Thursday, December 3, 2020

Assessment of Pulmonary Function Tests among Firefighters in Jerusalem Longitudinal Study

Assessment of Pulmonary Function Tests among Firefighters in Jerusalem Longitudinal Study


Firefighters are exposed to smoke and toxic Particulate Matter (PM) released during fire. Such exposure has adverse effects both acutely and chronically [1]. It is assumed that this population is at an increased risk for respiratory diseases and pulmonary function decline. Until recently, this assumption was not thoroughly studied. Research done after the collapse of the World Trade Center (WTC) shed light on this subject. Rescuers were exposed to high levels of PM and toxins which were released during the collapse [2,3]. Following this exposure several respiratory disorders have been described in rescue teams [4-7] and both acute and persistent changes in pulmonary functions were demonstrated [8-11]. However, longitudinal assessment of non-WTC firefighters compared to control subjects did not show greater pulmonary function decline [12]. There is a lack of evidence regarding the respiratory risk’s firefighters face. From December 2nd to 5th , 2010, Israel experienced the most severe forest fire in its history. The fire took place in the Carmel area and resulted in the deaths of 43 rescue workers and the hospitalization of others, mainly for acute smoke inhalation and traumatic injury. Consequently, many firefighters were exposed to smoke and other PM in a prolonged and mainly unprotected manner.
Assessment of pulmonary function tests among firefighters in Israel is not regularly performed and therefore little is known about this population. In this research we sought to determine whether firefighters are at an increased risk for obstructive pulmonary disorders and pulmonary function decline. About half of the firefighters in Jerusalem were involved in the Carmel forest fire in 2010. We aimed to compare this group to the firefighters who did not participate in the rescue operations at the Carmel forest fire site.

This prospective cohort study was conducted among firefighters employed in Jerusalem from 2014 to 2016. Firefighters were employed by the Jerusalem Firefighting Department during the recruitment period. The Firefighters worked in 5 different stations in the Jerusalem area. The study was approved by our institutional ethical committee. Written informed consent was obtained from all subjects recruited. Baseline Spirometry was done at recruitment. All participants completed a simple questionnaire regarding demographic information, smoking status and basic medical information. Inclusion criteria required a prior history of direct fire exposure at any time during service. This was ascertained via a face-to-face interview conducted with each subject. There were no exclusion criteria for participation in this study.

A research team composed of a Pulmonologist and a pulmonary function technician went to each of the firefighting stations in Jerusalem. All subjects filled out a basic health questionnaire and a follow-up questionnaire at their next visit. All the participants performed a simple Pulmonary Function Testing (PFT) using a Koko Legend II Spirometer. The Spirometer was calibrated at the beginning of each day. Physical examination was performed by the Pulmonologist who also informed the subject about the PFT’s results. Smokers were briefly advised regarding smoking cessation. Two follow-up visits were done after one and two years.

Terms and Measures
Spirometry was done according to the ATS/ERS guidelines [13] and Forced Expiratory Volume in the first second (FEV1) as well as Forced Vital Capacity (FVC) were obtained. In accordance with Gold recommendations [14] FEV1/FVC ratio of less than 0.7 was used to diagnose an obstructive disorder. The severity of the obstructive disorder was defined by the FEV1 predicted percentage. FEV1 higher than 80% was defined as a mild obstructive disorder, 50- 80% as a moderate obstruction, 30-50% as a severe obstruction and values less than 30% as a very severe obstructive disorder. FVC values of less than 80% of the predicted value were defined as suggestive of a restrictive pulmonary disorder.

Other Parameters Included
Weight, height, years of service, smoking habits and respiratory complaints as reported by subjects at every visit. We also asked subjects to report the number of hours they had been exposed to smoking both actively and passively during the last 24 hours before they performed the pulmonary function test. In order to evaluate the level of exposure to fire the subjects were asked whether they were directly involved in the Carmel fire, and the number of fires they had been exposed to in the year prior to each testing. All data was recorded by the team in an Excel worksheet.

Data Analysis
Averages, standard deviations and absolute prevalence were calculated for all quantitative variables as well as 95% Confidence Intervals (CI) for all qualitative variables. To evaluate the base prevalence of an obstructive disorder with relation to smoking status and Carmel fire exposure we performed Chi-Square tests and a Fisher exact test. We used Eta and Pearson correlation coefficients to evaluate the strengths of correlations between active service years, participation in the Carmel forest fire, smoking pack years and exposure to smoking 24 hours before the Spirometry, with findings of an obstructive disorder, FEV1 and FVC values. In order to study the longitudinal changes in pulmonary functions with relation to smoking status and level of exposure to fire and smoke, we performed two-way ANOVA and Post-hoc tests. Criteria for acceptance of the research hypothesis for differences: Alpha(α) = 0.05, one-sided. Criterion for accepting research hypothesis for correlations: Alpha(α) = 0.05, two-sided. Data analysis was done with IBM SPSS Statistics V20 software.

Out of one hundred sixty-five firefighters working in the Jerusalem Firefighting Department that agreed to participate in the study, 153 were eligible for this study. Twelve subjects were administrative personnel and were therefore not included in the study. This group was not large enough to use as a control group. The study cohort was comprised mainly of male smokers in their 3rd to 5th decades of life of which about half participated in the Carmel forest fire (Table 1). For the second visit loss to follow-up was 14.4%, while another 13.1% were not included in the final statistical analysis because a full year had not passed since their first visit. In total, 111 subjects (72.5%) completed a second visit after one year. For the third visit, loss to follow-up was 22.2%, while another 34% were not included in the statistical analysis because a full year had not passed since their second visit. In total, 67 subjects (43.8%) completed three visits, after one year and after two years.

Obstructive Disorders and Pulmonary Function Parameters
An obstructive disorder was found in 6 subjects (3.9%; 95% CI, 1.5% to 8.3%). Five of these subjects also reported respiratory complaints but were never diagnosed before. While no subject had a severe obstructive disorder, 2 had a mild disorder and 4 had a moderate disorder. Throughout follow up no other subjects developed an obstructive disorder. All the subjects with an obstructive disorder were active smokers (Figure 1). Among smokers an obstructive disorder was present in 7% (95% CI, 2.2% to 14.9%) as opposed to 0% in those who had never smoked (95% CI, 0% to 6.4%).This difference was not statistically significant (p=0.102). Four of the subjects with an obstructive disorder participated in the Carmel fire (Figure 1). Of all subjects who participated in the Carmel fire, 5% were found to have an obstructive disorder (95% CI, 1.5% to 13.1%), while 3% of those who did not participate in the Carmel fire had an obstructive disorder (95% CI, 0.3% to 9%). This difference was also not statistically significant (p=0.322). A 13.1% prevalence rate of a restrictive pattern was shown in Table 1.

Table 1: Baseline study population characteristics.
Figure 1: Changes in FEV1 (a) and FVC (b) values in liters throughout a two year follow up of the general group: “All subjects” (Thick Black Line, n=67, p for trend a=0.078, p for trend b=0.0001) and subgroups: “Smokers” (Solid Triangle, n=52) and “Non- Smokers” (Empty Triangle, n=15, p for trend a difference=0.242, p for trend b difference=0.234), “Involvement in Carmel” (participated in the Carmel forest fire, Solid Diamond, n=41) and “No Involvement in Carmel” (did not participate in the Carmel forest fire, Empty Diamond, n=26, p for trend a difference=0.139, p for trend b difference=0.320).
We also analyzed the correlation between years of active duty and smoking status with pulmonary function parameters and the presence of an obstructive disorder or a restrictive pattern (Table 2). Lengthier service, heavier smoking and exposure to smoke in proximity to the time of testing showed a mild to moderate correlation with decreased pulmonary function parameters and were statistically significant (Table 2). The highest explained variance (29.48%) was between years of active duty and FEV1. All correlations with the presence of an obstructive disorder and a restrictive pattern were significant. The strongest correlation of 0.817 and effect size of 0.67 was for pack years and the presence of an obstructive disorder.

Table 2: Characteristics of correlations between exposures and pulmonary functions and respiratory disorders.
Assessment of Changes in Pulmonary Functions
Changes in FEV1 were statistically insignificant throughout follow up (Figure 1a). The average rate of FEV1 decline in the general group was 20 milliliters per year (95% CI, -50 to +10 mL/year). Smokers demonstrated an average FEV1 decline of 30 milliliters per year while non-smokers exhibited an average decline of 10 milliliters per year; this difference in changes (Figure 1a) and rates (Table 3) was statistically insignificant (p=0.242, p=0.176, respectively). The average decline in FEV1 among firefighters who had heavy fire exposure was of 30 milliliters per year. This rate was not significantly different from that of those with less fire exposure (40 milliliters per year, p=0.908). We found no significant differences in FEV1 changes between those who participated in the Carmel forest fire and those who did not. The general group had statistically significant changes in FVC throughout follow up (Figure 1b ) (p=0.0001) and exhibited an average decline of 110 milliliters per year (95% CI, -150 to -70 mL/year). Subgroup analysis showed no differences in changes (Figure 1b) and (Table 3).

Table 3: Rates of changes in pulmonary functions.
This is the first study to assess changes in pulmonary function among firefighters in Israel. We have found a prevalence of 3.9% of obstructive disorder in firefighters in Jerusalem. We did not find a statistically significant decline in FEV1, but we did find a significant decline in FVC. No significant differences were found among firefighters with different levels of exposure to fires including the Carmel forest fire. It appears that firefighters in Jerusalem are in general healthy with a low prevalence of obstructive disorders. It also seems the Carmel forest fire did not have an impact on the respiratory health of the firefighters who were involved. Our findings are consistent with those of other researchers. We found that the prevalence of obstructive disorders is lower than that reported in the general population of 10% [15] and similar to that reported in New York City firefighters [12]. The rate of FEV1 decline (-20 milliliters per year) is lower than the one measured in the general population (-30 milliliters per year) [16]. It is fair to assume that the reason for these findings is the healthy worker phenomena [17], in which a selection bias causes the exclusion of un-healthy workers who retire from the workplace or are not hired in the first place and the inclusion of healthy workers who continue to work.

Furthermore, it is possible that subjects who did develop a pulmonary disorder left their workplace and therefore our tests found a lower prevalence of obstructive disorders. Our research showed a negative correlation between years of service and FEV1 as well as FVC values (Table 2). This finding suggests that firefighting might be hazardous to the respiratory system leading to diminished pulmonary function parameters. However, we did not discover any findings suggesting long term pulmonary harm following involvement in the Carmel fire nor did we find significant differences between heavy and light fire exposure. This could indicate that forest fire exposure is different from the exposure in the WTC rescue operations. Although it is not possible to diagnose a restrictive lung disorder with simple Spirometry, we did note that the prevalence of a restrictive pattern (13.1%) was greater than that of an obstructive disorder. We also found a significant decline in FVC values (Figure 1b). A decline of 110 milliliter per year in FVC is of concern and should prompt continued follow up. Similar findings have been described in large studies among firefighters in the USA [8-12]. A possible explanation for this is the acquirement of restrictive lung diseases. For this reason, we believe that it is important to address these findings and conduct further research to identify possible restrictive lung diseases in firefighters, by doing serial lung volume measurements and follow up chest X-ray.

Although we did not find a significant difference in the prevalence of obstructive disorder between smokers and non-smokers our findings suggest that smoking affects pulmonary functions more than fire exposure (Table 2). It is likely that we failed to demonstrate a significant difference due to our small sample size. Regardless, it is important to note that 23.8% of smoking firefighters quit smoking following our brief smoking cessation counselling. This finding suggests that pulmonary function screening (Spirometry) coupled with a brief consultation to stop smoking is a crucial tool in smoking cessation, especially among firefighters. Another finding was a negative correlation between smoking immediately prior to testing and pulmonary functions (Table 2). This adds to the results of other researchers [18] about the immediate effect of smoking on pulmonary functions. This effect should be taken into consideration when performing Spirometry. Another incidental finding included the fact that at least two of the 56 subjects who were lost to follow up acquired neoplastic diseases. One had lung cancer and the other had lymphoma. Since we did not manage to contact all of the subjects who dropped out, there is a possibility that the incidence of these diseases is greater and could possibly require further evaluation in firefighters. Our study has several limitations, the most important of which is the sample size during continued visits. Three main factors influenced the loss to follow up. First, some firefighters were relocated to other cities. Second, developments in the security situation in Jerusalem prevented us from reaching subjects in a remote area of the city. Third, some of the subjects were recruited during 2015 and 2016 and could not be included in the follow up after one or two years (a full year had not passed since their first visit).

Another important limitation is that the time frame we followed our subjects was short compared to other researches. It is likely that more than 3 annual visits are required to gain a better understanding of the changes in pulmonary function parameters. In summary, we found a low prevalence of obstructive disorders in firefighters as well as an insignificant decline in FEV1 most likely due to the healthy worker phenomenon. We weren’t able to show any hazardous effects related to the Carmel fire similar to those reported among the WTC rescue workers. This is probably due to the different type of exposure in forest fires. We did find a concerning decline in FVC and the emergence of a restrictive pattern in lung function studies which requires further evaluation for restrictive lung disorders. Our study suggests that firefighters are not at increased risk of obstructive disorders but could be at risk for restrictive lung disorders. We also demonstrated that a brief consultation regarding smoking cessation coupled with pulmonary function test led to a smoking cessation rate of 23.8%. Further follow up and studies are required to evaluate the respiratory risks firefighters face.

The Effects of High and Low Dose Nicotine Administration on Neurogenesis-

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The Effects of High and Low Dose Nicotine Administration on Neurogenesis

The Effects of High and Low Dose Nicotine Administration on Neurogenesis


Tobacco is the most important substance abuse during pregnancy. About 20% of pregnant women smoke during their pregnancy. While pregnant women smoke, the developing fetus is exposed to nicotine, the main psychoactive component of tobacco and tobacco smoke ingredients [1,2]. Various pharmacological doses of nicotine during gestation have been tested and nicotine exposure alone is expected to be less harmful to the fetus than cigarette smoke [3]. Nicotine effects the dopaminergic and cholinergic neurochemical systems and alters the physiological and behavioural situations in the offspring [4]. During the development of the brain, neurotrophins are very important factors for neuronal plasticity proliferation, survival, development, and plasticity of neurons. One of the members of the neurotrophin family is Brain- Derived Neurotrophic Factors (BDNF). BDNF influences GABAergic neuronal phenotype [5]; regulates the efficacy of GABAergic synapses [6].

The other specific protein of neurons is the neuronal specific nuclear protein (NeuN). Monoclonal antibodies to the NeuN protein is important for neuronal differentiation. The normal and pathologic functions of neurons are evaluated by using this marker [7]. The other one of the specific protein is S100 protein. These proteins are called S100 because of their solubility in a 100%-saturated solution with ammonium sulfate at neutral pH [8]. These proteins are produced by astrocytes in the Central Nervous System (CNS). S100 protein’s functions are regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism and inflammation within cells [9]. In the present study, we investigated the effects of high and low dose nicotine administration on neurogenesis with immunohistochemical methods. Brain Derived Neurotrophic Factor (BDNF), Neuronal Specific Nuclear Protein (NeuN) and S-100 protein were analysed to evaluate the neurons and neuroglial cells in the rat hipocampus.

In this study, approved by the Animal Ethics Committee of Ege University School of Medicine (Bornova, Izmir, Turkey), the off springs of Swiss Albino rats were used. They were housed in a temperature-controlled room with a 12-hour light/dark cycle and maintained on standard laboratory animal chow and provided water ad libitum. All animals used in this study were maintained in accordance with the guidelines for animal welfare. Firstly, 10 female Swiss Albino rats were divided into 2 main groups; as a nicotine group (n=5), and a control group (n=5). They were conceived by adding 2 male rats to each group. While the control group was given normal drinking water, 0.4mg/kg BW-body weight nicotine was prepared freshly every day and added to the nicotine group’s drinking water. After birth, the off springs were left in the same cage with their mothers and fed through lactation. At the end of the sixth week as soon as the pups started to normal feeding, the pups in the nicotine group were divided split into 2 groups; one to be subjected to low, and one to high doses of nicotine (Low dose nicotine-LDN, 0.4mg nicotine/kg BW/day; High dose nicotine-HDN, 6.0mg nicotine/kg BW/day). In this way, we formed 3 groups; as control (n=10), LDN (n=10) and HDN (n=10) groups. At the end of the 12th month, rats were sacrificed under general anesthesia (ketamine 75 mg/kg ve xylazine 10 mg/kg i.p.) and their craniums were dissected so that their brain samples could be taken out.

The right brain samples containing the hippocampus were fixed in 10 % formaline solution and were prepared according to the routine paraffin tissue protocol and were embedded in paraffin. Five μm serial sections were taken on the polylisine coated lams and were stained histochemically with Hematoxylin-Eosin staining. After histological evaluation, serial sections, including the hippocampus were stained by using the immunohistochemical technique. In the samples, anti-BDNF, anti- NeuN, anti-calbindin, anti-S100 and anti-GFAP primary antibodies were used to determine whether nicotine exposure had any effect on the immunohistochemical distributions of these antibodies on neurons and neuroglial cells. Immunoreactivity scores were determined by using the semi-quantitative method. The intensity of immunoreactivity was evaluated as mild (+), moderate (++) or strong (+++) and the results were compared via using the ANOVA statistical test.

Hippocampus samples of study groups in paraffin blocks were stained with H&E and the molecular, pyramidal and polymorphic stages of the hippocampus were investigated under Olympus microscope (Olympus, Center Valley, PA) (Figure 1). Micrograph of control, N and S group’s neurons were active and included euchromatic nucleus. It was observed that whether the intense of BDNF immunoreactivities in the control group’s neurons were mild/moderate (+/++), the intense of BDNF immunoreactivities in nicotine group’s were moderate/strong (++/+++) (Figure 2). It was observed that whether the intense of Neuron Specific Neuronal Protein (NeuN) immunoreactivities in the control group’s neurons were mild/moderate (+/++), the intense of NeuN immunoreactivities in nicotine group’s were moderate (++) (Table 1) (Figure 3).

Figure 1: Hipocampus samples of study groups in parafin blockes. As the nicotine dose increased, a decrease in the number of neurons and shrinkage of cells and chromatolysis were observed. X40 (A), X100 (B), X200 (C), X400 (D).
Figure 2:Micrograph of control, N and S group’s neurons BDNF immunreactivities. X40 (A), X100 (B), X200 (C), X400 (D). The number of BDNF positive stained cells in hippocampus and ventricle was significantly higher than control groups.
Figure 3: Micrograph of control, N and S group’s neurons BDNF immunreactivities. X40 (A), X100 (B), X200 (C), X400 (D). The number of positive stained cells with S100 immunreactivities in nicotin group’s neuroglial cells was higher than the control group.
Table 1: Immunreactivity scores of the study groups.
In this study, the effects of pre/postnatal nicotine administration on neurogenesis was investigated. For this purpose; BDNF, NeuN and S100 protein immunoreactivities were analyzed by indirect immunohistochemical methods. When Joseph Altman showed the cell proliferation in adult hippocampus and bulbus olfactories, the studies on neurogenesis were accelerated [10]. Neurogenesis refers to the birth of neurons. In other words, it means as a process of producing neurons from neural stem cells. Neurogenesis has been implicated in the most prenatal period [11]. BDNF expression in the brains of laboratory animals was increased by behavioural interventions such as exercise and training /learning [12]. In this study new neurons and BDNF immunoreactivities of neurons in the hippocampus were found to be increased via nicotine administration. BDNF is a member of neurotrophins and it is widely expressed in the hippocampus, septum, cortex, and in adrenergic brainstem nuclei [13]. The dependency behaviors associated with the effect of addictive drugs are regulated by the change in BDNF concentration [14]. BDNF is important in regulating cell survival and prognosis. The results of Kenny et al. showed that acute administration of nicotine decreases BDNF level whereas chronic nicotine increases BDNF levels in the hippocampus [15].

Additionally, long-term low and high dose nicotine administration increased the neurotrophic factors in rat hippocampus. According to these findings, we thought that nicotine might be effective in adult neurogenesis. NeuN immunoreactivities were increased in the nicotine group. It is suggested that this neuron-specific antigen is an early marker of neuronal differentiation [16]. The hippocampal formation was processed for immunohistochemical staining of NeuN. Nicotine caused to a decrease in the number of NeuN (+) cells dose-dependently [17]. In contrast, Nagai T et al. showed that nicotine increased NeuN protein immunoreactivity in the hippocampal neurons [18]. Dentate gyrus has important functions in learning, memory and adult neurogenesis. The previous studies showing that Dentate gyrus proliferation is unaltered by short-term nicotine administration and the later stages neurogenesis may not be affected because of the lack of neurogenic effects [19].

S-100 protein is a dimeric, acidic calcium-binding protein which is a major component of the cytosol, particularly in astroglial cells. S- 100 protein has two subunits, S-100 A and S-100 B. S-100 B protein has regulatory functions on cell shape, growth, differentiation, and energy metabolism. S100 protein is a major component of astroglial cells. Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a glial scar, repairing the area and replacing the CNS cells that cannot regenerate so, nicotine might repair the nervous system by the indirect way. S 100 B protein levels are increased with acute cerebral damage [20]. Kenangil G et al. suggested that serum S-100 B measurement can be used as an early marker of brain damage [21]. In our study, anti S 100 immunoreactivities were higher in the nicotine group than the control group. It has been recently shown that nicotine was affecting memory and learning during adolescence. Considering the role of the hippocampus in both memory and learning, we investigated whether adolescent nicotine administration elicits apoptotic cell death and whether this results in neuronal and/or glial density alterations in the hippocampus [22].

In Alzheimer’s disease, the hippocampus is one of the first regions of the brain suffering from damage; memory problems and disorientation which appear frequently among the first symptoms. Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy.

Nicotine, the psychoactive ingredient in tobacco, can be neuroprotective but the mechanism is not exactly known. Nicotine administration can increase the expression of neurotrophic factors and growth factors. These factors can contribute to nicotine’s neuroprotective effects [22]. Nicotine exposure can enrich the reduced number of neurons or intraneuronal connections which are decreasing with aging so it can prevent or delay dementia [23]. The role of nicotine in neurodegenerative disorders is still incompletely understood, but it is suggested that progression of these diseases is related to oxidative stress, resulting from either a decrease in antioxidant levels or an increase in reactive oxygen species or reactive nitrogen species. Nicotine has both antioxidant and prooxidant effects [24]. More clinical studies are needed in this situation. 

Time of Maximum Action of Leaf-Methanol Extract of Pseudopanax arboreus (Araliaceae) on the Sexual Activity of Amitriptyline-Induced Sexually Impaired Male Rats-

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Time of Maximum Action of Leaf-Methanol Extract of Pseudopanax arboreus (Araliaceae) on the Sexual Activity of Amitriptyline-Induced Sexually Impaired Male Rats

Time of Maximum Action of Leaf-Methanol Extract of Pseudopanax arboreus (Araliaceae) on the Sexual Activity of Amitriptyline-Induced Sexually Impaired Male Rats

Leaves of Pseudopanax arboreus have been employed traditionally for male potency and virility for almost a century by the people of the Bayang Tribe of the Manyu Division of Cameroon without any scientific investigation. According to their folk medicine, its leaf-maceration is used to improve on male sexual performance or treat male sex-related ailments such as Erectile Dysfunction (ED), ejaculatory dysfunction, disorders of sexual desire and low sperm count by administering a total daily volume of 250 ml of maceration of 20 leaves to an adult male. In previous studies, we evaluated the effects of its leaf-aqueous extract on the sexual behaviour of normal male rats [1] and the effects of the leaf-methanolic extract on the sexual activity of amitriptyline-induced sexually impaired male rats [2]. In the present experiment, we aimed at determining the time of maximum action of the leaf-methanol extract of the plant on the sexual activity of amitriptyline-induced sexually impaired male rats using the number of ejaculatory series produced within every 30 minutes of observation.

Materials and Methods
Plant Material
Fresh leaves of P. arboreus were harvested from Mamfe and authenticated with the previous sample deposited at the National Herbarium in Yaounde at the voucher number 2734/SRFK (YA). Meanwhile, the extract was processed and administrative doses determined as described in our previous study [2].

Animals used were rats of the Wistar Strain of either sex that were bred in the Animal House of the Department of Zoology and Animal Physiology of the Faculty of Science, University of Buea under standard conditions of temperature, humidity and light (12H cycle). Females used as stimuli were brought into estrus following ovariectomy and subsequent sequential injection of 66.67μg of estradiol benzoate and 600μg of progesterone solutions, with the 2 injections separated by 48 ours and the progesterone administered 6 hours prior to observations [1-7]. The research protocol was approved by the University of Buea Institutional Animal Care and Use Committee (UB-IACUC) and an ethical clearance number (UB-IACUC No 003/2018) was given.

Experimental Design
Sexual impairment was induced according to the method described by Neelesh et al. [8] and like in our previous study [2]. Briefly, sexually trained males were subjected to chronic (56 days) administration of an oral dose of 10 mg/kg body weight of amitriptyline hydrochloride suspension (suspension prepared daily in distilled water). At the end of the 8th week (on day 57) after treatment with amitriptyline, they were randomly selected, their sexual performance assessed and only those that showed low libido, low arousal and delayed ejaculation were recruited into the next phase of the experiment. They were then divided into 4 groups of 8 rats each and treated as follow: groups 1 and 2 received 10ml/ kg distilled water and 6mg/kg of Viagra to serve as the neutral and positive controls respectively; while groups 3 and 4 were administered 46.5 and 93mg/kg of the leaf-methanol extract of P. arboreus. Males were housed singly in standard propylene cages and 30 minutes after administration of either substance, an estrous female was introduced into the cage and the sexual activity of the male evaluated. Treatment lasted for 3 calendar weeks (21 days) with sexual performance evaluated at the end of each week. The number of ejaculatory series produced within each 30 minutes of observation were noted. Each observation session lasted for 120 minutes but was considered terminated once the Mount Latency (ML) or Post Ejaculatory Interval (PEI) was 20 minutes.

Statistical Analyses
Values were expressed as Mean ± SEM. Mean values were calculated for each animal and quantitative comparisons between groups established from those means. Analysis of Variance (ANOVA) repeated measures followed by Duncan test were done using SPSS for windows version 20.0. Significant levels were tested at p< 0.05.

Results and Discussion
The time-effects of the leaf-methanol extract on the sexual performance of sexually impaired male rats are shown in Table 1. Generally speaking, although withdrawal of the drug resulted in improvement on the sexual activity, treatment with the leaf-methanol extract induced a significant (p< 0.05) increase in sexual performance, with a maximum effect noted on day 14 of treatment between the 60th and the 89th minute of observation. As shown in the Table, while sexual performance of extract-treated animals improved in a dose-dependent manner from day 1 through day 21 of treatment, the reverse was noticed with the Viagra-treated animals, whereas no significant change was noticed in distilled water-treated rats. The decrease in effect with duration of treatment noticed in Viagra-treated rats could be due to pharmacodynamic tolerance, which occurs when the same concentration at the receptor site results in reduced effect with repeated exposure [9,10]. On the contrary, the leaf-methanol extract of P. arboreus dosed at either 46.5 or 93mg/kg daily can be said to take 2 weeks or 14 days to reach full effect. This can be explained by the delay in the turnover of mediators of its actions that each probably has a half-life of several days. The physiological actions of the plant extract are a consequence of cumulative drug action [11,12].

Table 1: Number of ejaculatory series produced by amitriptyline-induced sexually impaired male rats treated with the leaf-methanol extract of Pseudopanax arboreus.
Note: Mean ± SEM; DW: Distilled Water; ME: Methanol Extract; A: Significant when compared to the neutral control (distilled water); p< 0.05.

Atypical Presentation of Synovial Osteochondromatosis At the Subtalar Joint Mimicking A Fracture Following Trauma: A Case Report-

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Wednesday, December 2, 2020

Atypical Presentation of Synovial Osteochondromatosis At the Subtalar Joint Mimicking A Fracture Following Trauma: A Case Report

Atypical Presentation of Synovial Osteochondromatosis At the Subtalar Joint Mimicking A Fracture Following Trauma: A Case Report

Synovial osteo chondromatosis (SOC) are benign tumors arising from synovial tissue of joints, bursae or tendon sheath. These synovial tissues undergo metaplasia to form cartilaginous or osteocartilaginous bodies which may break off from the synovial surface, causing pain or mechanical blockage to the joint [1]. Involvement is usually monoarticular, with the large joints being most frequently affected. The knee joint is involved in 60 to 70% of cases; the shoulder, elbow, and hip are the next most frequently involved joint. It rarely involves the joints of the foot and ankle region [2]. Here we report an atypical presentation of primary SOC of the right subtalar joint in a middle age gentleman, who presented with pain of the right ankle and was misdiagnosed as a right talus fracture, after a traumatic fall in his workplace.

Case Report
A 40-year-old male was referred to our Orthopedic Department with a history of trivial fall one week ago in his workplace and was diagnosed as a right neck of talus fracture. It is associated with pain and limited range motion of the affected ankle especially on eversion and inversion of ankle. He denied any pain or swelling over the ankle region prior to the above injury. On examination, there is a localized swelling just anterior to the lateral malleolus. On palpation it was tender and firm in consistency. The pain was aggravated with passive inversion and eversion of the subtalar joint. The ankle was otherwise stable. All bloods investigations were normal. Radiographs of the right ankle showed a large calcified mass that contained multiple radiopaque bodies, lateral to the subtalar joint. From the lateral view, there appeared to be a suspicious fracture line traversing the neck of talus (Figure 1). As we were unable to rule out a fracture, we proceeded with a CT scan of the right ankle that reported no obvious fracture but revealed a large bony mass measuring 5x4x4 cm within the sinus tarsi and extending to the lateral aspect of the ankle joint (Figure 2).

In view of the benign presentation of the tumor an excision biopsy was performed. The surgery was done through anterolateral approach to the talus, exposing the whitish bony hard mass that was sitting in the region of the sinus tarsi. Intraoperative findings showed a solitary whitish bony tumor measuring about 5x4x4 cm in size (Figure 3a), which was encased by hypertrophied synovium. The disease was noted to have eroded the adjacent plantar surface of the talar neck. The tumor was removed as a whole and sent for histopathology examination (HPE). The section showed few chondorocytes arranged in lobules within the synovial which was consistent with synovial chondromatosis. No nuclear atypia was seen, ruling out malignancy (Figure 3b).

Figure 1: a) AP view of the right ankle showing a calcific mass (arrow) that appears to be in continuity with the subtalar joint. b) Lateral view of the right ankle showing multi-lobulated calcified mass overlapping the talus with a mistaken fracture line at the neck of talus (arrow).
Figure 2: Mid-coronal view of the CT scan showing a bony mass (arrow) arising from the sinus tarsi of the right ankle joint, extending laterally.
Figure 3: a) Gross specimen of the glossy white osteocartilaginous tumor which was encased by hypertrophied synovium. b) Section from tissue showed clusters of chondrocytes (arrow) arranged in lobules consistent with diagnosis of SOC, without cellular atypia, ruling out malignancy.
Post operatively the patient’s ankle was immobilized with a below knee backslab for 2 weeks for pain management. After 2 weeks, he was allowed full weight bearing and referred to the physiotherapist for interferential and isometric therapy to achieve full range of movement and functional outcome of the affected ankle [3]. Patient was followed up for 1 year post-operatively and was ambulating normally without pain. There were also no clinical or radiographic evidence of recurrence.

The exact prevalence of SOC is unknown, but the disorder is rare worldwide. Occurrence are more common among males age between 20-40 years, and only a few case reports have described the condition occurring in children [4]. It commonly occurs in synovial joints including the knee, hip and shoulder. However, it is rarely seen in the foot and ankle region [2]. SOC may be divided into primary and secondary forms. Primary SOC differs from its secondary counterpart as it occurs in an apparent normal joint whereas secondary SOC develops in patients with pre-existing arthritis [5]. The pathogenesis of SOC can be divided into three stages. In stage one, there is only active synovial disease without presence of loose bodies. Stage two disease would include formation of loose bodies on top of active synovial disease and stage three would only have loose bodies without evidence of synovial disease. In our patient, the SOC was in stage two as evident by the bony tumor being encased by hypertrophied synovium after excision biopsy.

Patients usually present with a palpable nodule, mono-articular pain, swelling, stiffness with or without mechanical symptoms of the joint involved. On examination of the joint, there may be effusion, non-tender palpable mass with reduction of the range of motion. The blood investigations are normal and plain radiographs show large nodules with stippled or ring like calcified opacities. Secondary widening of the joints space may also be noted. CT scan is useful to detect calcified intra-articular loose bodies, bony erosions and the real extent of the lesion, which are difficult to assess using a plain radiograph. In cases like the above, a CT scan would also be useful to exclude the diagnosis of a fracture. Magnetic resonance imaging (MRI) is useful to evaluate the status of the ligaments and adjacent articular cartilage especially when the disease is at its early stages. Tissue biopsy remains the gold standard of diagnosis and will provide useful information to exclude other differential diagnosis especially malignant conditions [4].

Treatment of patients with SOC are tailored according to their presenting symptoms. Asymptomatic patients do not require surgical management and mere observation with regular follow-ups would be sufficient. In patients presenting with pain, or mechanical symptoms, surgical management may be offered. The traditional surgical approach is an open arthrotomy of the joint with removal of all loose bodies with extensive synovectomy. Recent advancements have enabled these loose bodies to be removed arthroscopically [6]. In the present case, open surgery was performed due to its large size and tightness of the subtalar joint.

Patients with SOC must also be counselled regarding the risk of recurrence. The recurrence risk after surgical removal are variable ranging from 3.2% to 22.3% [7]. In the above patient, there was no evidence of recurrence in six months post-operatively, but longer follow-up must be done in case of future recurrence.

Primary SOC even though rare in the foot and ankle region, must be taken into consideration in patients presenting with slow growing benign bony mass over the mentioned joint. Surgical excision offers good functional outcome with low rates of recurrence.

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