Resting Physiologic Dead Space as Predictor of Postoperative Pulmonary Complications After Robotic-Assisted Lung Resection: A Pilot Study.

Lung resection surgery carries significant risks of postoperative pulmonary complications (PPC). Cardiopulmonary exercise testing (CPET) is performed to predict risk of PPC in patients with severely reduced predicted postoperative forced expiratory volume in one second (FEV1) and diffusion of carbon monoxide (DLCO). Recently, resting end-tidal partial pressure of carbon dioxide (PETCO2) has been shown as a good predictor for increased risk of PPC. However, breath-breath breathing pattern significantly affects PETCO2. Resting physiologic dead space (VD), and physiologic dead space to tidal volume ratio (VD/VT), may be a better predictor of PPC than PETCO2. The objective of this study was to prospectively determine the utility of resting measurements of VD and VD/VT in predicting PPC in patients who underwent robotic-assisted lung resection for suspected or biopsy-proven lung malignancy. Thirty-five consecutive patients were included in the study. Patients underwent preoperative pulmonary function testing, symptom-limited CPET, and a 6-min walk test. In the first 2 min prior to the exercise portion of the CPET, we obtained resting VT, minute ventilation ( V ˙ E), VD (less instrument dead space), VD/VT, PETCO2, and arterial blood gases. PPC within 90 days were recorded. Fourteen (40%) patients had one or more PPC. Patients with PPC had significantly elevated resting VD compared to those without (0.318 ± 0.028 L vs. 0.230 ± 0.017 L (± SE), p < 0.006), and a trend toward increased VD/VT (0.35 ± 0.02 vs. 0.31 ± 0.02, p = 0.051). Area under the receiver operating characteristic (ROC) for VD was 0.81 (p < 0.002), VD/VT was 0.68 (p = 0.077), and PETCO2 was 0.52 (p = 0.840). Peak V ˙ O2, V ˙ E/ V ˙ CO2 slope, pulmonary function tests, 6-min walk distance and arterial blood gases were similar between the two groups. Intensive care unit and total hospital length of stay was significantly longer in those with PPC. In conclusion, preoperative resting VD was significantly elevated in patients with PPC. The observed increase in resting VD may be a potentially useful predictor of PPC in patients undergoing robotic-assisted lung resection surgery for suspected or biopsy-proven lung malignancy. A large prospective study is needed for confirmation.

Ingestion of A Common Plant's Leaves Leads to Acute Respiratory Arrest and Paralysis: A Case Report.

BACKGROUND: Nicotiana glauca is a plant known to cause acute toxicity upon ingestion or dermal exposure due to the nicotinic alkaloid, anabasine. Nicotinic alkaloids cause toxicity by acting as agonists on nicotinic-type acetylcholine receptors (nAChRs). Initial stimulation of these receptors leads to symptoms such as tachycardia, miosis, and tremors. The effects of high doses of nicotinic alkaloids are biphasic, and eventual persistent depolarization of nAChRs at the neuromuscular junction occurs. This causes apnea, paralysis, and cardiovascular collapse. CASE REPORT: In this report, we present a case of respiratory arrest due to nicotinic alkaloid poisoning from the ingestion of Nicotiana glauca. The diagnosis was suspected after the patient's family gave a history of the patient ingesting a plant prior to arrival. They were able to also provide a physical sample of the plant. CONCLUSION: The phone application, "Plant Snap", determined the plant species and helped confirm the diagnosis. This case describes how modern technology and thorough history taking can combine to provide the best possible patient care.

Survey of ticks of domestic dogs and cattle in Trinidad and Tobago

Objective: Ticks and the pathogens they transmit can cause high morbidity and mortality in domestic animals. As part of a larger study to determine the tickborne pathogens infesting domestic animals and wildlife, the aim of this study was to survey the tick species infesting the canine and cattle populations in Trinidad and Tobago. Design and Methodology: A total of 1,990 ticks were collected off of 179 dogs from 48 areas in Trinidad (n=163) and Tobago (n=16) only between June 2016 and 2018. Ticks were also collected from cattle throughout Trinidad (n=1098) and Tobago (n=306). Collected ticks were morphologically identified using standard taxonomic keys. Results: Only two tick species, Rhipicephalus sanguineus (1,926; 96.8%) and Amblyomma ovale (64; 3.2%) were found on the dogs sampled in Trinidad and Tobago (T&T). A total of 169 (94.4%) dogs and 10 (17.9%) dogs were infested with R. sanguineus and A. ovale respectively. Three dogs (1.7%) were infested with both tick species. Only hunting dogs or those closely associated with them were infested with A. ovale. R. sanguineus was very common throughout both islands whereas A. ovale was restricted to small foci in three rural settlements in both Trinidad (n=2) and Tobago (n=1). Rhipicephalus (Boophilus) microplus was the only tick species found infesting cattle on both islands. Conclusion: R. sanguineus is the most common tick infesting domestic dogs in T&T while A. ovale was found on fewer dogs. Only R. (B). microplus was detected on cattle. R. sanguineus is a known vector of tick-borne diseases in domestic dogs and humans while R. B. microplus can transmit harmful pathogens to cattle. These preliminary findings will aid in determining if there are any possible links between ticks and tick-borne pathogens associated with domestic and wildlife species and possibly humans and give further insight into the potential movement of ticks and their pathogens between the human, animal and tropical forest interface.

A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo.

Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2's negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show that when MDM2-ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B-cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared with control mice (27%). However, this phenotype is observable only at later stages in life (⩾18 months). Moreover, flow cytometric analyses for B-cell markers revealed an MDM2-ALT1-associated decrease in the B-cell population of the spleens of these animals. Our data suggest that the B-cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall, our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and -independent tumorigenesis, underscoring the complexity of MDM2 posttranscriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.

Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia.

Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.

Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503).

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.

Deletion of the thymidine kinase gene induces complete attenuation of the Georgia isolate of African swine fever virus.

African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal viral disease of domestic pigs. There are no vaccines to control Africa swine fever (ASF). Experimental vaccines have been developed using genetically modified live attenuated ASFVs obtained by specifically deleting virus genes involved in virulence, including the thymidine kinase (TK) gene. TK has been shown to be involved in the virulence of several viruses, including ASFV. Here we report the construction of a recombinant virus (ASFV-G/V-ΔTK) obtained by deleting the TK gene in a virulent strain of ASFV Georgia adapted to replicate in Vero cells (ASFV-G/VP30). ASFV-G/P-ΔTK demonstrated decreased replication both in primary swine macrophage cell cultures and in Vero cells compared with ASFV-G/VP30. In vivo, intramuscular administration of up to 10(6) TCID50 of ASFV-G/V-ΔTK does not result in ASF disease. However, these animals are not protected when challenged with the virulent parental Georgia strain.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder.

The µ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

Development of an improved live attenuated antigenic marker CSF vaccine strain candidate with an increased genetic stability.

Controlling classical swine fever (CSF) involves vaccination in endemic regions and preemptive slaughter of infected swine herds during epidemics. Live attenuated marker vaccines that confer effective protection against the disease and allow differentiation between infected and vaccinated animals (DIVA) could impact CSF control policies. Previously, we reported the development of FlagT4 virus (FlagT4v), a rationally designed live attenuated marker vaccine. During its vaccine assessment, FlagT4v reverted to a virulent virus during successive passages in piglets. Sequence analysis revealed deletions and substitutions almost exclusively in the areas of E1 and E2. To improve genetic stability of FlagT4v, we introduced changes in the codon usage in those areas. The newly developed virus, FlagT4Gv, was shown to retain the attenuated phenotype after successive passages in piglets. As observed with FlagT4v, the newly developed FlagT4Gv conferred effective protection against challenge with virulent CSFV at early (7 days) and at late (28 days) times post-vaccination.

Interaction of structural core protein of classical swine fever virus with endoplasmic reticulum-associated degradation pathway protein OS9.

Classical swine fever virus (CSFV) Core protein is involved in virus RNA protection, transcription regulation and virus virulence. To discover additional Core protein functions a yeast two-hybrid system was used to identify host proteins that interact with Core. Among the identified host proteins, the osteosarcoma amplified 9 protein (OS9) was further studied. Using alanine scanning mutagenesis, the OS9 binding site in the CSFV Core protein was identified, between Core residues (90)IAIM(93), near a putative cleavage site. Truncated versions of Core were used to show that OS9 binds a polypeptide representing the 12 C-terminal Core residues. Cells transfected with a double-fluorescent labeled Core construct demonstrated that co-localization of OS9 and Core occurred only on unprocessed forms of Core protein. A recombinant CSFV containing Core protein where residues (90)IAIM(93) were substituted by alanines showed no altered virulence in swine, but a significant decreased ability to replicate in cell cultures.

Response of the µ-opioid system to social rejection and acceptance.

The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an µ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.

Serological evidence for a hepatitis e virus-related agent in goats in the United States.

Hepatitis E virus (HEV) causes an important public health disease in many developing countries and is also endemic in some industrialized countries. In addition to humans, strains of HEV have been genetically identified from pig, chicken, rat, mongoose, deer, rabbit and fish. While the genotypes 1 and 2 HEV are restricted to humans, the genotypes 3 and 4 HEV are zoonotic and infect humans and other animal species. As a part of our ongoing efforts to search for potential animal reservoirs for HEV, we tested goats from Virginia for evidence of HEV infection and showed that 16% (13/80) of goat sera from Virginia herds were positive for IgG anti-HEV. Importantly, we demonstrated that neutralizing antibodies to HEV were present in selected IgG anti-HEV positive goat sera. Subsequently, in an attempt to genetically identify the HEV-related agent from goats, we conducted a prospective study in a closed goat herd with known anti-HEV seropositivity and monitored a total of 11 kids from the time of birth until 14 weeks of age for evidence of HEV infection. Seroconversion to IgG anti-HEV was detected in seven of the 11 kids, although repeated attempts to detect HEV RNA by a broad-spectrum nested RT-PCR from the faecal and serum samples of the goats that had seroconverted were unsuccessful. In addition, we also attempted to experimentally infect laboratory goats with three well-characterized mammalian strains of HEV but with no success. The results indicate that a HEV-related agent is circulating and maintained in the goat population in Virginia and that the goat HEV is likely genetically very divergent from the known HEV strains.

Escalation of daunorubicin and addition of etoposide in the ADE regimen in acute myeloid leukemia patients aged 60 years and older: Cancer and Leukemia Group B Study 9720.

Untreated de novo (n=421) and secondary (n=189) acute myeloid leukemia (AML) patients ≥60 years received intensified chemotherapy, including daunorubicin 60 mg/m(2) and etoposide 100 mg/m(2) during days 1, 2, 3 with cytarabine 100 mg/m(2) during days 1-7, with a second induction if needed and one consolidation course with these drugs and doses for 2, 2 and 5 days, respectively. In all, 287 (47%) achieved complete remission (CR), 136 (22%) died and 187 (31%) were non-responders. CR rates were 27, 44 and 52% for complex karyotypes, rare aberrations and neither (P<0.001), 52 and 37% for de novo and secondary AML (P=0.003), and 53 and 42% for age 60-69 and ≥70 years (P=0.015). In multivariable analysis, CR predictors included non-complex/non-rare karyotypes (P<0.001), de novo AML (P<0.001), better performance status (PS) (P<0.001) and younger age (P=0.001). Disease-free (DFS) and overall (OS) survival medians were 6.8 (95% CI: 6.2, 7.8) and 7.2 (95% CI: 6.4, 8.6) months. In multivariable analysis, DFS was shorter for complex karyotypes (P<0.001) and increasing white blood count (WBC) (P<0.001) and age (P=0.038), and OS for complex karyotypes (P<0.001), increasing WBC (P=0.001) and age (P<0.001), poorer PS (P<0.001) and secondary AML (P=0.010). Outcomes and prognostic factors were similar to those in previous Cancer and Leukemia Group B studies.

Developing a disease prevention strategy in the Caribbean: the importance of assessing animal health-related risks at regional level.

In 2009 CaribVET conducted a survey among Caribbean national Veterinary Services to assess perceptions of risk assessment and to identify the principal exotic diseases of concern in the region and their means of introduction. The results showed that the introduction of live animals was considered the most likely route of introduction of exotic animal pathogens, followed by the uncontrolled introduction of animal products by boat passengers. The results were used to define a regional strategy for assessing animal health risks that highlights the importance of within-region exchanges.

Analysis of Amblyomma surveillance data in the Caribbean: lessons for future control programmes.

Amblyomma variegatum, the Tropical Bont Tick (TBT), is the principal vector of heartwater and is associated with dermatophilosis, major causes of losses in animal production and mortality in Caribbean livestock. From 1995 to 2007, the Caribbean Amblyomma Programme (CAP) supported treatment and surveillance activities in 11 islands of the Eastern Caribbean with an initial objective of eradicating TBT. In addition to control activities, surveillance data were collected between 1997 and 2006 in a unique regional database. We report the analysis of the surveillance data from four islands (Nevis, St Kitts, St Lucia, and Barbados) where control and surveillance followed the initial protocol and where enough data were collected. We describe the evolution of TBT infestation levels and the efforts carried out throughout the surveillance period. Logistic regression identified factors associated with herds found infested with TBT. Overall, treatment programmes were associated with a decrease in proportion of TBT-infested farms. High surveillance efforts were carried out throughout the 1997-2007 period for all island of interest, but inadequate level of surveillance was observed in several quarters especially for St Kitts. Third quarter of the year, as indication of adult TBT seasonality on livestock, was significantly associated with the risk of detecting TBT in Nevis and St Kitts livestock farms. Also, presence of cattle in Nevis farms was shown associated with an increasing probability of farms being declared TBT-infested. Outcomes of these analyses provide basis for recommendations to improve future national and regional control and surveillance activities. This analysis demonstrates the usefulness of long term and adequate surveillance data for control programmes and identification of factors associated with risk of having infested herds.

A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102.

BACKGROUND: This phase II trial (Cancer and Leukemia Group B 90102) sought to determine the efficacy of cisplatin, standard infusion of gemcitabine and gefitinib in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Eligible patients had previously untreated measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of zero to two and creatinine clearance >50 ml/min. Treatment consisted of cisplatin 70 mg/m(2) day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8 given every 3 weeks concurrent with gefitinib 500 mg/day orally for six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease. RESULTS: Fifty-four of 58 patients were assessable. Twelve patients (22%) had node-only disease, and 25 (46%) had an ECOG performance status of zero. There were 23 objective responses for an overall response rate of 42.6% [95% confidence interval (CI) 29.2% to 56.8%]. The median survival time was 15.1 months (95% CI 11.1-21.7 months) and the median time to progression was 7.4 months (95% CI 5.6-9.2 months). CONCLUSIONS: The combination of cisplatin, gemcitabine and gefitinib is well tolerated and active in advanced transitional cell carcinoma. The addition of gefitinib does not appear to improve response rate or survival in comparison to historical controls of cisplatin and gemcitabine alone.

Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207.

BACKGROUND: There is no standard second-line treatment for advanced urothelial carcinoma (UC). Response rates to second-line chemotherapy for advanced UC are low and response duration is short. Bortezomib is a proteasome inhibitor with preclinical activity against UC. PATIENTS AND METHODS: Treatment consisted of bortezomib 1.3 mg/m(2) i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival. RESULTS: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0-12]. The median time to progression was 1.4 months (95% CI = 1.1-2.0 months), and the median survival time was 5.7 months (95% CI = 3.6-8.4 months). There were no treatment-related deaths. CONCLUSION: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.

JAK2(V617F): Prevalence in a large Chinese hospital population.

Recently, the JAK2(V617F) mutation was found in patients with myeloproliferative disorders (MPDs), including most with polycythemia vera (PV). The mutant JAK2 has increased kinase activity, and it was shown to be pathogenic in mouse models. Herein, we analyzed blood samples randomly collected from a clinical laboratory. Surprisingly, as many as 37 samples from a total of 3935 were found positive for the JAK2 mutation. However, only one of these samples had blood test results indicative for probable PV, but several had nonhematologic diseases. On average, samples with the mutation had normal red cell counts but significantly higher white blood cell and platelet counts, although most were within the normal range. The data suggest that the JAK2(V617F) mutation is apparently much more common than MPDs. Its occurrence may be a prelude to full blood cell abnormalities and other diseases, but it cannot by itself diagnose MPDs.

Role of tyrosine kinases and phosphatases in polycythemia vera.

Protein tyrosine kinases (PTKs) and phosphatases (PTPs) play a crucial role in normal cell development, and dysfunction of these enzymes has been implicated in human cancers. Polycythemia vera (PV) is a clonal hematologic disease characterized by hypersensitivity of hematopoietic progenitor cells to growth factors and cytokines. Recently, a unique and clonal mutation in the JAK homology 2 (JH2) domain of JAK2 that results in a valine to phenylalanine substitution at position 617 (V617F) was found in the majority of PV patients. This mutation leads to constitutive JAK2 activation and abnormal signaling and induces erythrocytosis in an animal model. The mutation is also found in a significant percentage of patients with idiopathic myelofibrosis (50%) and essential thrombocythemia (30%). Thus, it seems probable that this mutation associates with other molecular genetic events to cause different myeloproliferative disorders (MPDs). One of these secondary events is the transition to homozygosity of the mutated gene in 30% of the PV patients. Other events may include defects in PTPs, but these remain to be characterized. Recent studies represent a great step forward in the molecular pathogenesis in PV and the development of targeted new drugs to treat the disease.