Importance of plasmapheresis in the treatment of paraneoplastic cerebellar degeneration

Paraneoplastic neurologic syndromes are disorders of the nervous system function caused by cancer but not due to metastatic disease, vascular or metabolic deficits, infections, nutritive deficiency, nor side effects of antineoplastic drugs or irradiation. Immunologic factors probably play the crucial role in the pathogenesis of paraneoplastic neurologic syndromes, but nonimmunologic mechanisms that include metabolic abnormalities and competition for substrate are also involved. Paraneoplastic cerebellar degeneration most commonly occurs in the setting of gynecologic cancers, but it accompanies the small-cell lung cancer too. Other tumors are infrequently associated with cerebellar degeneration. Several paraneoplastic antibodies have been identified in patients with paraneoplastic cerebellar degeneration. Their association with particular cancers may help identify an occult lesion. Anti-Yo antibodies are directed against Purkinje cell antigens and occur in patients with cerebellar degeneration who have breast cancer or gynecologic tumors. A target antigen of anti-Yo antibody is CDR2 protein that is normally expressed only in the brain and testis. Patients with paraneoplastic cerebellar degeneration present with dizziness, nausea and vomiting followed by gait instability, diplopia, gait and appendicular ataxia, dysarthria and dysphagia. Therapeutic options include tumor excision, chemotherapy and/or irradiation, and adjuvant therapy with glucocorticoids, immunoglobulins and plasmapheresis. The role of plasmapheresis in the treatment of paraneoplastic cerebellar degeneration is still uncertain. Reports of its efficacy are anecdotal. We present patient with paraneoplastic cerebellar degeneration with positive anti-Yo antibodies and tumor of the ovaries whose neurologic status significantly improved after four daily plasmaphereses, which was accompanied by a fourfold decrease in the anti-Yo antibodies titer. Further investigations are needed to define a protocol for plasmapheresis in the treatment of patients with paraneoplastic syndromes.     

Is There Association between Altered Adrenergic System Activity and Microvascular Endothelial Dysfunction Induced by a 7-Day High Salt Intake in Young Healthy Individuals

This study aimed to test the effect of a 7-day high-salt (HS) diet on autonomic nervous system (ANS) activity in young healthy individuals and modulation of ANS on microvascular endothelial function impairment. 47 young healthy individuals took 7-day low-salt (LS) diet (3.5 g salt/day) followed by 7-day high-salt (HS) diet (~14.7 g salt/day). ANS activity was assessed by 24-h urine catecholamine excretion and 5-min heart rate variability (HRV). Skin post-occlusive reactive hyperemia (PORH) and acetylcholine-induced dilation (AChID) were assessed by laser Doppler flowmetry (LDF). Separately, mental stress test (MST) at LS and HS condition was conducted, followed by immediate measurement of plasma metanephrines’ level, 5-min HRV and LDF microvascular reactivity. Noradrenaline, metanephrine and normetanephrine level, low-frequency (LF) HRV and PORH and AChID significantly decreased following HS compared to LS. MST at HS condition tended to increase HRV LF/HF ratio. Spectral analysis of PORH signal, and AChID measurement showed that MST did not significantly affect impaired endothelium-dependent vasodilation due to HS loading. In this case, 7-day HS diet suppressed sympathetic nervous system (SNS) activity, and attenuated microvascular reactivity in salt-resistant normotensive individuals. Suppression of SNS during HS loading represents a physiological response, rather than direct pathophysiological mechanism by which HS diet affects microvascular endothelial function in young healthy individuals.     

Dietary polyamines promote the growth of azoxymethane-induced aberrant crypt foci in rat colon

We have examined whether dietary polyamines influence the formation and initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colon. Effects of a combination of dietary polyamines at three dose levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g; spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied in animals in two different experimental situations: animals treated with AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a specific inhibitor of endogenous polyamine synthesis. In both experimental situations, dietary polyamines enhanced the growth of ACF, expressed as the number of large ACF (foci with three or more aberrant crypts, ACF > or = 3), whereas the formation of ACF, expressed as the number of ACF, was apparently not altered. In animals treated with AOM alone, maximal growth enhancing effect on ACF was nearly obtained with the median level of dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of DFMO was counteracted by dietary polyamines in a dose- dependent manner, and it was abolished at the highest level of polyamines. In conclusion, it was demonstrated that dietary polyamines are able to enhance the growth of AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused inhibition of ACF growth, probably by compensating for the DFMO-reduced endogenous polyamine synthesis.      

The Effect of Tobacco Smoking on Salivation

Aim

The purpose of this study was to examine the detrimental effect of smoking on the function of the salivary glands.

Material and Methods

The study was conducted on 60 patients who were divided into two groups: a test group which included smokers and control group represented by non-smokers. Each group included 30 patients. General information was collected from all the respondents via a questionnaire as well as the data on the duration of smoking and number of cigarettes smoked per day. Saliva was collected by spitting method in a graduated tube and the amount of unstimulated and stimulated saliva was measured and recorded in ml per minute. Stimulated saliva was collected immediately after rinsing the mouth with a 2% aqueous solution of citric acid which is carried salivary stimulation. The presence of pigmentation on the teeth and coated tongue were recorded during clinical examination. The degree of oral hygiene was determined by plaque index. All the obtained data were statistically analyzed with significance level p <0.05.

Results

The results showed no significant differences in the amount of saliva between smokers and non-smokers, however, the amount of saliva decreases significantly with the duration of smoking and increasing age of smokers. Also proven was the difference in the quality of saliva: smokers have thick saliva and nonsmokers predominantly serous. In addition, smokers have poorer oral hygiene status than non-smokers, and demonstrated a positive correlation between the level of oral hygiene and length of smoking tobacco.

Conclusion

This study has proven that smoking adversely affects salivation: long-term smoking reduces the secretion of saliva and changes its quality.Key words: Smoking, Tobacco Use Disorder, Saliva, Salivation, Xerostomia     

Selective silencing of DNA-specific B lymphocytes delays lupus activity in MRL/lpr mice

The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory FcgammaIIb surface receptors. A hybrid molecule was constructed by coupling the DNA-mimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FcgammaRIIb antibody. This chimeric antibody was added to cultured spleen cells from sick MRL/lpr mice, immunized with diphtheria toxoid, resulting in reduction of the numbers of anti-DNA but not of anti-diphtheria IgG antibody-producing cells. Intravenous infusions with the DNA-peptide antibody chimera to 7-wk-old animals prevented the appearance of IgG anti-DNA antibodies and of albuminuria in the next 2 months. The administration of the DNA-peptide chimeric antibody to 18 wk-old mice with full-blown disease resulted in the maintenance of a flat level of IgG anti-DNA antibodies and in delay of the aggravation of the lupus glomerulonephritis. The use of chimeric antibodies targeting inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of autoreactive disease-associated B cells in autoimmune diseases.     

Effects of fulminant hepatic encephalopathy on the adult rat brain antioxidant status and the activities of acetylcholinesterase, (Na+,K+)- and Mg2+-ATPase: comparison of the enzymes’ response to in vitro treatment with ammonia

Hepatic encephalopathy can be a life-threatening complication of fulminant hepatic failure. By understanding the pathophysiology involved in the induction of this neuropsychiatric disorder, future therapeutic and/or preventive attempts could be considered. In this study, an attempt has been made in order to shed more light on the mechanisms involved in the effects of thioacetamide (TAA)-induced fulminant hepatic encephalopathy on: (a) the adult rat brain total antioxidant status (TAS) and (b) the activities of acetylcholinesterase (AChE), (Na(+),K(+))-ATPase and Mg(2+)-ATPase. Moreover, in vitro experiments were conducted in order to evaluate the possible role of ammonia (incubated as NH(4)Cl, in a toxic concentration of 3mM) in the observed effects of TAA-induced fulminant hepatic encephalopathy on the examined adult rat brain enzyme activities. Fulminant hepatic encephalopathy caused a significant decrease in TAS (-22%, p < 0.001) and the activity of Na(+),K(+)-ATPase (-26%, p < 0.001), but had non-significant effects on the whole brain AChE and Mg(2+)-ATPase activities. The in vitro experiments (conducted through a 3h incubation with ammonia), showed no significant alterations in any of the examined parameters. Our in vitro and in vivo findings suggest that alterations in AChE and Mg(2+)-ATPase activities are not involved in the pathophysiology of the adult-onset fulminant hepatic encephalopathy, while the observed Na(+),K(+)-ATPase inhibition could be a result of the oxidative stress, neurotransmission deregulation, and/or of the presence of other toxic substances (that appear to act as direct or indirect inhibitors of the enzyme) and not due to the excess accumulation of ammonia in the brain.     

Bloom of resident antibiotic-resistant bacteria in soil following manure fertilization

The increasing prevalence of antibiotic-resistant bacteria is a global threat to public health. Agricultural use of antibiotics is believed to contribute to the spread of antibiotic resistance, but the mechanisms by which many agricultural practices influence resistance remain obscure. Although manure from dairy farms is a common soil amendment in crop production, its impact on the soil microbiome and resistome is not known. To gain insight into this impact, we cultured bacteria from soil before and at 10 time points after application of manure from cows that had not received antibiotic treatment. Soil treated with manure contained a higher abundance of β-lactam–resistant bacteria than soil treated with inorganic fertilizer. Functional metagenomics identified β-lactam–resistance genes in treated and untreated soil, and indicated that the higher frequency of resistant bacteria in manure-amended soil was attributable to enrichment of resident soil bacteria that harbor β-lactamases. Quantitative PCR indicated that manure treatment enriched the bla_CEP-04 gene, which is highly similar (96%) to a gene found previously in a Pseudomonas sp. Analysis of 16S rRNA genes indicated that the abundance of Pseudomonas spp. increased in manure-amended soil. Populations of other soil bacteria that commonly harbor β-lactamases, including Janthinobacterium sp. and Psychrobacter pulmonis, also increased in response to manure treatment. These results indicate that manure amendment induced a bloom of certain antibiotic-resistant bacteria in soil that was independent of antibiotic exposure of the cows from which the manure was derived. Our data illustrate the unintended consequences that can result from agricultural practices, and demonstrate the need for empirical analysis of the agroecosystem.Agriculture affects human health through both the consumption and production of food for the human diet. Manure from pig and cattle farms is commonly used as a substitute for inorganic nitrogen and phosphorus fertilizers for agricultural crops worldwide, especially in organic farming practices (1–6). With the increasing consumer demand for organically produced food, the use of animal manure, which conforms to organic conventions, will likely increase in the future. According to the National Organic Program, raw manure may be used up to 90–120 d before harvest, depending on the crop, and composted manure may be applied at any time. There are no restrictions on the source of manure (1).Animal manure is an important reservoir of antibiotic-resistant bacteria, antibiotic-resistance genes (collectively known as the “resistome”), and pathogens (2, 7–12). Although antibiotic use increases antibiotic-resistance genes and resistant bacteria in manure (13–16), antibiotic-resistant bacteria are also abundant in manure from animals with no history of antibiotic treatment, indicating the natural presence of bacteria intrinsically resistant to antibiotics in animal gastrointestinal tracts (2, 17, 18).There is increasing concern about the use of manure as an agricultural amendment because of its possible contribution to the pool of resistance genes to resident soil bacteria and pathogens (2, 19). Antibiotic-resistance genes from the soil resistome can enter the food chain via contaminated crops or groundwater (5, 20), and have potential consequences for human health if transferred to human pathogens. Studies assessing the impact of fertilization with pig manure on the soil resistome have shown that excessive application of manure from farms with intensive sulfonamide use can lead to an increase of antibiotic-resistance genes in soil (2, 3); however, most studies have found that such increases are transient when the manure is applied at recommended rates (2, 21, 22). Cow manure from dairy farms, which use β-lactam antibiotics predominantly to prevent and treat diseases (23), is commonly used in crop production, but its impact on the soil resistome has yet to be investigated.Along with its impact on the soil resistome, the application of manure can affect the composition and functional properties of soil microbial communities, as has been demonstrated by community fingerprinting (21, 24). Recent advances in DNA-based analysis, such as metagenomics and quantitative PCR (qPCR), offer greater precision in such studies, enabling identification of affected community members (25) and their resistance genes (4).In the present study, we assessed the impact of cow manure on the composition and resistance profiles of bacterial communities in soil. Our results show that manure from cows that had not been treated with antibiotics increased the populations of resident soil bacteria harboring genes for resistance to β-lactam antibiotics, whereas inorganic fertilizers did not. These results demonstrate the complexity, and at times nonintuitive consequences, of agricultural practices.     

Characteristics of unintentional ingestion of oral non-steroidal anti-inflammatory drugs and analgesics in preschool children

We characterised accidental ingestion of non-steroidal anti-inflammatory drugs and non-opioid analgesics in children aged 0–5 years between 2009 and 2019 by analysing records of telephone consultations with the Croatian Poison Control Centre (CPCC) and cases treated at the Children’s Hospital Zagreb (CHZ). Among the total of 466 identified cases (411 from CPPCC records and 55 from CHS hospital records), the most frequently ingested drugs were ibuprofen (47 %), paracetamol (20 %), ketoprofen (15 %), and diclofenac (11 %). In 94 % of the cases unsupervised children ingested the drug left within their reach. The remaining 6 % were dosing errors by parents or caregivers and involved liquid formulations as a rule. Our findings can serve as real-life examples informing preventive measures.KEY WORDS: diclofenac, ibuprofen, ketoprofen, NSAIDs, overdose, paracetamol, poisoning, toddlers