Results from two-year rodent oral carcinogenicity studies of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine is a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence. To assess its carcinogenic potential, cizolirtine was administered by oral route once daily for up to 104 weeks to CD-1 mice at doses of 40, 90, or 200 mg/kg/day, and to Han Wistar rats at doses of 40, 90 or 200 mg/kg/day to males and 40, 110 or 160 mg/kg/day to females. There were treatment-related neoplastic findings both in mice and rats. In mice, administration of cizolirtine was associated to an increase in skin fibrosarcomas and sarcomas among high-dose males, considered secondary to increased aggression and specific to the animal model. In rats, there was an increased incidence of liver adenomas in males and females, and carcinomas in males, in association with an increased incidence of hepatocyte hypertrophy, vacuolation and clear cell foci, and considered related to sustained long-term enzyme induction resulting in increased liver metabolism and associated hypertrophic changes. The observed neoplastic findings in mouse skin and rat liver after life-time oral administration of cizolirtine are considered related to rodent-specific non-genotoxic mechanisms of questionable relevance to man.

Characterization of novel papillomavirus from free-ranging Antillean manatee Trichechus manatus manatus with genital papillomatosis.

The Antillean manatee Trichechus manatus manatus is an Endangered species living along the Atlantic coasts of the Americas from Florida (USA), throughout the Caribbean, to Brazil. In July 2020, a manatee with multiple wounds due to boat-inflicted trauma was rescued from the coast east of Cayo Mata, Salinas, Puerto Rico. This manatee had neutropenia, leukopenia, and monocytosis associated with immunosuppression and nutritional deficiency anemia, as well as bacteria and fungi within the lesions. The manatee had genital lesions which included papules and linear plaques, microscopically characterized by mucosal hyperplasia with cytopathic changes typical of papillomavirus infection. Superficial epithelial cells had strong nuclear immunolabeling when examined using a monoclonal antibody specific to papillomavirus. The sequencing data of PCR products with papillomavirus-specific degenerative primers indicated that these lesions contained a novel manatee papillomavirus (Trichechus manatus papillomavirus, TmPV). The genomic DNA was amplified using a rolling circle amplification, and fully sequenced to be 7586 bp (GenBank accession no. OK073977). Other TmPVs were previously isolated from Florida manatees T. manatus latirostris. This novel virus was designated TmPV type 5 (TmPV5) based on its genomic characterization and sequence comparison. The TmPV5 genome shared 50.7, 48.9, 69.4, and 62.1% similarities with TmPV1, TmPV2, TmPV3, and TmPV4, respectively. TmPV5 is classified in the genus Rhopapillomavirus together with other manatee papillomaviruses. After 2.5 mo of veterinary treatment and rehabilitation, the manatee recovered and was released. This is the first report of papillomatosis in a free-ranging Antillean manatee.

Medical management and resolution of perinatal bilateral exophthalmia and secondary corneal ulcers in an Antillean manatee (Trichechus manatus manatus) neonate from Puerto Rico.

OBJECTIVE: To present a novel case of perinatal bilateral exophthalmos and corneal ulcers in a neonate Antillean manatee and describe the medical treatment that led to the resolution of the observed clinical signs and vision restoration. ANIMAL STUDIED: A manatee stranded alone in Puerto Rico on July 5, 2020. RESULTS: The manatee was found in critical condition with pronounced exophthalmos, lagophthalmos, and corneal opacification of both eyes (OU). Vision impairment was evident due to the lack of ocular menace reflex and bumping into the tank's walls. Biomicroscopy revealed conjunctival hyperemia and chemosis, limited third eyelid movement, but had viscous tears present OU. Dense, full-thickness, white to cream-colored cellular infiltrates affected 70% of the cornea with peripheral active vascularization OU. Rubeosis iridis was also present OU. Treatment consisted of supportive medical management, including nutritional support and topical treatment for ulcerative keratitis. Resolution of the corneal ulcers and functional vision were achieved after 6 weeks of therapy. Currently, bilateral, mild, intermittent exophthalmos is observed with no adverse clinical signs, and the calf is in good health. CONCLUSIONS: The extent of bilateral corneal disease on a neonatal calf may be a result of an intrauterine infection or possible trauma at or right after birth. While the latter may have led to exophthalmia and consequent corneal disease, the exact cause could not be determined. Supportive therapy and medical management of infectious keratitis were successful and led to vision recovery. This is the first report of ocular pathology in a neonatal manatee.

What students with intellectual disabilities know about writing planning.

BACKGROUND: Studies on the writing of students with intellectual disabilities have been scarce and unrepresentative. Therefore, the purpose of this research was to analyse this group of students' abilities to plan their texts METHOD: A collective case study was carried out, with an eminently qualitative approach, although aided by an initial quantitative analysis. Fifteen students with unspecified intellectual disabilities were interviewed using open-ended questions. For data interpretation, content analysis and quantification of responses were used. RESULTS: The results revealed the abilities and limitations of these students regarding the knowledge and use of one of the key processes of written expression (writing planning). CONCLUSION: The cognitive operations of planning, in which these students admitted the greatest problems, were the ordering and recording of ideas, and textual structuring.

Long-term safety evaluation of Daxocox® tablets (enflicoxib) in dogs after weekly oral administrations for seven months.

BACKGROUND: Daxocox® [Ecuphar/Animalcare Group] contains the selective COX-2 inhibitor enflicoxib, approved in the EU for the treatment of pain and inflammation associated with osteoarthritis in dogs. The safety of Daxocox® was evaluated in a target animal safety study: Groups of 4 dogs per sex each were treated once weekly with placebo or Daxocox tablets at 1-, 3- and 5-times (1X, 3X and 5X) the maximum recommended therapeutic dose of enflicoxib (0, 4, 12 or 20 mg/kg, respectively). After an initial loading dose, dogs in the placebo control, 1X and 3X groups were administered for 32 weeks, and those in the 5X group were administered for 13 weeks. Dogs were subjected to daily food consumption measurements and clinical and dose observations. Body weight measurements, physical examinations, clinical pathology, urinalysis, faecal occult blood (FOB) and electrocardiographic (ECG) and blood pressure measurements, buccal mucosal bleeding time (BMBT), ophthalmology and gastroduodenal endoscopy examinations were conducted throughout the study. At study completion, all dogs were subjected to gross necropsy. Histopathology was performed on selected tissues from all animals in all groups. RESULTS: No clinical signs were noted, and no toxicologically relevant dose-associated effects were observed. CONCLUSIONS: Results show that Daxocox® is well-tolerated and has a broad safety margin when administered as directed in dogs.

Twenty six-week repeat dose oral rat toxicity study of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals. Slight increases in plasma alkaline phosphatase activity, and cholesterol and phospholipid concentrations were observed in mid- and/or high-dose animals. Low urinary volume, pH and sodium and potassium outputs were observed after 12-weeks, and low urinary pH, low sodium and high potassium outputs at end of treatment. Increased relative (to bodyweight) liver weight was observed in high-dose animals. Treated males and high-dose females showed a dose-related increase in the incidence and severity of periacinar hepatocytic hypertrophy and midzonal/periacinar hepatocytic fat vacuolization. Increased incidences of hepatic clear cell foci were observed in all cizolirtine-treated male groups and, to a lesser extent, in treated females. Ovaries of treated females showed a dose-dependent increased incidence of absent corpora lutea and, occasionally, follicular cysts. The dosages of 20 and 60 mg/kg/day were considered as the No-Observed-Adverse-Effect Levels for males and females, respectively.

Towards the elimination of hepatitis C: implementation of reflex testing in Andalusia.

BACKGROUND AND AIM: undiagnosed hepatitis C virus (HCV) infection and/or inadequate access to care are barriers to the elimination of HCV. Reflex testing has proven to facilitate referral to care, treatment and viral elimination. In this study, a reflex testing program was implemented in Andalusia and its impact on access to care was evaluated. PATIENTS AND METHODS: an observational, retrospective and prospective study was performed across diagnostic laboratories responsible for HCV diagnosis in southern Spain. After surveying the barriers to performing reflex testing, the number of patients that were not referred for care in 2016 was retrospectively studied (pre-reflex cohort). Subsequently, several measures were proposed to overcome the identified barriers. Finally, reflex testing was implemented and its impact evaluated. RESULTS: the pre-reflex cohort included information from 1,053 patients. Slightly more than half of the patients (n = 580; 55%) visited a specialist for treatment evaluation during a median period of 71 days (interquartile range = 35-134) since the date of diagnosis. The post-reflex cohort (September 2017 to March 2018) included 623 patients. Only 17% (n = 106) of the patients had not been referred for care or evaluated for treatment in a median period of 52 days (interquartile range = 28-86). CONCLUSIONS: in 2016, nearly half of new HCV diagnoses in southern Spain were not referred for care. Barriers to the implementation of reflex testing were overcome in our study. Moreover, this strategy was effectively implemented in 2017. Reflex testing contributed to improving referral for care. This program will contribute to the micro-elimination of hepatitis C in Spain.

Pupal productivity in rainy and dry seasons: findings from the impact survey of a randomised controlled trial of dengue prevention in Guerrero, Mexico.

BACKGROUND: The follow-up survey of a cluster-randomised controlled trial of evidence-based community mobilisation for dengue control in Nicaragua and Mexico included entomological information from the 2012 rainy and dry seasons. We used data from the Mexican arm of the trial to assess the impact of the community action on pupal production of the dengue vector Aedes aegypti in both rainy and dry seasons. METHODS: Trained field workers inspected household water containers in 90 clusters and collected any pupae or larvae present for entomological examination. We calculated indices of pupae per person and pupae per household, and traditional entomological indices of container index, household index and Breteau index, and compared these between rainy and dry seasons and between intervention and control clusters, using a cluster t-test to test significance of differences. RESULTS: In 11,933 houses in the rainy season, we inspected 40,323 containers and found 7070 Aedes aegypti pupae. In the dry season, we inspected 43,461 containers and counted 6552 pupae. All pupae and entomological indices were lower in the intervention clusters (IC) than in control clusters (CC) in both the rainy season (RS) and the dry season (DS): pupae per container 0.12 IC and 0.24 CC in RS, and 0.10 IC and 0.20 CC in DS; pupae per household 0.46 IC and 0.82 CC in RS, and 0.41 IC and 0.83 CC in DS; pupae per person 0.11 IC and 0.19 CC in RS, and 0.10 IC and 0.20 CC in DS; household index 16% IC and 21% CC in RS, and 12.1% IC and 17.9% CC in DS; container index 7.5% IC and 11.5% CC in RS, and 4.6% IC and 7.1% CC in DS; Breteau index 27% IC and 36% CC in RS, and 19% IC and 29% CC in DS. All differences between the intervention and control clusters were statistically significant, taking into account clustering. CONCLUSIONS: The trial intervention led to significant decreases in pupal and conventional entomological indices in both rainy and dry seasons. TRIAL REGISTRATION: ISRCTN27581154 .

"Where we put little fish in the water there are no mosquitoes:" a cross-sectional study on biological control of the Aedes aegypti vector in 90 coastal-region communities of Guerrero, Mexico.

BACKGROUND: In the Mexican state of Guerrero, some households place fish in water storage containers to prevent the development of mosquito larvae. Studies have shown that larvivorous fish reduce larva count in household water containers, but there is a lack of evidence about whether the use of fish is associated with a reduction in dengue virus infection. We used data from the follow up survey of the Camino Verde cluster randomised controlled trial of community mobilisation to reduce dengue risk to study this association. METHODS: The survey in 2012, among 90 clusters in the three coastal regions of Guerrero State, included a questionnaire to 10,864 households about socio-demographic factors and self-reported cases of dengue illness in the previous year. Paired saliva samples provided serological evidence of recent dengue infection among 4856 children aged 3-9 years. An entomological survey in the same households looked for larvae and pupae of Aedes aegypti and recorded presence of fish and temephos in water containers. We examined associations with the two outcomes of recent dengue infection and reported dengue illness in bivariate analysis and then multivariate analysis using generalized linear mixed modelling. RESULTS: Some 17% (1730/10,111) of households had fish in their water containers. The presence of fish was associated with lower levels of recent dengue virus infection in children aged 3-9 years (OR 0.64; 95% CI 0.45-0.91), as was living in a rural area (OR 0.57; 95% CI 0.45-0.71), and being aged 3-5 years (OR 0.65; 95% CI 0.51-0.83). Factors associated with lower likelihood of self-reported dengue illness were: the presence of fish (OR 0.79; 95% CI 0.64-0.97), and living in a rural area (OR 0.74; 95% CI 0.65-0.84). Factors associated with higher likelihood of self-reported dengue illness were: higher education level of the household head (OR 1.28; 95% CI 1.07-1.52), living in a household with five people or less (OR 1.33; 95% CI 1.16-1.52) and household use of insecticide anti-mosquito products (OR 1.68; 95% CI 1.47-1.92). CONCLUSIONS: Our study suggests that fish in water containers may reduce the risk of dengue virus infection and dengue illness. This could be a useful part of interventions to control the Aedes aegypti vector.

Aedes aegypti breeding ecology in Guerrero: cross-sectional study of mosquito breeding sites from the baseline for the Camino Verde trial in Mexico.

BACKGROUND: Understanding the breeding patterns of Aedes aegypti in households and the factors associated with infestation are important for implementing vector control. The baseline survey of a cluster randomised controlled trial of community mobilisation for dengue prevention in Mexico and Nicaragua collected information about the containers that are the main breeding sites, identified possible actions to reduce breeding, and examined factors associated with household infestation. This paper describes findings from the Mexican arm of the baseline survey. METHODS: In 2010 field teams conducted household surveys and entomological inspections in 11,995 households from 90 representative communities in the three coastal regions of Guerrero State, Mexico. We characterized Ae. aegypti breeding sites and examined the effect of two preventive measures: temephos application in water containers, and keeping the containers covered. We examined associations with household infestation, using bivariate and multivariate analysis adjusted for clustering effects. RESULTS: We conducted entomological inspections in 11,995 households. Among 45,353 water containers examined, 6.5% (2958/45,353) were positive for larvae and/or pupae. Concrete tanks (pilas) and barrels (tambos) together accounted for 74% of pupal productivity. Both covering water containers and inserting temephos were independently associated with a lower risk of presence of larvae or pupae, with the effect of covering (OR 0.22; 95% CIca 0.15-0.27) stronger than that of temephos (OR 0.66; 95% CIca 0.53-0.84). Having more than four water containers was associated with household infestation in both rural areas (OR 1.42; 95% CIca 1.17-1.72) and urban areas (1.81; 1.47-2.25), as was low education of the household head (rural: 1.27; 1.11-1.46, and urban: 1.39; 1.17-1.66). Additional factors in rural areas were: household head without paid work (1.31; 1.08-1.59); being in the Acapulco region (1.91; 1.06-3.44); and using anti-mosquito products (1.27; 1.09-1.47). In urban areas only, presence of temephos was associated with a lower risk of household infestation (0.44; 0.32-0.60). CONCLUSION: Concrete tanks and barrels accounted for the majority of pupal productivity. Covering water containers could be an effective means of Ae. aegypti vector control, with a bigger effect than using temephos. These findings were useful in planning and implementing the Camino Verde trial intervention in Mexico.

[Military medicine in Mexico in 1915]. / La medicina militar en México en 1915.

As a part of the symposium titled "Mexico in 1915, Epidemics, Hunger, and Medical Assistance", presented at the National Academy of Medicine on August 5, 2015, this section will underscore the most important and transcendent facts inherent tot he military medicine and surgery that happened during the turmoil of the year 1915.

Occurrence of scorpion sting and associated factors in a highly marginalized municipality in Guerrero, Mexico: A cross-sectional study.

BACKGROUND: Scorpion sting is a neglected public health problem, despite a global estimate of 1.2 million scorpion stings and some 3,250 deaths annually. METHODS: This cross-sectional study estimates the occurrence of scorpion stings and identifies associated factors in seven communities in the highly marginalized municipality of Chilapa, in the Mexican state of Guerrero. After informed consent, 1,144 households provided information on 4,985 residents. The questionnaire collated sociodemographic data, characteristics of the dwelling, efforts to avoid scorpion stings, and individual information of scorpion stings suffered in the last year. Cluster-adjusted (acl), bivariate and multivariate analysis relied on the Mantel-Haenszel procedure. RESULTS: The overall period prevalence of scorpion stings in the year prior to the study was 4.4% (218/4985), 5.4% in men (126/2320), and 3.5% in women (92/2665), p<0.01. The majority occurred at home 68.3% (149/218), followed by agricultural fields 26.6% (58/218), street 2.8% (6/218), and work 2.3% (5/218). Factors associated with scorpion sting were carrying firewood (OR 2.1; CI95%acl 1.40-3.09), keeping free-range hens around of the home (OR 1.9; CI95%acl 1.19-2.85), residing in a rural area (OR 1.7; CI95%acl 1.04-2.78), being male (OR 1.6; CI95%acl 1.18-2.28), and helping with housework (OR 1.6; CI95%acl 1.04-2.40). CONCLUSION: This study confirms scorpion bites are a public health problem in these marginalized communities in Guerrero State, with risk factors related to living conditions and the work process at home and in the fields. Almost all risk factors identified could be reduced with low-cost interventions implemented by the communities themselves.

Therapeutic Management and Long-Term Outcome of Hyperthyroidism in Patients with Antithyroid-Induced Agranulocytosis: A Retrospective, Multicenter Study.

BACKGROUND: Antithyroid drug-induced agranulocytosis (AIA) (neutrophils <500/µL) is a rare but serious complication in the treatment of hyperthyroidism. METHODOLOGY: Adult patients with AIA who were followed up at 12 hospitals in Spain were retrospectively studied. A total of 29 patients were studied. The etiology of hyperthyroidism was distributed as follows: Graves' disease (n = 21), amiodarone-induced thyrotoxicosis (n = 7), and hyperfunctioning multinodular goiter (n = 1). Twenty-one patients were treated with methimazole, as well as six patients with carbimazole and two patients with propylthiouracil. RESULTS: The median (IQR) time to development of agranulocytosis was 6.0 (4.0-11.5) weeks. The most common presenting sign was fever accompanied by odynophagia. All of the patients required admission, reverse isolation, and broad-spectrum antibiotics; moreover, G-CSF was administered to 26 patients (89.7%). Twenty-one patients received definitive treatment, thirteen patients received surgery, nine patients received radioiodine, and one of the patients required both treatments. Spontaneous normalization of thyroid hormone values occurred in six patients (four patients with amiodarone-induced thyrotoxicosis and two patients with Graves' disease), and two patients died of septic shock secondary to AIA. CONCLUSIONS: AIA is a potentially lethal complication that usually appears around 6 weeks after the initiation of antithyroid therapy. Multiple drugs are required to control hyperthyroidism before definitive treatment; additionally, in a significant percentage of patients (mainly in those treated with amiodarone), hyperthyroidism resolved spontaneously.

Disseminated toxoplasmosis in Antillean manatees Trichechus manatus manatus from Puerto Rico.

Necropsies were conducted on 4 Antillean manatees Trichechus manatus manatus that were stranded in single events on the coastal beaches of Puerto Rico from August 2010 to August 2011. Three manatees were emaciated and the gastrointestinal tracts were devoid of digesta. Microscopically, all manatees had severe widespread inflammatory lesions of the gastrointestinal tract and heart with intralesional tachyzoites consistent with Toxoplasma gondii identified by histological, ultrastructural and immunohistochemical techniques. The gastrointestinal lesions included severe, multifocal to diffuse, chronic-active enteritis, colitis and/or gastritis often with associated ulceration, necrosis and hemorrhage. Enteric leiomyositis was severe and locally extensive in all cases and associated with the most frequently observed intralesional protozoans. Moderate to severe, multifocal, chronic to chronic-active, necrotizing myocarditis was also present in all cases. Additionally, less consistent inflammatory lesions occurred in the liver, lung and a mesenteric lymph node and were associated with fewer tachyzoites. Sera (n = 30) collected from free-ranging and captive Puerto Rican manatees and a rehabilitated/released Puerto Rican manatee from 2003 to 2012 were tested for antibodies for T. gondii. A positive T. gondii antibody titer was found in 2004 in 1 (3%) of the free-ranging cases tested. Disease caused by T. gondii is rare in manatees. This is the first report of toxoplasmosis in Antillean manatees from Puerto Rico. Additionally, these are the first reported cases of disseminated toxoplasmosis in any sirenian. The documentation of 4 cases of toxoplasmosis within one year and the extremely low seroprevalence to T. gondii suggest that toxoplasmosis may be an emerging disease in Antillean manatees from Puerto Rico.

Evaluation of the Genotoxic Potential of the Selective COX-2 Inhibitor Enflicoxib in a Battery of in vitro and in vivo Genotoxicity Assays.

AIM: Enflicoxib, a selective COX-2 inhibitor approved for the treatment of pain and inflammation associated with osteoarthritis in dogs (Daxocox® [Ecuphar/Animalcare Group]) was assessed for its genotoxic potential in a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse mutation assay (Ames test), an in vitro human lymphocyte chromosome aberration assay and an in vivo mouse bone marrow micronucleus assay. METHODS: Relevant vehicle and positive control cultures and animals were included in all assays. In the Ames test, enflicoxib was tested at concentrations of up to 5000 µg/plate. Signs of cytotoxicity were observed at the highest tested concentrations for several of the bacterial strains, both in absence and presence of S9. In human lymphocytes, enflicoxib was assessed for the induction of chromosomal aberrations when exposed at concentrations of up to 62.5 (3 hours) and 29.6 µg/mL (20 hours) in the absence of S9, and up to 66.7 µg/mL (3 hours) in presence of S9. Signs of cell toxicity, evidenced as a decrease in the mitotic index, were observed at these concentrations. In the mouse micronucleus assay, enflicoxib dose levels of up to 2000 mg/kg were administered (single dose) to male and female animals, and bone marrow samples were taken 24 and 48 hours (high-dose animals only) after administration. RESULTS: Enflicoxib was shown to lack genotoxic activity in the conducted assays. CONCLUSIONS: The administration of enflicoxib as a therapeutic analgesic agent would not pose a genotoxic risk to animals or humans.

Metformin, testosterone, or both in men with obesity and low testosterone: A double-blind, parallel-group, randomized controlled trial.

BACKGROUND: Men with obesity tend to be insulin resistant and often have low-normal testosterone concentrations. We conducted a clinical trial aimed to evaluate potential therapeutic strategies for low testosterone in men with obesity. METHODS: We did a 1-year, parallel, randomized, double-blind, placebo-controlled trial, where we evaluated the independent and combined effects of metformin and testosterone in 106 men with obesity, aged 18-50 years, who had low levels of testosterone and no diabetes mellitus. The primary outcome was change in insulin resistance, measured as Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index. Secondary outcomes included changes in total and free serum testosterone, body composition, metabolic variables, erectile function, and health-related quality of life (HRQoL). RESULTS: In the intention-to-treat analysis, the HOMA-IR index decreased significantly in all active groups compared to placebo (metformin -2.4, 95 % CI -4.1 to -0.8, p = 0.004; testosterone -2.7, 95 % CI -4.3 to -1.1, p = 0.001; combination -3.4, 95 % CI -5.0 to -1.8, p < 0.001). Combination therapy was not superior to testosterone alone in decreasing insulin resistance (-0.7, 95 % CI -2.3 to 0.9, p = 0.383). Only the combination of metformin plus testosterone significantly increased total and free testosterone concentrations, compared to placebo. No significant changes in body composition (except for a higher decrease in fat mass in the metformin and combination group), metabolic variables, erectile function, or HRQoL were found with any treatment. CONCLUSIONS: Among men with obesity and low testosterone concentrations, the combination of metformin plus testosterone, metformin only, and testosterone only, compared to placebo, reduced insulin resistance with no evidence of additive benefit.

A Case of Rare Subtype of Multiple Myeloma: Secondary Plasma Cell Leukemia.

Description Plasma cell leukemia is a rare, aggressive form of multiple myeloma with the presence of circulating plasma cells in the peripheral blood. There are two types of plasma cell leukemia, primary and secondary, depending on if there was previous evidence of multiple myeloma. The diagnostic criterion of plasma cell leukemia is based on a percentage (>20%) or an absolute number of (≥2 × 109/L) plasma cells in the peripheral circulation. We present the clinical course of a rare case of secondary plasma cell leukemia in a patient from the time of initial diagnosis of multiple myeloma, its remission period of about 5 years, and its final progression into refractory secondary plasma cell leukemia. This case report details the patient's presenting symptoms, pertinent laboratory and diagnostic imaging findings, and histopathology of peripheral blood and bone marrow. This case report presents a chronological comparison of key laboratory findings that manifest the progression of multiple myeloma into secondary plasma cell leukemia. It also offers a brief review of the literature for the diagnosis and treatment of plasma cell leukemia.

Assessment of the Genotoxic Potential of Cizolirtine a Substance-P and Calcitonin Gene-Related Peptide Release Modulator.

The analysis of the genotoxic potential of cizolirtine, a compound being developed as a drug for analgesia and for urinary incontinence, was carried out using a battery of in vitro and in vivo assays as recommended in the guidelines for medicinal products. Negative results were obtained in an Ames test (up to 5000 µg/plate), in a Mouse Lymphoma assay (up to 2000 µg/ml) and in a single dose mouse bone marrow micronucleus assay (up to 300 mg/kg). In a human lymphocyte chromosome aberration assay, a slight statistical increase in the frequency of cells with chromosome aberrations including gaps was reported for the concentrations of 200 and 1600 µg/ml at the 24-h sampling time. This minor increase in chromosome aberrations was considered of questionable biological relevance since it was moderate, was within the laboratory historical control values, did no show a dose-dependent effect and was not observed at similar concentrations in a repeat assay. Taking into considerations the results obtained in the different in vitro and in vivo assays and a weight-of-evidence analysis, it suggests that cizolirtine would not pose a genotoxic risk when administered to humans.

Video Game Streaming in Young People and Teenagers: Uptake, User Groups, Dangers, and Opportunities.

In recent years, live video streaming platforms for video games have been gaining popularity. These types of services, which enable anyone to broadcast and consume live content, are revolutionising the current video game landscape. Users approach the emergence of and participation in these platforms driven by a range of motivations. It is essential to characterise the different forms of participation in services such as Twitch to evaluate the phenomenon and reflect on its advantages and disadvantages. To that end, a survey was carried out of 580 young people and adolescents aged between 14 and 24. The aim of this study is thus to explore the uptake of these platforms, as well as identify user groups, distinguish between different motivations, and address the associated benefits and harms. Applying a methodology based on factor analysis and cluster analysis, user profiles were characterised according to their specific features, gaming/viewing hours, self-perception of their skill level as a player, devices used, and type or genre of video game. Four subgroups of gamers/viewers were thus identified: casual, social, hobby, and problematic. The results showed that older users and female users feature more prominently in the first two groups, as do those spending less time on video games and live streaming platforms. Conversely, in the hobby and problematic groups, we observe just the opposite. The existence of profiles at possible risk of addiction underlines how, at a preventive level, there is a need for more in-depth research on these types of services and greater public awareness of the dangers of uncontrolled use.

Baseline urinalysis results in 32 healthy Antillean manatees (Trichechus manatus manatus).

OBJECTIVE: To describe results of analysis of free-catch urine samples collected from Antillean manatees (Trichechus manatus manatus) under human care in the Caribbean. ANIMALS: 32 Antillean manatees in 5 Caribbean oceanaria and rescue centers. PROCEDURES: Urine samples were obtained by opportunistic free catch during physical examination or through the use of operant conditioning procedures. Urinalyses consisted of macro- and microscopic evaluations, biochemical analyses with test strips, and refractometry. Results were compared for manatees grouped on the basis of age, sex, and habitat. RESULTS: Urine samples were typically clear, straw colored, and alkaline (mean pH, 8.0); had a urinoid odor and low specific gravity (mean, 1.010); and had results on qualitative test strips that were consistently negative for the presence of glucose, bilirubin, ketones, proteins, nitrites, RBCs, and WBCs. Microscopically, the mean ± SD number of RBCs and WBCs/hpf was 0.5 ± 0.3 RBCs/hpf and 1.1 ± 1.5 WBCs/hpf. The presence of some epithelial cells and crystals was typical. Spermatozoa were found in urine from 1 of 15 sexually mature males, and parasite larvae and eggs were found in urine from 2 manatees. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study yielded the first compilation of baseline urinalysis values in healthy Antillean manatees under human care, which, when combined with physical examination and other diagnostic procedures, can help in monitoring the health of these animals. We encourage the use of free-catch urine collection methods, as used in the present study, for routine urinalyses of manatees under human care in zoos, aquaria, or rescue centers.