Research Note: Oxidative stress and immune response following the administration of live attenuated Mycoplasma gallisepticum vaccination in backyard chicken.

In the present study, we investigated a possible relationship between the immune response and the oxidative stress (OS) state trend in a group of 12 chickens after intraocular administration of an attenuated Mycoplasma gallisepticum (MG) vaccine. Blood samples were collected at the vaccination time (T0), after 14 (T1) and 21 d (T2). White blood cell count (WBC), differential leucocyte count, and anti-MG antibodies titer (S/P) were studied as immune response indexes. As plasmatic OS biomarkers levels, we considered malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), reactive oxygen metabolites derived compounds (d-ROMs), the ferric reducing ability of plasma (FRAP), and superoxide anion (O2-). After antigenic stimulation, it was observed a significant decrease in monocythemia and a significant increase in thrombocythemia, S/P, MDA, and SOD. Furthermore, subjects with high d-ROMs levels at T0 tended to develop higher cellular mobilization with increases in WBC and lymphocytes accompanied by lower antibody release. It was also observed that the antioxidant components FRAP and SOD were moderately positively correlated to the entity of antibody response.

Using data from a private provider of telemedicine to assess the severity of the early 2021 Covid-19 wave in Brazil.

In early 2021, Brazil saw a dramatic recurrence in Covid-19 cases associated to the spread of a novel variant of the SARS-CoV-2 virus, the P1 variant. In light of previous reports showing that this variant is more transmissible and more likely to infect people who had recovered from previous infection, a retrospective analysis was conducted to assess if the early 2021 Covid-19 wave in Brazil was associated with an increase in the number of individuals presenting with a more severe clinical course. Fifty-one thousand and fourteen individuals who underwent telemedicine consultations were divided into two groups: patients seen on or before January 31, 2021, and on or after February 1, 2021. These dates were chosen based on the spread of the P1 variant in Brazil. Referral to the emergency department (ED) was used as a marker of a more severe course of the disease. No differences were seen in the proportion of patients referred to the ED in each group nor in the odds ratio of being referred to the ED from the 1st of February 2021 (OR=0.909; 95%CI: 0.81-1.01). Considering the entire cohort, age had an impact on the odds of being referred to the ED, with individuals older than 59 years showing twice the risk of the remaining population and those less than 19 years showing a lower risk.

The effects of nanoplastics on adipose stromal cells from swine tissues.

Plastic is one of the main sources of marine and terrestrial pollution. This material can fragment into micro- (<-5 mm) and nanoplastics (NPs) (<100 nm) following degradation. Animals are exposed to these particles by ingesting contaminated food, respiration or filtration, and transdermally. In organisms, NPs can cross biological membranes, and cause oxidative stress, cell damage, apoptosis, and endocrine interference. We previously demonstrated that polystyrene - NPs interfered with ovarian cell functions. Since reproduction involves a high energy expenditure and a crucial role is played by adipose tissue, the aim of the present study was to evaluate the effects of NPs on primary adipose stromal cells (ASCs) isolated from swine adipose tissues. In particular, the effects on cell viability, proliferation, metabolic activity, inflammatory process mediators and oxidative stress markers were assessed. The obtained results did not reveal a significant variation in cell proliferation, metabolic activity was increased (P < 0.01) but only at the lowest concentration, while viability showed a significant decrease after prolonged exposure to NPs (P < 0.01). TNF-α was increased (P < 0.05), while PAI-1 was inhibited (P < 0.001). Redox status was significantly modified; in particular, the production of O2-, H2O2 and NO was stimulated (P < 0.05), the non-enzymatic antioxidant power was reduced (P < 0.05) while catalase activity was significantly (P < 0.01) increased.

Using data from a private provider of telemedicine to assess the severity of the early 2021 Covid-19 wave in Brazil

In early 2021, Brazil saw a dramatic recurrence in Covid-19 cases associated to the spread of a novel variant of the SARS-CoV-2 virus, the P1 variant. In light of previous reports showing that this variant is more transmissible and more likely to infect people who had recovered from previous infection, a retrospective analysis was conducted to assess if the early 2021 Covid-19 wave in Brazil was associated with an increase in the number of individuals presenting with a more severe clinical course. Fifty-one thousand and fourteen individuals who underwent telemedicine consultations were divided into two groups: patients seen on or before January 31, 2021, and on or after February 1, 2021. These dates were chosen based on the spread of the P1 variant in Brazil. Referral to the emergency department (ED) was used as a marker of a more severe course of the disease. No differences were seen in the proportion of patients referred to the ED in each group nor in the odds ratio of being referred to the ED from the 1st of February 2021 (OR=0.909; 95%CI: 0.81-1.01). Considering the entire cohort, age had an impact on the odds of being referred to the ED, with individuals older than 59 years showing twice the risk of the remaining population and those less than 19 years showing a lower risk.

Nanoplastics impair in vitro swine granulosa cell functions.

Soil, water, and air pollution by plastic represents an issue of great concern since the particles produced by degradation of plastic materials can be ingested by animals and humans, with still uncertain health consequences. As a contribution on this crucial subject, the present work reports an investigation on the in vitro effects of different concentrations of polystyrene nanoplastics (5, 25, and 75 µg/mL) on swine granulosa cells, a model of endocrine reproductive cells. In particular, cell growth (BrDU incorporation and ATP production), steroidogenesis (17-ß estradiol and progesterone secretion) and redox status (superoxide and nitric oxide production, enzymatic and non-enzymatic scavenging activity) were studied. Nanoplastics, at the highest concentration, stimulated cell proliferation (P < 0.05), while cell viability resulted unaffected. Steroidogenesis was disrupted (P < 0.05). Both enzymatic and non-enzymatic scavenging activity were increased after exposure at the highest nanoplastic dose (P < 0.05, P < 0.001). Nitric oxide secretion was increased by 25 and 75 µg/mL (P < 0.05) while superoxide generation was stimulated (P < 0.001) only by the highest concentration tested. Taken together, main features of cultured swine granulosa cells resulted affected by exposure to nanoplastics. These results raise concerns since environment nanoplastic contamination can represents a serious threat to animal and human health.

Comparative evaluation of the novel IMMUNOCATCHTM Streptococcus pneumoniae (EIKEN CHEMICAL CO., LTD) test with the Uni-GoldTM Streptococcus pneumoniae assay and the BinaxNOW® Streptococcus pneumoniae antigen card for the detection of pneumococcal capsular antigen in urine samples.

Community-acquired pneumonia (CAP) is one of the major causes of morbidity, mortality and hospitalization, and S. pneumoniae is the most frequently isolated etiologic agent. The pneumococcal urinary antigen test (PUAT) is among the recommended methods to identify the causative agent in CAP patients. A novel PUAT (IMMUNOCATCHTMStreptococcus pneumoniae) was compared with the Uni-GoldTMS. pneumoniae assay routinely used in our laboratory and with the widely used BinaxNOW® S. pneumoniae antigen card. A total of 218 (183 freshly harvested and 35 frozen) urine samples (US) submitted for the detection of pneumococcal urinary antigen (PUAT) between December 2016 and November 2018 were evaluated. A number of 160 negative and 41 positive concordant results were scored for all the three assays. A total of 17 US gave discrepant results. The sensitivity and specificity of Immunocatch compared with Uni-Gold were 73.2% and 98.8%, respectively, and compared with BinaxNOW were 97.6% and 98.8%, respectively. The overall percent agreement (OPA) and the Cohen's kappa coefficient between the Immunocatch and the Uni-Gold resulted 92.2% and 0.78%, respectively, and compared with BinaxNOW were 98.6% and 0.95%, respectively. These performances suggest that the novel Immunocatch S. pneumoniae test is a useful tool for qualitative detection of S. pneumoniae capsular antigen in US.

Comparison of the Novel Immunocatch Legionella Test with Sofia Legionella FIA Assay and with BinaxNOW Legionella Card Assay for Detection of Legionella pneumophila (Serogroup 1) Antigen in Urine Samples.

Legionnaires' disease (LD) refers to a serious form of acute pneumonia caused by Legionella species. LD can be difficult to diagnose because the signs and symptoms are nonspecific, and therefore a rapid laboratory diagnosis is of paramount importance. In this study, a recently introduced immunochromatographic test (Immunocatch Legionella; Eiken Chemical Co., Ltd.) for Legionella pneumophila (serogroup 1) urinary antigen detection was compared with the Sofia Legionella fluorescent immunoassay (FIA) (Quidel) (routinely used in our laboratory) and with the widely used BinaxNOW Legionella assay (Alere). A total of 248 urine samples (60 frozen and 188 fresh) were evaluated. All of the samples were collected from patients with high clinical suspicion of Legionnaires' disease. The three assays were performed simultaneously according to the manufacturers' instructions. A total of 180 concordant negative and 66 concordant positive results were obtained. Only 2 discrepant results were registered. The sensitivity and specificity of Immunocatch compared with Sofia were, respectively, 98.5% and 99.4%. Cohen's kappa coefficient and overall percent agreement between Immunocatch and Sofia were also calculated and resulted in, respectively, 0.97 and 99.2%. These performances suggest that the Immunocatch test is a useful tool for Legionella pneumophila (serogroup 1) urinary antigen detection.

Concentrations of chlorinated pollutants in adipose tissue of yellow-legged gulls (Larus michahellis) from Spain: Role of gender and age.

Concentrations of 7 different polychlorinated biphenyl (PCB) congeners, and eleven organochlorine pesticides (OCPs) and metabolites, including DDTs (dichlorodiphenyltrichloroethane), HCHs (hexachlorocyclohexane isomers), Endosulfan, Endosulfan sulfate, Endrin, Dieldrin and HCB (hexachlorobenzene), were determined in adipose tissue of 57 yellow-legged gulls collected from NW and N Spain. Furthermore, the possible differences due to two endogenous factors, age and gender, were determined. All the analyzed PCBs were detected in over 66% of the samples, with levels of 291.9 (PCB 180), 34.5 (PCB 118), 0.7 (PCB 28), 432.6 (PCB 153), 225.5 (PCB 138), 1.3 (PCB 101) and 0.4 (PCB 52) µg/kg of adipose tissue. With respect to the OCPs and metabolites, only 4,4'-DDE and HCB were detected in more than 50% of the samples, with means of 360.6 and 2.5 µg/kg of adipose tissue, respectively. From all the considered contaminants, only 4,4'-DDE levels presented significant differences depending on the gender, with females showing higher values than males (p < 0.01). Significant differences (p < 0.001) were also found related to age for the levels of PCBs 180, 138, 101, 28 and 153, as well as 4,4'-DDE, with adult levels being higher than those in young birds. The results of the present study constitute a baseline to better assess the environmental impacts of PCB and OCP contamination at other coastal sites for future biomonitoring studies, with particular emphasis on gender- and age-related differences.

Shewanella algae infection in Italy: report of 3 years' evaluation along the coast of the northern Adriatic Sea.

Shewanella algae are Gram-negative, nonfermentative, motile bacilli, classified in the genus Shewanella in 1985. These environmental bacteria are occasionally identified in human infections, with a relatively strong association with exposure to seawater during warm seasons. This report describes a case series of 17 patients with infection correlated to S. algae in the coastal area of Romagna, Italy, from 2013 to 2016. The types of infection included otitis, pneumonia, sepsis and soft tissue (wound). Exposure to the marine environment during hot months was confirmed in 12 of 17 patients. An apparent correlation between increased severity of infection and patient age was also observed.

Effects of selective α2 -adrenergic receptor agonists on electrical field-stimulated contractions of isolated bronchi in horses.

We investigated the effects of different selective α2 -adrenergic receptor (AR) agonists (detomidine, medetomidine, xylazine, and brimonidine) on the contractions of horse-isolated bronchi induced by electrical field stimulation (EFS) and by carbachol. No effects were observed on the contraction induced by carbachol, while α2 -AR agonists reduced EFS-evoked contractions in a concentration-related fashion. The rank order of potency (pD2 ) was brimonidine (7.40 ± 0.20) >medetomidine (7.09 ± 0.24) >detomidine (6.13 ± 0.55) >xylazine (4.59 ± 0.16). The maximal effects (Emax ) were -56.3% ± 6.3%, -40.4% ± 6.9%, -48.6% ± 9.9%, and -72.7% ± 12.7% for brimonidine, medetomidine, detomidine, and xylazine, respectively. Adrenergic block by guanethidine enhanced the potency (8.10 ± 0.05, 7.30 ± 0.15, 6.83 ± 0.41, and 5.40 ± 0.22) and the efficacy (-95.2% ± 0.7%, -45.2% ± 11.7%, -58.5% ± 9.8%, and -97.9% ± 0.6%) of brimonidine, medetomidine, detomidine, and xylazine, respectively. Selective α2 -AR antagonist, atipamezole, competitively antagonized the inhibition of EFS-evoked contractions induced by all agonists except xylazine. These results suggest the existence of presynaptic α2 -ARs on cholinergic neurons, negatively regulating the release of acetylcholine in horse bronchial muscle, and that α2 -AR agonists may be beneficial against vagally mediated bronchoconstriction.

Sildenafil improves clinical signs and radiographic features in dogs with congenital idiopathic megaoesophagus: a randomised controlled trial.

We evaluated the efficacy of oral sildenafil citrate in dogs with congenital idiopathic megaoesophagus (CIM). Twenty-one puppies were randomly assigned to two groups (treatment and control). The dogs were given sildenafil oral suspension 1 mg/kg every 12 hours for 14 days or placebo in a masked fashion. Clinical signs (frequency of regurgitation and weight gain) and oesophagrams (relative oesophageal diameter, ROD) were evaluated in order to assess the efficacy of drug treatment, by examiners who were unaware of the study protocol. In addition, a set of in vitro experiments on isolated samples of canine lower oesophageal sphincter (LOS) was performed, and the effects of increasing concentrations of sildenafil on basal tone and electrically-stimulated motility were assessed. Sildenafil administration significantly reduced the number of regurgitation episodes (0.88±1.40 v 2.65±1.56, P<0.0001) and significantly increased weight gain in the treated dogs compared to controls (79.76±28.30 per cent v 53.40±19.30 per cent, P=0.034). ROD values, at the end of the treatment period, were significantly decreased in the sildenafil group, compared to pre-treatment values (0.97±0.19 v 0.24±0.14, P<0.0001), in contrast to control subjects (0.98±0.17 v 1.10±0.25, P=0.480). In accordance with the in vivo findings, sildenafil dose-dependently reduced basal tone and increased electrically-induced relaxation of dog LOS samples. These results suggest that sildenafil citrate helps ameliorate clinical and radiographic signs in dogs with CIM by reducing LOS tone, and could represent a novel therapeutic tool for the treatment of this disease.

First report of sepsis due to Catabacter hongkongensis in an Italian patient.

The first isolation of Catabacter hongkongensis in Italy is reported. Pleomorphic Gram-positive rods were grown in blood cultures from samples obtained from a 55-year-old patient admitted to the intensive care unit with sepsis after he experienced massive thoracic and abdominal trauma. The identification was obtained by amplification and sequencing of the 16S rRNA gene.

Development of an HPLC/UV assay for the evaluation of inhibitors of human recombinant monoacylglycerol lipase.

Monoacylglycerol lipase (MAGL) is a membrane-associated cytosolic serine hydrolase which catalyses the hydrolysis of the endocannabinoid 2-arachidonoylglycerol into arachidonic acid and glycerol. MAGL represents the link between the endocannabinoid and the eicosanoid system indeed its inhibition enhances endocannabinoid signalling and lowers eicosanoid production. Here we present a radioactive-free, sensitive and solid HPLC-UV based method to evaluate MAGL activity by using 4-nitrophenylacetate (4-NPA) as substrate. The enzymatic activity is measured by quantifying the 4-nitrophenol (PNP) (λ = 315 nm) formation on a C18 stationary phase. The method was validated by calculating IC50 values of the reference inhibitors JZL184, CAY10499 and JW642 and confirming the irreversible and non-competitive mechanism of inhibition for JZL184. Furthermore in order to resemble the catalytic conditions of MAGL at cell membrane level, the surfactant Triton X-100 was added, as a micelle forming agent and 4-nitrophenyldodecanoate (4-NPDo) was used as lipophilic substrate for MAGL. The data obtained confirmed that the HPLC method is an alternative, radioactive-free approach for the screening and characterization of new MAGL inhibitors. Finally this assay prevents, in an unequivocal manner, any interference related to the intrinsic absorbance of screened compounds or metabolites generated upon enzymatic cleavage which could seriously affect the assay readout.

Doxycycline levels and anti-Wolbachia antibodies in sera from dogs experimentally infected with Dirofilaria immitis and treated with a combination of ivermectin/doxycycline.

Sera from Dirofilaria immitis-experimentally infected dogs treated with a combination of ivermectin/doxycycline were analysed for doxycycline levels by HPLC and anti-Wolbachia Surface Protein (rWSP) antibodies by ELISA and compared with sera from dogs treated with doxycycline alone. Results show that doxycycline levels were not statistically different between the two groups. Circulating anti-WSP antibody titres were markedly lower in both treatment groups when compared to control D. immitis infected dogs, indicating that doxycycline is able to reduce Wolbachia and prevent the immune response against the bacteria. The combination treatment protocol has been shown to be highly adulticidal and further studies are needed to better understand the interaction between doxycycline and ivermectin in D. immitis infected dogs.

Pharmacological characterization of muscarinic receptors in the contractions of isolated bronchi in the horse.

We investigated the effects of nonselective muscarinic antagonist (atropine) and of selective muscarinic subtype 1 (M1), 2 (M2), 3 (M3) antagonists (VU0255035, methoctramine, pFHHSiD, respectively) on the contractions evoked by electrical field stimulation (EFS) or by exogenous ACh in isolated horse bronchial muscle. Atropine completely inhibited neurogenic contractions in a concentration-dependent fashion, whereas selective muscarinic antagonists induced relevant modifications only at the highest concentration tested. Experiments with selective muscarinic antagonists in combination showed that only the simultaneous blockade of M1 /M3 or M2 /M3 receptors was able to induce a nearly complete suppression of contractions. The contractions induced by exogenous ACh were competitively antagonized only by atropine (pA2 = 9.01 ± 0.05). M3 selective antagonist, up to 10(-6) m, caused a moderate concentration-dependent rightward shift of ACh curve (pA2 = 7.96 ± 0.10). These data show that M3 muscarinic receptors possess a central role in mediating cholinergic contraction of horse bronchi, while M1 and M2 receptors seem to have a cooperative role. Selective muscarinic antagonists seem unlikely to be useful against bronchoconstriction associated with airway diseases in horses. Conversely, compounds with selectivity for both M1 and M3 receptors could be as effective as traditional anticholinergics and induce fewer cardiac side effects.

Telemonitoring in chronic ventilatory failure: a new model of survellaince, a pilot study.

BACKGROUND AND AIM: The efficiency of tele-monitoring or tele-assistance in patients with severe chronic ventilatory failure in home mechanical ventilation (HMV) is still being investigated. Our aim was to test the feasibility of a model which consisted in: 1) once a week nocturnal telemonitoring, supervised by a doctor in charge in a Respiratory Intensive Care Unit, who also provided a telephone-counselling (24/7) on demand; 2) a scheduled visit every two months. METHODS: A 2-year observational study was carried out on 16 patients ventilated for at least 1 year and for > or = 8 hours/day. Once a week patients underwent a nocturnal monitoring during HMV. The compliance was evaluated by regular transmission of data and regular follow-up, the level of satisfaction by a telephone-questionnaire. RESULTS: The adherence to the protocol study was good in 9/16 (56%) and poor in 7/16 (44%) patients. For each patient, the mean number of connections was 46.12 +/- 36.39 (70.7% of that expected), in those with good compliance it increased to 63.8 +/- 32.7 (114% of that expected). The median hours of connection was 343 (138-1019) and 89 (0-521) for patients with good and poor compliance respectively, p = 0.038. The mean scheduled visits for patient with good compliance was 6.9 +/- 4.14 (100% of that expected). Emergency visits were avoided in 62.5% of cases. The satisfaction score was higher in compliant versus non compliant patients (p = 0.019). CONCLUSION: This pilot study showed that the telemonitoring system employed was feasible and effective in more compliant patients who claimed a high rate of satisfaction.

Inhibition of motility in isolated horse small intestine is mediated by κ but not µ opioid receptors.

The effects of preferential µ (morphine), selective µ (fentanyl), selective κ (compound U69593) opioid receptor agonists, and nonselective (naloxone) and selective µ (naloxonazine) antagonists on equine small intestinal motility were evaluated in vitro. Samples of circular muscle from equine jejunum were placed in isolated organ baths and drug-induced modifications of both spontaneous and electrically evoked contractile activity were measured. None of the opioid agonists induced a significant change in spontaneous contractions. Fentanyl and U69593 reduced electrically induced contractions, whereas morphine reduced them only slightly. Naloxone competitively antagonised U69593, but both naloxone and naloxonazine were unable to counteract the inhibition of contractions induced by fentanyl. The inhibition of contractions shown by fentanyl is therefore probably not mediated by opioid receptors, but due to an anticholinergic activity of this drug. In summary, these data showed an inhibitory effect exerted by κ receptors on equine small intestinal motility, whereas the role of µ receptors seemed marginal and would need further characterisation.

Study of apoptosis induction and deoxycytidine kinase/cytidine deaminase modulation in the synergistic interaction of a novel ceramide analog and gemcitabine in pancreatic cancer cells.

This study investigated the interaction between the novel ceramide analog AL6 and gemcitabine in MIA PaCa-2 and PANC-1 pancreatic cancer cell lines, harboring different polymorphic variants of the gemcitabine catabolism enzyme cytidine deaminase (CDA). AL6 dose-dependently inhibited cell growth, induced apoptosis and synergistically enhanced the cytotoxic activity of gemcitabine. Moreover, it triggered apoptosis, which was significantly enhanced by the combination, and increased the ratio between gene expression of the activating enzyme deoxycytidine kinase (dCK) and CDA, potentially favoring gemcitabine activity. In conclusion, AL6 displays synergistic cytotoxic activity, enhances apoptosis, and favorably modulates enzymes involved in gemcitabine metabolism, supporting future investigation of this combination in pancreatic cancer.

Long-term oxygen therapy in COPD: evidences and open questions of current indications.

Long term oxygen therapy (LTOT) has been shown to improve the survival rate in Chronic Obstructive Pulmonary Disease (COPD) patients with severe resting hypoxemia by NOTT and MRC studies, published more than 25 years ago. The improved survival was found in patients who received oxygen for more than 15 hours/day. The effectiveness of LTOT has been documented only in stable COPD patients with severe chronic hypoxemia at rest (PaO2 < 55 mmHg (7.3 kPa) or PaO2 ranging from 56 to 59 mmHg (7.4-7.8 kPa) in presence of signs of Cor Pulmonale, hematocrit > 55%. In fact no evidence supports the use of LTOT in COPD patients with moderate hypoxemia (55 < PaO2 < 65 mmHg), and in those with decreased oxygen saturation (SO 2 <90%) during exercise or sleep. Furthermore, it is generally accepted without evidence that LTOT in clinical practice is warranted in other forms of chronic respiratory failure not due to COPD when a-terial blood gas criteria match those established for COPD patients. The prescription of oxygen in these circumstances, as for unstable patients, increases the number of patients receiving supplemental oxygen and the related costs. Comorbidities are likely to affect both prognosis and health outcomes in COPD patients, but at the moment we do not know if LTOT in these patients with complex chronic diseases and mild-moderate hypoxemia could be of any use. For these reasons a critical revision of the actual guide lines indications for LTOT in order to optimise effectiveness and costs, and future research in the areas that have not previously been addressed by NOTT and MRC studies, are mandatory.

Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials.

In many different species, lactate dehydrogenase (LDH) constitutes a major checkpoint of anaerobic glycolysis, by catalyzing the reduction of pyruvate into lactate. This enzyme has recently received a great deal of attention since it may constitute a valid therapeutic target for diseases so different as malaria and cancer. In fact, the isoform expressed by Plasmodium falciparum (pfLDH) is a key enzyme for energy generation of malarial parasites. These species mostly depend on anaerobic glycolysis for energy production, since they lack a citric acid cycle for ATP formation. Therefore, inhibitors of pfLDH would potentially cause mortality of P. falciparum and, to this purpose, several small organic molecules have been recently designed and developed with the aim of blocking this new potential antimalarial chemotherapeutic target. Moreover, most invasive tumour phenotypes show a metabolic switch (Warburg effect) from oxidative phosphorylation to an increased anaerobic glycolysis, by promoting an upregulation of the human isoform-5 of lactate dehydrogenase (hLDH-5 or LDH-A), which is normally present in muscles and in the liver. Hence, inhibition of hLDH-5 may constitute an efficient way to interfere with tumour growth and invasiveness. This review provides an overview of the LDH inhibitors that have been developed up to now, an analysis of their possible isoform-selectivity, and their therapeutic potentials.