Hospital workers mental health during the COVID-19 pandemic: methods of data collection and characteristics of study sample in a university hospital in Milan (Italy).

BACKGROUND: The COVID-19 pandemic is currently a severe challenge for healthcare workers, with a considerable impact on their mental health. In order to focus preventive and rehabilitation measures it's fundamental to identify risk factors of such psychological impairment. We designed an observational longitudinal study to systematically examine the psychological wellbeing of all employees in a large University Hospital in Italy, using validated psychometric scales in the context of the occupational physician's health surveillance, in collaboration with Psychiatric Unit. METHODS: The study started after ethical approval in August 2020. For each worker, the psychological wellbeing is screened in two steps. The first level questionnaire collects sociodemographic characteristics, personal and occupational COVID-19 exposure, worries and concerns about COVID-19, general psychological discomfort (GHQ-12), post-traumatic stress symptoms (IES-R) and anxiety (GAD-7). Workers who score above the cut-off in at least one scale are further investigated by the second level questionnaire composed by PHQ-9, DES-II and SCL-90. If second level shows psychological impairments, we offer individual specialist treatment (third level). We plan to follow-up all subjects to monitor symptoms and possible chronicization; we aim to investigate potential risk factors through univariate analysis and multivariate logistic regressions. RESULTS: Preliminary results refer to a sample of 550 workers who completed the multi-step evaluation from August to December 2020, before vaccination campaign started. The participation rate was 90%. At first level screening, 39% of the subjects expressed general psychological discomfort (GHQ-12), 22% post-traumatic stress symptoms (IES-R), and 21% symptoms of anxiety (GAD-7). Women, nurses, younger workers, subjects with COVID-19 working exposure and with an infected family member showed significantly higher psychological impairment compared to colleagues. After the second level screening, 12% and 7% of all workers showed, respectively, depressive and dissociative symptoms; scorings were significantly associated with gender and occupational role. We are currently extending sample size and evaluating subjects over a period of further 12 months. CONCLUSIONS: The possibility to perform a systematic follow-up of psychological wellbeing of all hospital workers, directly or indirectly exposed to pandemic consequences, constitutes a unique condition to detect individual, occupational, and non-occupational risk factors for psychological impairment in situations of prolonged stress, as well as variables associated with symptoms chronicization.

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

[p53 expression in the gastric mucosa of patients infected with Helicobacter pylori]. / p53 expresado en la mucosa gástrica de pacientes infectados por Helicobacter pylori.

BACKGROUND: Helicobacter pylori (Hp) is recognized as a type 1 carcinogen for gastric cancer associated with pre-neoplastic lesions (atrophy and intestinal metaplasia [IM]). Its relation with p53, which intervenes in the cell cycle, has had contradictory results. AIMS: To analyze p53 expression in gastric mucosa and its relation with Hp infection. METHODS: A 3-month prospective, observational, cross-sectional study was conducted. Patients that had no evidence of acute or clinically significant gastric pathology had biopsies taken according to the Sydney system at the Hospital Juárez de México and the histopathologic studies were done at the Hospital Español de México. RESULTS: Hp prevalence was 32.7% in 104 patients. There were no cases of atrophy or dysplasia. A total of 91% of the infected patients were positive for p53. Of the non-infected patients, 14% were positive for p53 and 60% of them had IM. Of the IM patients, 75% presented with positive p53. Of the patients without IM, 31 presented with positive p53, and Hp was positive in 85% of them. There was association between Hp and p53 and between p53 and IM (P<.0001 and P<.0006, respectively). CONCLUSIONS: Significant association was shown between Hp and p53 expression, even in patients with pre-neoplastic lesions that no longer presented with Hp. Given that the identification of pre-neoplastic lesions is important for the prevention of cancer, immunohistochemistry could benefit routine biopsy carried out during endoscopy for the detection of Hp, by identifying patients with expression of the important oncogene regulator, p53.

Maxillofacial Injuries in Padel Game.

Background: Maxillofacial injuries are very frequent in the sports environment. Padel is a new sport of Mexican origin, very popular in Mexico, Spain, and Italy, but with a rapid spread in Europe and other continents. Aims: The aim of this article is to report our experience of 16 patients with maxillofacial injuries that occurred during padel matches in 2021. All these injuries occurred due to the racket bouncing against the glass of the padel court. The bounce of the racquet is given either because the player was trying to hit the ball near the glass or by throwing the racket against the glass for an act of nervousness. Methods: We carried out a literature review about sports traumas, and we calculated the possible force with which the racket, once bounced off the glass, hits the players' faces. Results and Conclusions: The racket, bouncing off the glass wall, arrives with a specific force in the face of the player who threw the racket, being able to cause skin wounds, injuries, and fractures mainly at the level of the dentoalveolar junction.

Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement.

OBJECTIVE: The aim of this study was to investigate the relationship between SP-D and KL-6 serum concentrations and the extent of interstitial lung involvement, as measured by a quantitative HRCT score and the functional impairment, in patients with systemic sclerosis (SSc). Moreover we analysed the association between these lung-specific biomarkers and skin involvement, anti-Scl-70 antibody titres and an index of disease activity. METHODS: Serum SP-D, KL-6 and anti-Scl-70 concentrations were determined by ELISA in 25 SSc patients. Disease activity and lung function parameters were assessed, and the extent of ILD was measured by a HRCT score. RESULTS: SP-D and KL-6 concentrations were higher in patients with SSc and lung fibrosis than in healthy controls. KL-6 correlated positively with the HRCT-fibrosis score (r=0.68, p<0.001), SP-D showed a weaker correlation (r=0.44, p=0.025). Increased KL-6 concentrations were associated with decreased DLCO and decreased FVC in SSc patients, SP-D showed no association. Furthermore KL-6, but not SP-D, showed a strong association with skin involvement as expressed by the modified Rodnan skin score (r=0.71, p<0.0001) and a disease activity index (r=0.73, p<0.0001). CONCLUSION: KL-6 is more strongly associated than SP-D with the HRCT-fibrosis score, and, different from SP-D, it correlates with skin involvement and disease activity. We suggest that KL-6 may be a useful biomarker in the assessment of scleroderma patients.

Analysis of a CT patient dose database with an unsupervised clustering approach.

PURPOSE: This study investigated the benefits of implementing a cluster analysis technique to extract relevant information from a computed tomography (CT) dose registry archive. METHODS: A CT patient dose database consisting of about 12,000 examinations and 29,000 single scans collected from three CT systems was interrogated. The database was divided into six subsets according to the equipment and the reference phantoms in the definition of the dose indicators. Hierarchical (single, average, and complete linkage, Ward) and not hierarchical (K-means) clustering methods were implemented using R software. The suitable number of clusters for each CT system was determined by analysing the dendrogram, the within clusters sum of squares, and the cluster content. Summary statistics were produced for each cluster, and the outliers of the dose indicator distribution were investigated. RESULTS: Ward clustering identified the most common combinations of scanning parameters for each group. The optimal number of clusters for each CT equipment system ranged from 5 to 15. The main diagnostic applications were then extracted from each cluster. Outlier analysis of the dose indicator distribution of each cluster revealed potential improper settings that resulted in increased patient dose. CONCLUSIONS: Clustering methods applied to CT patient dose archives provide a quick and effective overview of the main combinations of currently used exposure parameters and the consequences for dose indicator distributions, also when protocol labels and/or study descriptions are not homogeneous.

Effects of preparation and experimental conditions on removal of phenol by surfactant-modified zeolites.

The removal of phenol from aqueous solutions using surfactant-modified clinoptilolite-rich tuffs (SMZ) prepared from two Mexican zeolitic tuffs (Chihuahua and Oaxaca) was investigated. Sodium homoionization of the zeolitic rocks was performed before they were modified with the surfactants: hexadecyltrimethylammonium chloride or bromide and bencylcetildimethylammonium chloride. The surfactants in the modified zeolitic materials were determined considering the total carbon in the samples. The phenol removal was determined in a batch system taking into consideration the different quantities of surfactants in the zeolitic tuffs, contact time, pH and initial phenol concentration. The phenol was determined in the aqueous solutions by UV/Vis spectroscopy. Results showed that the formation of a hemimicelle or admicelle on the zeolites depended on the initial surfactant concentration and they were responsible for the type of interactions between the phenol and the surfactant-modified zeolites. Phenol adsorption by the surfactant-modified zeolites was carried out in approximately three hours. Phenol adsorption data was best adjusted to the pseudo-second order kinetic model. Both, surface properties of the surfactant-modified zeolites and pH of solution play an important role in the removal of this pollutant from aqueous solutions and they are responsible for the type of mechanism involved.

Inter-sexual habitat and isotopic niche segregation of the endangered Monteiro's storm-petrel during breeding.

At-sea distribution and trophic ecology of small seabird species (i.e.<100 g) is far less known when compared to their larger relatives. We studied the habitat use (spatial ecology) and isotopic niches (trophic ecology) of the endangered Monteiro's storm-petrel Hydrobates monteiroi during the incubation and chick-rearing periods of 2013. There was a sexual foraging segregation of Monteiro's storm-petrels during the breeding period (tracking data) but also during the non-breeding stage (stable isotope analysis). Females took advantage of their longer wings to forage over the shallower Mid-Atlantic ridge (MAR) north of Azores, under colder and windier regimes when compared to males, who mostly exploited northern deep waters comparatively closer to the breeding colony. Between-sex differences in the spatial distribution were more obvious during the incubation period, with the overlap in their distribution increasing during the chick-rearing phase. There was also an isotopic segregation between sexes both during the previous breeding and the non-breeding stages, with females exhibiting a narrower, lower level isotopic niche when compared to males. Though the distribution patterns reported here should be useful for the at-sea conservation of this endangered species, future research should focus on (1) performing year-round tracking to map the species' distribution during the non-breeding period and (2) gathering multi-year tracking information to understand the effect of inter-annual environmental stochasticity on the foraging choices and trophic habits of the species.

Excess of beta-subunit of thyrotropin (TSH) in patients with idiopathic central hypothyroidism due to the secretion of TSH with reduced biological activity.

alpha-Subunit and beta-subunit of TSH were measured in the sera of five patients with idiopathic central hypothyroidism due to the secretion of biologically inactive TSH, in seven normal controls matched for bone age and sex, and in five subjects with mild primary thyroid failure before and after TRH (200 micrograms, iv) stimulation. Basal serum alpha-subunit concentration in patients did not differ from that in normal controls (mean +/- SD, 0.40 +/- 0.20 vs. 0.38 +/- 0.28 ng/ml; P, NS), whereas TSH and TSH-beta were significantly higher in patients (TSH, 1.51 +/- 0.74 vs. 0.59 +/- 0.53 ng/ml, P less than 0.025; TSH-beta, 0.56 +/- 0.18 vs. 0.10 +/- 0.02 ng/ml, P less than 0.001). The concentration of TSH-beta was also significantly higher in patients with central hypothyroidism than in subjects with mild primary thyroid failure (0.56 +/- 0.18 vs. 0.24 +/- 0.08 ng/ml; P less than 0.01), although serum TSH levels did not differ in the two groups (1.51 +/- 0.74 vs. 2.16 +/- 0.52 ng/ml; P, NS). alpha-Subunit was significantly higher in primary hypothyroid subjects (1.50 +/- 0.87, P less than 0.05 compared with patients with central hypothyroidism). After TRH, alpha-subunit, TSH, and TSH-beta net increases (peak) were significantly higher in patients with central hypothyroidism than in normal controls (alpha-subunit: 0.95 +/- 0.5 vs. 0.47 +/- 0.19 ng/ml, P less than 0.05; TSH: 7.1 +/- 3.1 vs. 2.9 +/- 1.8 ng/ml, P less than 0.005; TSH-beta: 0.89 +/- 0.35 vs. 0.22 +/- 0.18 ng/ml, P less than 0.005), whereas they did not significantly differ from those recorded in hypothyroid controls. The beta/alpha ratio, which was 1.67 +/- 0.86 in patients and 0.35 +/- 0.18 in normal controls (P less than 0.005), slightly decreased after TRH to 1.24 +/- 0.78 in patients, but remained unchanged in normal controls (0.39 +/- 0.1). After TRH the alpha-subunit peak occurred at 20 min both in patients and in controls, whereas TSH and TSH-beta peaked at 60 min in patients and at 20 min in controls. One patient was given oral TRH (40 mg/day for 4 weeks). The beta/alpha ratio fell from 1.85 to 0.13. Interestingly, serum thyroid hormones, which did not increase after iv TRH and after the first doses of oral TRH, showed a definite increase. Sera from two patients were filtered on Sephadex G-100: in one of them TSH-beta eluted in the same position as labeled reference standard, whereas in the other one radioimmunoassayable TSH-beta eluted near the void volume. The above data indicate that in patients with idiopathic central hypothyroidism due to biologically inactive TSH there is an excess of circulating TSH-beta and suggest that TRH is implicated in the secretion of TSH of full biological potency.

RBE of spleen CFU-S to low dose rate Cf-252 or photon radiation in vivo.

The biological effects of low dose rate (LDR) Cf-252 radiation were compared to LDR Cs-137 photon radiation and acute 60Co radiation. The RBEn for endogenous CFU-S in vivo was 2.1 for neutron radiation at a dose rate of 9.9 cGy/hr of Cf-252 radiation. The value was consistent with previous in vitro experiments where a value of 2.1 was found. For the low doses and low dose rates studied, we tested an acute assay dose following the LDR irradiation to determine dose-effect and RBEn. Organ size shrinkage and regeneration patterns after LDR Cf-252 and Cs-137 were also studied and showed greater growth delay for Cf-252 irradiated lympho-hemopoietic tissues.

Evidence for host resistance in 1,3 bis(2-chloroethyl)-1-nitrosourea treatment induced in syngeneic LSA lymphoma.

The anticancer agent 1,3 Bis(2-chloroethyl)-1-Nitrosourea (BCNU) cures the advanced syngeneic LSA lymphoma of C57BL mice with high efficiency. The cured animals resist further tumor challenge by large numbers of viable syngeneic tumor cells. Growth assays of spleen proliferation of the intravenously inoculated tumor revealed a progressive-regressive pattern of spleen growth after LSA-tumor injection. Lymphoma colony forming units (LCFU) in the spleen initially increased then regressed. In vitro assays of serum showed a lack of cytotoxic activity in mice cured by BCNU. Added spleen, thymus, or bone-marrow cells were similarly ineffective. Spleen and bone-marrow cells from immune mice passively transferred to normal mice showed weak cytotoxic activity against the LSA tumor. BCNU-cured mouse cells were more effective in protection than those cured with Chlorozotocin (CLZ).

Face recognition as a function of social attention in non-human primates: an ERP study.

Epidural event related potentials (ERPs) were recorded from four squirrel monkeys (Saimiri sciureus) during the presentation of pictoral stimuli that comprised real human and monkey faces. Subjects viewed tachistoscopically presented stimuli belonging to four different categories: familiar and unfamiliar human faces, and familiar and unfamiliar monkey faces. Familiar faces were subcategorized into top, middle and bottom according to the perceived individual's dominance ranking in a social hierarchy, as rated by human judges observing the group's social behavior. Waveform peak components to monkey and human faces showed similarities in their spatial distribution. However, larger amplitude N1 and N2 components were elicited in response to monkey compared to human faces, particularly over lateral temporo-parietal sites. A similar trend was observed for the P3 component, with maximal differences along midline electrode site. Responses to familiar and unfamiliar monkey faces showed larger N1s to familiar monkey faces and larger P3s to unfamiliar monkey faces. N1 and P3 components elicited by human faces showed no significant differences between conditions. N2 amplitudes were larger over posterior sites for top-ranked monkeys and larger over frontal sites for middle- and bottom-ranked monkeys. Top-ranked human faces elicited the largest N2 components, middle-ranked faces the next largest, and bottom-ranked faces the smallest. N1, N2, and P3 latencies were similarly sensitive to the ranking of human but not monkey faces. These data suggest that non-human primates exhibit evoked potentials to conspecific and non-conspecific faces that are similar in morphology but different in function. Larger amplitude responses to monkey faces suggests increased processing for that category of stimuli. Additionally, monkey ERPs reflect familiarity with conspecifics but not with human faces. Finally, the social status of the perceived individual, or at least the perceived threat posed by an individual, affects the latencies and magnitudes of ERP components produced by the viewer. These data are consistent with social attention hypotheses which propose that higher status (i.e. more dominant or socially meaningful) members of a group receive more attention than lower status individuals.

Event-related potentials in macaque monkey during passive and attentional processing of faces in a priming paradigm.

Epidural event-related potentials (ERPs) were recorded in monkeys using a priming (S1-S2) paradigm. One juvenile and 2 young adult macaque monkeys (Macaca fascicularis) viewed tachistoscopically presented pairs of faces in four possible combinations: human-human, monkey-monkey, monkey-human, human-monkey. Faces were presented upright to untrained subjects. Subsequently, one adult monkey was trained to associate the occurrence of a monkey-monkey pair of faces with juice reward. In a separate control experiment, the same stimuli were presented upside down. In both the upright and inverted conditions, adult monkey ERPs exhibited a P1-N1-P2 complex of peaks in the 400 ms following stimulus presentation. However, only upright faces elicited a prominent, widely distributed negativity (N4) in the 400-800 ms interval and a long-duration negativity (LDN) in the last 400 ms of the 1,400-ms epoch. N4 was earlier in latency, larger in amplitude, and larger over left hemisphere in response to monkey faces compared to human faces. It was also sensitive to the preceding or priming stimulus, exhibiting larger amplitudes when S1 matched S2 than when it did not. Trained monkey waveforms differed from untrained monkey responses in terms of the appearance of an N2-P3 complex. P3 was bilaterally symmetrical, larger in magnitude, and delayed in latency in response to monkey faces. The differences in components in the two conditions suggest that monkey ERPs can distinguish between passive and attentional processing of faces. N4 appears to reflect the recognition of conspecifics, is sensitive to priming, and occurs primarily over left hemisphere. Rewarded presentation of faces results in P3-like components that may reflect the novelty, meaningfulness, or active nature of the response. The differences in distribution between P3 and N4 suggest that they do not share the same neural sources.

Presynaptic modulation of the release of GABA by GABAA receptors in pars compacta and by GABAB receptors in pars reticulata of the rat substantia nigra.

The effect of GABA agonists and antagonists on K+-stimulated [3H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABAA autoreceptors in the pars compacta and by GABAB receptors in the pars reticulata.

Mutagenicity of products generated by the reaction between several antiparasitic drugs and nitrite.

Drugs containing secondary aliphatic amines, heterocyclic nitrogen, or secondary aliphatic amido groups (chloroquine, dehydroemetine, mebendazole, and piperazine) and pyrimidine derivatives such as pyrantel pamoate were reacted in vitro with sodium nitrite at pH 3.7 and became mutagenic for Salmonella typhimurium strain TA1535. The products derived from the nitrosation of chloroquine and dehydroemetine required metabolic activation by mammalian hepatic S9 to be mutagenic. The N-nitroso derivatives of mebendazole, piperazine, and pyrantel pamoate were mutagenic with and without S9, although more activity was noted in the presence of S9 with the nitrosated compounds formed from mebendazole and piperazine. Under identical conditions, no mutagenic products were detected from quaternary ammonium salts such as bephenium hydroxynaphthoate or drugs containing tertiary heterocyclic amino groups, such as iodochlorhydroxyquin.

Mutagenicity of urine from mice exposed orally to nitrite and various aminated antiparasitic drugs.

Mutagenic N-nitroso compound formation from the in vitro reaction of amebicides and anthelmintic drugs, which are pyrimidine derivatives or contain secondary aliphatic amines or heterocyclic nitrogens, has been previously described (Arriaga Alba et al.: Environmental and Molecular Mutagenesis 12:65-73, 1988). Under similar conditions, antiparasitic drugs containing halogenated derivatives of tertiary amines or quaternary ammonium salts do not form mutagenic nitrosated compounds. In the present study the mutagenic activity of mouse urine was determined after oral administration of sodium nitrite and the two above-mentioned groups of drugs (pyrantel pamoate, chloroquine, piperazine and dehydroemetine/iodochlorhydroxyquin and bephenium hydroxynaphthoate, respectively). Results show that the simultaneous administration of piperazine or chloroquine with sodium nitrite produced urinary mutagens that appeared conjugated as glucuronides, whereas pyrantel pamoate and dehydroemetine in the presence of nitrite caused only slightly mutagenic urine. No mutagenic activity was detected in the urine of mice to which halogenated derivatives of tertiary amines (iodochlorhydroxyquin) or quaternary ammonium salts (bephenium hydroxynaphthoate) were administered together with nitrite.

Clinical use of pre- and postsurgical evaluation of abnormal GH responses in acromegaly.

The criteria by which acromegalic patients are considered "cured" after surgical therapy are still controversial. Since the abnormal growth hormone (GH) increase after the administration of some agents has been demonstrated to be characteristic of the tumoral somatotrophs, its disappearance after surgery may be taken as an index of the complete removal of the tumor. Serum GH increases after thyrotropin-releasing hormone (TRH, 200 micrograms intravenously), gonadotropin-releasing hormone (Gn-RH, 100 micrograms intravenously), and sulpiride (100 mg intramuscularly) injected during dopamine infusion (DA-Slp test), were evaluated in 68 acromegalic patients before and after transnasosphenoidal adenomectomy, and every 12 to 18 months during a follow-up period of 6 months to 11 years (average 42 months). Forty-two patients had abnormal responses to at least one test before surgery: 32 out of 68 (47%) to TRH, six out of 40 (15%) to Gn-RH, and 20 out of 28 (71%) to the DA-Slp test. Of 18 patients who underwent all three tests, 78% had abnormal responses to at least one of them. Twenty-three patients became unresponsive after surgery, and none of them had a recurrence or became abnormally responsive again during the follow-up period. Three out of six patients with postoperative serum GH levels between 5.1 and 10 ng/ml and three out of six patients with postoperative serum GH levels between 2.1 and 5 ng/ml remained abnormally responsive: one of them relapsed 1 year after the operation. The abnormal responses were lost in all 11 patients whose postoperative serum GH levels were below 2 ng/ml, and abnormal responses were maintained in all the patients in whom surgery was considered unsuccessful because postoperative serum GH levels were higher than 10 ng/ml. The TRH, Gn-RH, and DA-Slp tests should thus be considered useful tools in verifying the total removal of an adenoma. The reappearance of active acromegaly in the patient with low postoperative GH levels, who was still responsive to TRH, should be regarded as a reactivation and not a true recurrence of the disease.