall, this study estimated a cut-off, DSe and DSp for the MilA ELISA with less dependence on prior information than previous analyses and demonstrated that the MilA ELISA has higher DSe than the BIO K260 and BIO K302 assays.

Evaluation of the MilA ELISA for the diagnosis of herd infection with Mycoplasma bovis using bulk tank milk and estimation of the prevalence of M. bovis in Australia.

Infection with Mycoplasma bovis has been identified as a growing threat in dairy industries worldwide and there is an urgent need for an inexpensive and accurate herd-level screening tool to identify herds that have been exposed to M. bovis. This study aimed to evaluate the use of the MilA ELISA for testing bulk tank milk (BTM) samples for antibodies against M. bovis and estimate a suitable cut-off and diagnostic sensitivity (DSe) and specificity (DSp) for this assay. An optimal cut-off was then applied for investigating the geographical and seasonal distribution of infection with M. bovis in Australia. A total of 5554 BTM samples from 2683 dairy herds were collected during March, August and December 2017. BTM samples were tested in the MilA ELISA and a cut-off of 29 antibody units (AU) was estimated to be optimal using Bayesian latent class analysis which makes no assumption about the true disease status of herds under investigation. At this cut-off, the DSe and DSp were estimated to be 96.6% (95% highest probability density [HPD] interval: 87.0, 99.8) and 94.2% (95% HPD: 89.9, 97.4), respectively. The diagnostic specifications were found to vary markedly with stage of the production cycle, suggesting that targeted sampling was needed to maximize accuracy. We also found distinct differences in the apparent prevalence of M. bovis in different dairying regions, as well as seasonal variation. The highest apparent prevalence of M. bovis was observed in samples collected in March and an overall drop in the proportion of positive herds was seen from March to December. Overall, this study provides insights into the dynamics of BTM antibodies against M. bovis in Australian dairy herds and how the MilA ELISA can be applied for bulk tank milk testing.

Characterisation of the course of Mycoplasma bovis infection in naturally infected dairy herds.

Mycoplasma bovis causes bovine respiratory disease, mastitis, arthritis and otitis. The importance of M. bovis has escalated because of recent outbreaks and introductions into countries previously free of M. bovis. We characterized the course of M. bovis infection on 19 recently infected dairy farms over 24 months. Our objective was to identify diagnostic tools to assess the efficacy of control measures to assess low risk infection status on M. bovis infected farms. PCR assays and culture were used to detect M. bovis, and in-house and BioX ELISAs were used to follow antibody responses. Cows and young stock were sampled on four separate occasions, and clinical cases were sampled when they arose. On 17 farms, a few cases of clinical mastitis were detected, mostly within the first eight weeks after the index case. Antibodies detected by in-house ELISA persisted in the serum of cows at least for 1.5 years on all farms, regardless of the M. bovis infection status or signs of clinical disease or subclinical mastitis on the farm. Six out of 19 farms became low risk as the infection was resolved. Our results suggest that, for biosecurity purposes, regular monitoring should be conducted on herds by screening for M. bovis in samples from cows with clinical mastitis and calves with pneumonia, in conjunction with testing young stock by screening longitudinally collected nasal swabs for M. bovis and sequential serum samples for antibody against recombinant antigen.

A new species of Pamphagus (Orthoptera: Pamphagidae) from Algeria with a key to all the species of the genus.

The authors describe Pamphagus milevitanus n. sp. occurring in the North and South highlands of Constantine, in Mila, Setif and Oum-el Bouaghi provinces, where it is fairly common. They compare the characters of this species with those of the most related species of the genus and present a complete plate and a key to all the species of the genus Pamphagus known to date.

Ethnobotanical investigations on plants used in folk medicine in the regions of Constantine and Mila (North-East of Algeria).

ETHNO-PHARMACOLOGICAL RELEVANCE: Constantine and Mila regions have been investigated in an ethnobotanical study for the first time. A total of 102 medicinal plants have been cited to treat human ailments. Twenty-eight new species of 31 common plants with 151 new therapeutic applications and 12 new cited species including one endemic specie Zygophyllum cornutum Coss were found as compared to other Algerian regions. In addition, to the best of our knowledge, 369 new medicinal uses of 75 known plants, were reported for the first time in the Mediterranean basin. AIM OF THE STUDY: This study is aimed at contributing to safeguard world cultural heritage and document ethnomedicinal uses of plants in Algeria and the Mediterranean basin; data on the national and global uses in the world were obtained to extract new potential species for further phytochemical and clinical investigations. MATERIALS AND METHODS: The survey was carried out in two cities in the northeast of Algeria: Constantine and Mila. It was based on semi-structured interviews of 79 local informants. Data were analyzed using quantitative indices, namely, informant consensus factor, fidelity level (FL), use value (UV), and relative frequency citation (RFC), to evaluate the reliability and richness of herbal knowledge in the region. RESULTS: The interviewed persons used 102 plant species belonging to 90 genera and distributed among 53 families, represented mainly by Lamiaceae, Apiaceae, and Asteraceae (30%, 13%, and 10%, respectively), which were used to treat 14 ailment categories. The category of most frequent ailments (16%) was digestive disorders (diarrhea, constipation, and stomach bloating). The highest RFC was found for Origanum glandulosum Desf. With regard to the fidelity level, a higher FL was found for Tilia cordata Mill. (100%), followed by Artemisia herba alba Asso. with an FL of 95.74% and Punica granatum L. with an FL of 93.09%) to treat gastrointestinal system diseases, and Aloe sp. L. with an FL of 96.67% for skin diseases. The highest UV was found for Origanum glandulosum Desf. (2.280). Moreover, new medicinal uses were recorded for the first time in Algeria and Mediterranean regions. CONCLUSION: The present study has highlighted the rich herbal knowledge about newfound medicinal plants and their new uses in the Mediterranean region, which could be useful not only in facilitating other studies such as phytochemical and pharmacological investigations and upgrading the sources of biomolecules beneficial to people but also in reopening discussion on pharmacovigilance in herbal medicine as an imperative requirement for local authorities.

Federico Milá de La Roca: un personaje inolvidable / Federico Milá de la Roca: an unforgettable character

En este artículo se presenta una semblanza de la vida y obra del Dr. Federico Milá de la Roca, médico venezolano, quien fue uno de los fundadores del Instituto Nacional de Higiene, resaltando diferentes rasgos de su personalidad y sus destacadas actuaciones en el campo profesional y personal.

This paper presents a brief biography of Federico Milá de la Roca, Venezuelan medical doctor, who was one of the founders of the Instituto Nacional de Higiene, highlighting various features of his personality and outstanding performances related with his personal and profesional life.

Minimally invasive levator advancement: a practical approach to eyelid ptosis repair.

There are many established plastic surgical techniques to effectively address blepharoptosis. Minimally invasive levator advancement (MILA) causes limited disruption to the anatomy while maintaining good height, contour, lid folds, function, and long-term stability. This procedure has been performed in more than 1000 patients since 1993 by the author with consistent, durable results and is a reliable method to correct blepharoptosis. It is not indicated in cases with absent to very poor levator function, where frontalis suspension is the preferred procedure. The MILA technique will be described and illustrated.

Yolanda Irureta de Milá de la Roca Creadora del Fermentador "Caracas" Valioso aporte en la lucha contra el tétano en Venezuela

Yolanda Irureta Story de Milá de la Roca nació el 9 de enero de 1923 en Puerto España (Trinidad). Ocupó diversos cargos en el Instituto Nacional de Higiene, en la División de Elaboración de Productos Biológicos, en las secciones de Vacuna Antivariólica y Toxoide Tetánico, así como en el Departamento de Vacunas Bacterianas, ocupando el cargo de Microbiólogo Jefe hasta su jubilación en 1983. En la década de los setenta, Yolanda Irureta y su equipo asumen el reto de aumentar la producción de Toxoide Tetánico para satisfacer la creciente demanda de este producto, por parte del Ministerio de Sanidad y Asistencia Social (MSAS). Después de 18 meses de trabajo creativo lograron desarrollar un equipo bautizado como Fermentador "Caracas", el cual permitió triplicar la producción de Toxoide Tetánico. El aspecto más resaltante de esta adaptación radica en su sencillez y facilidad de fabricación, el bajo costo de sus componentes y la facilidad de mantenimiento. En aquella ocasión, el Presidente de la República donó el exceso de producción a Costa Rica, Honduras y Bolivia. En 1977, los expertos de la Organización Mundial de la Salud consideraron al laboratorio de Toxoide Tetánico del Instituto Nacional de Higiene "Rafael Rangel" (INH "RR") como el mejor de América Latina. Debido a su valiosa contribución a la tecnología, el CONICIT les otorgó el Premio de Desarrollo Tecnológico, en el año 1979. El 9 de marzo de 1982, el Fermentador "Caracas" logra obtener la patente número 4.318.992, en USA, asegurando así que el INH "RR" conserve los derechos legales sobre esta tecnología, y se reconozca la propiedad intelectual a sus verdaderos autores.

Yolanda Irureta Story de Milá de la Roca was born on January 9, 1923 in Port of Spain, Trinidad. She joined the National Institute of Hygiene (NIH), as a staff member of the Division that manufactures human vaccines. Through the years she was promoted to various positions in the Smallpox Vaccine and Tetanus Toxoid Units, being Head of the Department of Bacterial Vaccines until her retirement in 1983. During the seventies, the Ministry of Health and Social Assistance increased their demand of Tetanus Toxoid. To fulfill this need, Yolanda Irureta and her team faced this challenge, working 18 months to develop a fermentor that allowed them to triplicate the production. The fermentor was named "Caracas" Fermentor and it has many important features. It is simple and economic; it is made up of parts that are easy to obtain and the maintainance cost are very low. At that time, the Venezuelan President donated the surplus of production to Costa Rica, Honduras and Bolivia. In 1977, experts of the World Health Organization considered the Tetanus Toxoid laboratory of National Institute of Hygiene "Rafael Rangel" (NIH"RR"), the best in Latin America. Due to their valuable contribution to technology, they received the 1979 CONICIT Award for Technological Development. On March 9, 1982, it was granted to the Caracas Fermentor, the U.S.A. patent number 4.318.992, securing to the NIH"RR" the exclusive rights to this technology and the intellectual property to theirs authors.