Sporadic Onset Research Articles

Hereditary vascular cognitive decline

A number of monogenic forms of cerebral small vessel disease (SVD) cause early onset lacunar stroke and dementia. By far the most common of these is CADASIL due to NOTCH3 mutations, although other underlying genes causing similar diseases include HTRA1 and COL4A1/2. Characteristic MRI features include white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. The pattern of cognitive impairment usually shows prominent executive dysfunction and information processing speed. Diagnosis depends on family history, characteristic clinical features, and characterised MRI markers, and is confirmed by genetic testing, made much simpler with newer gene arrays. Although there is little evidence based management, recent European Neurological Association guidelines provide a useful management framework. Increasing evidence has implicated a key role of disruption in the matrisome and extracellular matrix (ECM) of the small perforating arteries within the brain in disease pathogenesis, with disruption in different genes converging on shared pathways. Recent evidence suggests that more common variants in the same genes can predispose to sporadic younger onset stroke and dementia. Interestingly study of community cohorts has demonstrated that the mutations causing familial SVD are much commoner in the general population than would be expected from familial SVD prevalence. Why mutations sometimes result in early onset disease and on other occasions do not is still being investigated. However these population variants have also been associated with an increased risk of sporadic stroke and sporadic vascular dementia.

Animal Models of Autosomal Recessive Parkinsonism.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the substantia nigra pars compacta. The clinical manifestations of PD are bradykinesia, rigidity, resting tremors and postural instability. PD patients often display non-motor symptoms such as depression, anxiety, weakness, sleep disturbances and cognitive disorders. Although, in 90% of cases, PD has a sporadic onset of unknown etiology, highly penetrant rare genetic mutations in many genes have been linked with typical familial PD. Understanding the mechanisms behind the DA neuron death in these Mendelian forms may help to illuminate the pathogenesis of DA neuron degeneration in the more common forms of PD. A key step in the identification of the molecular pathways underlying DA neuron death, and in the development of therapeutic strategies, is the creation and characterization of animal models that faithfully recapitulate the human disease. In this review, we outline the current status of PD modeling using mouse, rat and non-mammalian models, focusing on animal models for autosomal recessive PD.

TUBEROUS SCLEROSIS: PRESENTATION OF A CASE AND REVIEW OF THE LITERATURE

Tuberous Sclerosis Complex (TSC) also known as Bournneville disease. TSC is a multisystemic genetic disorder with autosomal dominant inheritance, of variable expression, which is mainly characterized by the presence of benign tumors or hamartomas in the nervous system and skin, but which may also be present in the heart, kidney, lung and other organs. The most frequent symptom is epilepsy, affecting 80-90% of patients with TSC which manifests itself in childhood between 1 to 3 years of age. We present a case of sporadic onset tuberous sclerosis with epilepsy that had a causal link with TSC after admission to the emergency room in a convulsive status.

When Your Thyroid Causes Muscle Paralysis

Background: Periodic paralysis represents a spectrum of disorders characterized by ion channel dysfunction, mainly Na-K-ATPase channels. Thyrotoxic periodic paralysis (TTP) is defined by the presence of hypokalemia and diffuse muscular paralysis in a pre-existing hyperthyroid state. Diagnosis can be challenging, especially in cases of undiagnosed hyperthyroidism due to the non-specific presentation of this illness. We present a case of a young male who presented with recurrent, spontaneous paralysis found to have Graves’ disease. Clinical Case: A 38-year-old Asian male presented with sudden onset diffuse weakness, numbness, and tingling. The weakness was so severe that he could barely walk more than a few steps. However, his symptoms resolved in less than 24 hours without any intervention. Five months later, the patient experienced a recurrent episode of this similar constellation of diffuse muscle weakness and paresthesia. The patient was taken to a nearby hospital, where he was provided with intravenous fluid resuscitation. Initial laboratory workup was notable for hypokalemia to 1.4 mmol/L (n: 3.6 - 5.3 mmol/L), hypophosphatemia to 0.6 mmol/L (n: 2.4 – 4.8 mmol/L), and elevated creatinine kinase to 807 U/L (n: 22 – 198 U/L). Additionally, TSH was <0.001 mU/L (n: 0.45 – 4.5 mU/L) along with free T4 3.4 ng/dL (n: 0.80 – 1.70 ng/dL. The patient denied any other symptoms or a family history of similar symptoms. Lumbar puncture and brain/spine MRIs were unremarkable. Symptoms gradually improved throughout hospitalization with fluid and electrolyte repletion. Hyperthyroidism was treated with methimazole 5mg twice daily, later changed to PTU 50mg every eight hours due to recurrent headaches. Thyroid uptake scan showed diffuse bilateral uptake to 39.11% at 4 hours and 61.8% at 24 hours. Follow up labs revealed: TSH 0.3 mU/L, free T4 1.44 ng/dL, free T3 3.5 pg/mL (n: 2.3 – 4.1 pg/mL). Patient denied recurrent episodes of weakness or paresthesia. Definitive hyperthyroidism treatment with RAI was planned. Conclusions: The prevalence of TPP is higher in Asian males compared to other ethnic groups. TPP manifests as a sporadic onset of muscle weakness ranging from mild weakness to flaccid paralysis. It has been described that thyroid hormone itself augments the activity of the Na-K-ATPase channel and increases its responsiveness to beta-adrenergic stimulation. In addition, hyperthyroidism is associated with insulin resistance leading to hyperinsulinemia. Both beta-agonism and insulin promote potassium to be driven into cells resulting in hypokalemia. As such, activities which increase beta adrenergic stimulation, like stress and exercise, and promote the secretion of insulin, such as heavy carbohydrate intake, are well described triggers of TPP. Treatment revolves around acutely treating hypokalemia followed by preventing subsequent attacks via regulation of the altered thyroid state.

C-Jun N-Terminal Kinases in Alzheimer's Disease: A Possible Target for the Modulation of the Earliest Alterations.

Given the highly multifactorial origin of Alzheimer's disease (AD) neuropathology, disentangling and orderly knowing mechanisms involved in sporadic onset are arduous. Nevertheless, when the elements involved are dissected into smaller pieces, the task becomes more accessible. This review aimed to describe the link between c-Jun N-terminal Kinases (JNKs), master regulators of many cellular functions, and the early alterations of AD: synaptic loss and dysregulation of neuronal transport. Both processes have a role in the posterior cognitive decline observed in AD. The manuscript focuses on the molecular mechanisms of glutamatergic, GABA, and cholinergic synapses altered by the presence of amyloid-β aggregates and hyperphosphorylated tau, as well as on several consequences of the disruption of cellular processes linked to neuronal transport that is controlled by the JNK-JIP (c-jun NH2-terminal kinase (JNK)-interacting proteins (JIPs) complex, including the transport of AβPP or autophagosomes.

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

Animal and human mechanistic studies have consistently shown an association between obesity and Alzheimer’s disease (AD). AD, a degenerative brain disease, is the most common cause of dementia and is characterized by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles disposition. Some studies have recently demonstrated that Aβ and tau cannot fully explain the pathophysiological development of AD and that metabolic disease factors, such as insulin, adiponectin, and antioxidants, are important for the sporadic onset of nongenetic AD. Obesity prevention and treatment can be an efficacious and safe approach to AD prevention. Adiponectin is a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation. It has been shown to be inversely correlated with adipose tissue dysfunction and may enhance the risk of AD because a range of neuroprotection adiponectin mechanisms is related to AD pathology alleviation. In this study, we summarize the recent progress that addresses the beneficial effects and potential mechanisms of adiponectin in AD. Furthermore, we review recent studies on the diverse medications of adiponectin that could possibly be related to AD treatment, with a focus on their association with adiponectin. A better understanding of the neuroprotection roles of adiponectin will help clarify the precise underlying mechanism of AD development and progression.

Association of years to parent's sporadic onset and risk factors with neural integrity and Alzheimer biomarkers.

To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors. This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [18F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid42/40 ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE ε4, education, and vascular and mental health. Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and APOE ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age. The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions. NCT02485730. This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.

Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis.

Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-β)/BMP signaling are linked to both sporadic and hereditary phenotypes. However, the low incidence of inherited cases makes the genetic bases of the disease unclear. To increase this knowledge, we performed a whole exome sequencing on five patients, on DNA purified by peripheral blood. Variants were filtered based on frequency and functional class. Those selected were validated by Sanger sequencing. Genes carrying selected variants were prioritized to relate these genes with those already known to be linked to bAVM development. Most of the prioritized genes showed a correlation with the TGF-βNotch signaling and vessel morphogenesis. However, two novel pathways related to cilia morphogenesis and ion homeostasis were enriched in mutated genes. These results suggest novel insights on sporadic bAVM onset and confirm its genetic heterogeneity. The high frequency of germline variants in genes related to TGF-β signaling allows us to hypothesize bAVM as a complex trait resulting from the co-existence of low-penetrance loci. Deeper knowledge on bAVM genetics can improve personalized diagnosis and can be helpful with genotype–phenotype correlations.

Gut Microbiota Imbalance is Related to Sporadic Colorectal Neoplasms. A Pilot Study

(1) Background: Colorectal cancer (CRC) development is sustained by multiple factors including the gut microbiota, as suggested by a growing body of evidence. Most CRCs have a sporadic (non-hereditary) onset and develop from sporadic colorectal adenomas/polyp (SCA/P). In the present study, we investigated the characteristic of anaerobic microorganisms in stool samples obtained from 20 patients with SCA/P and 20 subjects without evidence of proliferative lesions at colonoscopy (Controls). (2) Material and Methods: We designed this clinical trial using adaptive randomization by minimization. Selective culture media and Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectrometry techniques were used to identify the components of microbiota. The data obtained revealed a different variability of gut microbiota in stool samples of controls and SCA/P subjects. (3) Results: The most interesting difference was observed for Bacteroides species, which represent the 50% of all bacterial species identified in the stool samples: two species, Bacteroides stercoris and Parabacteroides distasonis, were found only in the feces from control group, whereas Bacteroides fragilis and Prevotella melaningenica species were presents only in SCA/P patients. Among Gram+ bacteria also, specific species were found in the two groups of feces: Clostridium clostridioforme, Propionibacterium avidum and Pediococcus pentasaceus were identified only in controls, while Eubacterium limosum, Clostridium innocuum and Corybebacterium xerosus were identified in SCA/P stool samples only. (4) Conclusions: Our findings suggest that, compared to control stool samples, a different intestinal microbiota is present in SCA/P stool samples, that may create a micro-environment predisposing for the development of proliferative phenomena. As a consequence, gut microbiota manipulation could be a future target for personalized treatments.

A Summary of the Fight Colorectal Cancer Working Meeting: Exploring Risk Factors and Etiology of Sporadic Early-Age Onset Colorectal Cancer.

A Summary of the Fight Colorectal Cancer Working Meeting: Exploring Risk Factors and Etiology of Sporadic Early-Age Onset Colorectal Cancer.

Targeting Apolipoprotein E for Alzheimer's Disease: An Industry Perspective.

Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer’s disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to “drug-ability” of this target.

Parkinson's Disease and the Environment.

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder that affects an estimated 10 million sufferers worldwide. The two forms of PD include familial and sporadic, and while the etiology of PD is still largely unknown, the condition is likely to be multifactorial with genetic and environmental factors contributing to disease genesis. Diagnosis of the condition is attained through the observation of cardinal clinical manifestations including resting tremor, muscle rigidity, slowness or loss of movement, and postural instability. Unfortunately, by the time these features become apparent extensive neurological damage has already occurred. A cure for PD has not been identified and the current therapy options are pharmaceutical- and/or surgical-based interventions to treat condition symptoms. There is no specific test for PD and most diagnoses are confirmed by a combination of clinical symptoms and positive responses to dopaminergic drug therapies. The prevalence and incidence of PD vary worldwide influenced by several factors such as age, gender, ethnicity, genetic susceptibilities, and environmental exposures. Here, we will present environmental factors implicated in sporadic PD onset. By understanding the mechanisms in which environmental factors interact with, and affect the brain we can stride toward finding the underlying cause(s) of PD.

Superhydrophobic lab-on-chip measures secretome protonation state and provides a personalized risk assessment of sporadic tumour

Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at-risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual’s diagnosis and/or help clarify risk in healthy populations.

Assessment of Cognitive Impairment in a Mouse Model of High-Fat Diet-Induced Metabolic Stress with Touchscreen-Based Automated Battery System.

Obesity-related metabolic disorders can affect not only systemic health but also brain function. Recent studies have elucidated that amyloid beta deposition cannot satisfactorily explain the development of Alzheimer's disease (AD) and that dysregulation of glucose metabolism is a critical factor for the sporadic onset of non-genetic AD. Identifying the pathophysiology of AD due to changes in brain metabolism is crucial; however, it is limited in measuring changes in brain cognitive function due to metabolic changes in animal models. The touchscreen-based automated battery system, which is more accurate and less invasive than conventional behavioral test tools, is used to assess the cognition of mice with dysregulated metabolism. This system was introduced in humans to evaluate cognitive function and was recently back-translated in monkeys and rodents. We used outbred ICR mice fed on high-fat diet (HFD) and performed the paired associates learning (PAL) test to detect their visual memory and new learning ability loss as well as to assess memory impairment. The behavioral performance of the HFD mice was weaker than that of normal mice in the training but was not significantly associated with motivation. In the PAL test, the average number of trials completed and proportion of correct touches was significantly lower in HFD mice than in normal diet-fed mice. Our results reveal that HFD-induced metabolic dysregulation has detrimental effects on operant learning according to the percentage of correct responses in PAL. These findings establish that HFD-induced metabolic stress may have an effect in accelerating AD-like pathogenesis.

Class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion.

Despite the important role of apolipoprotein E (apoE) secretion from astrocytes in brain lipid metabolism and the strong association of apoE4, one of the human apoE isoforms, with sporadic and late onset forms of Alzheimer’s disease (AD) little is known about the regulation of astrocytic apoE. Utilizing annotated chemical libraries and a phenotypic screening strategy that measured apoE secretion from a human astrocytoma cell line, inhibition of pan class I histone deacetylases (HDACs) was identified as a mechanism to increase apoE secretion. Knocking down select HDAC family members alone or in combination revealed that inhibition of the class I HDAC family was responsible for enhancing apoE secretion. Knocking down LXRα and LXRβ genes revealed that the increase in astrocytic apoE in response to HDAC inhibition occurred via an LXR-independent pathway. Collectively, these data suggest that pan class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion.

Role of CYP1B1, p.E229K and p.R368H mutations among 120 families with sporadic juvenile onset open-angle glaucoma.

To determine the frequency of CYP1B1 p.E229K and p.R368H, gene mutations in a cohort of sporadic juvenile onset open-angle glaucoma (JOAG) patients and to evaluate their genotype/phenotype correlation. Unrelated JOAG patients whose first-degree relatives had been examined and found to be unaffected were included in the study. The patients and their parents were screened for p.E229K and p.R368H mutations. The phenotypic characteristics were compared between probands carrying the mutations and those who did not carry these mutations. Out of 120 JOAG patients included in the study, the p.E229K mutation was seen in 9 probands (7.5%) and p.R368H in 7 (5.8%). The average age of onset of the disease (p = 0.3) and the highest untreated IOP (p = 0.4) among those carrying mutations was not significantly different from those who did not have these mutations. The proportion of probands with angle dysgenesis among those with p.E229K and p.R368H mutations was 70% (11 out of 16) in comparison to 65% (67 out of 104) of those who did not harbour these mutations (p = 0.56). Similarly, the probands with moderate to high myopia among those with p.E229K and p.R368H mutations was 20% (3 out of 16) in comparison to 18% (18 out of 104) of those who did not harbour these mutations (p = 0.59). The frequency of p.E229K and p.R368H mutations of the CYP1B1 gene is low even among sporadic JOAG patients. Moreover, there is no clinical correlation between the presence of these mutations and disease severity.

ApoE isoforms differentially regulates cleavage and secretion of BDNF

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for sporadic or late onset Alzheimer’s disease (AD). Brain-derived neurotrophic factor (BDNF) is decreased by 3 to 4-fold in the brains of AD patients at autopsy. ApoE4 mice also have reduced BDNF levels. However, there have been no reports relating the different ApoE isoforms or AD to differential regulation of BDNF. Here we report that in the hippocampal regions of AD patients both prepro-BDNF and pro-BDNF expression showed a 40 and 60% decrease respectively compared to that expression in the hippocampi of age-matched control patients. We further report that ApoE isoforms differentially regulate maturation and secretion of BDNF from primary human astrocytes. After 24 h, ApoE3 treated astrocytes secreted 1.75- fold higher pro-BDNF than ApoE2-treated astrocytes, and ApoE2-treated astrocytes secreted 3-fold more mature-BDNF (m-BDNF) than ApoE3-treated astrocytes. In contrast, ApoE4-treated cells secreted negligible amounts of m-BDNF or pro-BDNF. ApoE2 increased the level of intracellular pre-pro BDNF by 19.04 ± 6.68%, while ApoE4 reduced the pre-pro BDNF by 21.61 ± 5.9% compared to untreated cells. Similar results were also seen in ApoE2, ApoE3 or ApoE4 treated cells at 4 h. Together, these results indicate that an ApoE2 or ApoE3 mediated positive regulation of BDNF may be protective while ApoE4 related defects in BDNF processing could lead to AD pathophysiology. These interactions of the ApoE isoforms with BDNF may help explain the increased risk of AD associated with the ApoE4 isoform.

Genomic profiling of young adults with colorectal cancer: A single-institution experience.

e15168 Background: 2-8% of all colorectal cancer (CRC) cases are in younger adults (YAs), patients (pts) less than age 50. However, current understanding of CRC in YAs is inadequate, especially that of sporadic onset. We conducted a study to describe the landscape of genomic alterations in YA CRC pts presenting to a large academic practice. Methods: Adult pts with CRC presenting to The Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing (NGS) through a customized 22-gene Ion AmpliSeq Mutation Panel as part of clinical care. Commonly mutated areas of select genes (including AKT1, ALK, BRAF, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS/NRAS, MET, NOTCH1, PIK3CA, PTEN, TP53) were sequenced from tumor sections. Institutional review board approval was obtained to retrospectively analyze this NGS testing between 1/2013-3/2016. Results: 258 CRC pts underwent genomic profiling. 57 pts (22.1%) were YAs at diagnosis (range 22-49 years); 20 pts (7.8%) were 40 years old or younger. 31 YA pts (54.4%) had metastatic disease. Of the YAs with CRC, 18 pts (31.6%) were diagnosed with R-sided colon, 16 pts (28.1%) with L-sided colon, and 22 pts (38.6%) with rectal cancer. 110 genomic alterations were found in YA pts, with a mean of 1.9 mutations per tumor (range 0-6); 35 (31.8%) of these in 32 (56.1%) YA pts were actionable. Of these 110 alterations, 41.8% were in TP53, 28.2% in KRAS/NRAS, 10.0% in PIK3CA, 3.6% in BRAF, 3.6% in FBXW7, and 2.73% in PTEN. 6 YA pts (10.5%) had microsatellite instability (MSI-H). Only 1 pt had concomitant MSI-H and a BRAF mutation; 4 pts with BRAF mutations were microsatellite stable. Comparing our YA pts to a separate cohort of pts age &gt; 50 who had testing done, no significant difference was seen in mutation incidence in KRAS/NRAS (p = 1.0), TP53 (p = 0.3), PIK3CA (p = 0.128), or BRAF (p = 1.0). Conclusions: Genomic profiling through a targeted NGS panel is feasible as part of routine clinical practice. There is disagreement in the literature on genetic mutations in YA compared to older age CRC pts. Knowledge of the genomic landscape in YAs with CRC will lead to improved understanding of the underlying biology of CRC in YAs as it differs from CRC in older pts, and could impact future care of this cohort.

Different clinical characteristics in sporadic young-age onset colorectal cancer.

The incidence of colorectal cancer (CRC) is increasing in young-age patients, but the clinical history is not established. Authors analyzed the clinical characteristics of young-age onset CRC to support basic information for setting treatment policies.Between January 2006 to January 2014, 100 CRC patients diagnosed at the age of 10 to 39 were analyzed. The clinicopathologic characteristics were reviewed based on medical records. Survival outcomes including overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were analyzed. This study was conducted as a retrospective, observation study.Among 100 patients, 86 patients were diagnosed as CRC at their thirties. Seventy-nine patients had no familial history of cancer. At initial diagnosis, 59 patients showed the normal CEA level (≤3 ng/mL), and 61 patients were diagnosed as advanced CRC (40% stage III, 21% stage IV). Sixty-four patients had lower location-sigmoid colon, rectosigmoid junction, or rectum. Recurrence rate was 7.9% in stage I to III CRC. Although median OS was not reached, patients with normal CEA level showed better survival outcome (P = 0.013) and patients with perineural invasion showed poorer survival (P = 0.011). The 5-year survival rate of total patient population was estimated as 75%. However, median OS of stage IV patients were 19 months (range 7.9–60.63 months), shorter than historical data of >24 months.Young-age CRC was most commonly diagnosed at their thirties, with no familial history, normal range of CEA and located below sigmoid colon. In young-age onset stage IV CRC, patients showed inferior OS compared to historical data. Based on our data, different surveillance program other than serum CEA level (e.g., sigmoidoscopy) is needed in young-age patient population.

Frequency of tail lesions and risk factors for tail biting in heavy pig production from weaning to 170 kg live weight

Tail biting lesions have a negative effect on both the welfare of pigs and on the revenue of the pig farm. Due to the multifactorial nature of this abnormal behaviour and its sporadic onset, an epidemiological approach was adopted to identify the management and housing factors influencing the occurrence of tail biting and the frequency of bitten pigs in the weaning and fattening phases up to 170 kg live weight in heavy pig production. Data were collected from a sample of 67 commercial pig farms via an on-farm visit and a questionnaire to the farmer. Data collected included general farm information, hygiene and herd health, prevention, management, climate control, feeding and production traits.In the weaning phase, the occurrence of tail biting was increased by a factor of 16.64 for tipped vs. short-docked tails, by a factor of 68.09 when the observer detected poor air quality, and by a factor of 14.44 when the feeding time was variable. In fattening pigs, a high stocking density increased the risk of tail biting by a factor of 18.00. The frequency of lesions in weaners was greater in pigs with tipped tails (0.29 vs. 0.03%; P = 0.034), whereas in fatteners the frequency of lesions was greater when drinkers were not present in the lying area (0.71 vs. 0.05%; P = 0.009) and when air turnover was not detected in the barn (0.70 vs. 0.07%; P = 0.005). There was also a trend for increased tail biting when the stocking density was high (1.06 vs. 0.33%; P = 0.057). Many of the risk factors that emerged for heavy pigs in the present study could be easily managed to reduce the risk of tail biting and the frequency of tail lesions through the systematic evaluation and control of stocking density, climate, and feed and water management.