Changing Clinical Epidemiology of Plasmodium vivax Malaria as Transmission Decreases: Population-Based Prospective Panel Survey in the Brazilian Amazon.

BACKGROUND: Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to elicit symptoms change as transmission declines remains unclear. METHODS: We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention. RESULTS: We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission. CONCLUSIONS: P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases.

Clinical expression and mitochondrial deoxyribonucleic acid study in twins with 14484 Leber's hereditary optic neuropathy: A case report.

BACKGROUND: This study aimed to explore clinical and molecular factors that cause discordance for clinical expression of Leber's hereditary optic neuropathy (LHON) in a pair of identical twins with the 14484 point mutation. CASE SUMMARY: Twin patients with the 14484 point mutation were studied for zygosity by using the Short Tandem Repeats Typing system. For the monozygotic twins, the radioactive restriction and densitometric analyses were used to quantitate the heteroplasmy level for the 14484 point mutation. The mitochondrial genome was analyzed to determine influential factors by mitochondrial deoxyribonucleic acid (DNA) sequencing, denaturing high-performance liquid chromatography and next generation sequencing. For the dizygotic twins, the nuclear DNA was analyzed. The twins with 14484 LHON were monozygotic with homoplasmy. No difference in the point mutation in mitochondrial DNA was found. No modifying genes that potentially influenced the disparity in phenotypic expression of LHON were detected in these twins. CONCLUSION: This 11-year follow-up of monozygotic twins showed additional genetic modifications and epigenetic factors are possibly associated with discordance for LHON.

Differential Diagnosis of Chorea-HIV Infection Delays Diagnosis of Huntington's Disease by Years.

BACKGROUND: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington's disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. METHODS: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. RESULTS: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). CONCLUSIONS: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

Up-regulation of hypoxia inducible Factor-1α in patients with diabetic nephropathy.

OBJECTIVE: To study the role of hypoxia inducible factor-1α (HIF-1α) in patients with diabetic nephropathy (DN). METHODS: In total, 133 participants were selected to conduct the investigation, parameters such as fasting blood sugar (FBS), blood urea nitrogen (BUN), and urine albumin-creatinine ratio (UACR) were tested and recorded. The biopsy assessment was conducted when renal function or urinary abnormalities. Western blotting was used to test the expression of serum HIF-1α in all patients and control group. RESULTS: The values of FBS, BUN, and UACR were higher in DN and diabetes groups than in the healthy control. The values of FBG, BUN, and UACR were higher in DN patients than in the diabetes patients with no nephropathy. eGFR in DN patients was lower than the other two groups. The expression of HIF-1α was higher than both diabetes patients with no nephropathy and healthy control, P < 0.05. Patients with lots of albuminuria showed the highest expression of HIF-1α than the other groups. HIF-1α in normoalbuminuria and microalbuminuria groups showed no significant difference. CONCLUSIONS: HIF-1α was up-regulated in DN patients, which might give clinical basis to the role of HIF-1α in the development of DN.

The Mitochondrial tRNAHis G12192A Mutation May Modulate the Clinical Expression of Deafness-Associated tRNAThr G15927A Mutation in a Chinese Pedigree.

BACKGROUND: Mutations in mitochondrial tRNA (mt-tRNA) genes have been found to be associated with both syndromic and non-syndromic hearing impairment. However, the pathophysiology underlying mt-tRNA mutations in clinical expression of hearing loss remains poorly understood. OBJECTIVE: The aim of this study was to explore the potential association between mttRNA mutations and hearing loss. METHODS AND RESULTS: We reported here the molecular features of a pedigree with maternally transmitted non-syndromic hearing loss. Among 12 matrilineal relatives, five of them suffered variable degree of hearing impairment, but none of them had any medical history of using aminoglycosides antibiotics (AmAn). Genetic screening of the complete mitochondrial genomes from the matrilineal relatives identified the coexistence of mt-tRNAHis G12192A and mt-tRNAThr G15927A mutations, together with a set of polymorphisms belonging to human mitochondrial haplogroup B5b1b. Interestingly, the G12192A mutation occurred 2-bp from the 3' end of the TψC loop of mt-tRNAHis, which was evolutionarily conserved from various species. In addition, the well-known G15927A mutation, which disrupted the highly conserved C-G base-pairing at the anticodon stem of mt-tRNAThr, may lead to the failure in mt-tRNA metabolism. Furthermore, a significant decreased in ATP production and an increased ROS generation were observed in polymononuclear leukocytes (PMNs) which were isolated from the deaf patients carrying these mt-tRNA mutations, suggested that the G12192A and G15927A mutations may cause mitochondrial dysfunction that was responsible for deafness. However, the absence of any functional mutations/variants in GJB2, GJB3, GJB6 and TRMU genes suggested that the nuclear genes may not play important roles in the clinical expression of non-syndromic hearing loss in this family. CONCLUSION: Our data indicated that mt-tRNAHis G12192A mutation may increase the penetrance and expressivity of deafness-associated m-tRNAThr G15927A mutation in this family.

Human leukocyte antigens-DRB1*03 is associated with systemic lupus erythematosus and anti-SSB production in South Tunisia.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease with various presentations. This variation is due to the interaction of hormonal, environmental, and genetic factors. Associations between human leukocyte antigens and SLE have long been recognized in different ethnic populations and have been suggested to represent the most important association. OBJECTIVES: The objectives of this paper were to determine susceptibility and protection human leukocyte antigens (HLA) Class II markers for SLE and to highlight, for the first time, associations between HLA alleles and clinical and serological features in South Tunisia. METHODS: We conducted a case-control study on 75 SLE patients and 123 healthy controls. The HLA Class II DRB1/DQB1 of all patients and controls was genotyped using polymerase chain reaction-sequence specific primer technique. Statistical analysis was performed using SPSS software. RESULTS: HLA-DRB1*03 was the principal Class II allele associated with the genetic susceptibility to SLE (pc = 0.02; OR = 2.57; CI = [1.39-4.75]; this allele was also associated with anti-SSB production (P = 0.016; OR = 4.00; CI = [1.24-12.96]). HLA-DRB1*01 was significantly more expressed in SLE patients with neurologic disorders (P = 0.013; OR = 20.25; CI = [1.87-219.21]). No allele was found to be protective against SLE in our study group. CONCLUSION: Our results show that in South Tunisia SLE is associated with HLA-DRB1*03 and that some clinical features of SLE may be influenced by specific DRB1 and DQB1 alleles.

Serum LncRNA PCAT-1 Expression Level of Patients with Multiple Myeloma and Clinical Value / 现代检验医学杂志

Objective To explore serum long stranded noncoding RNA (lncRNA) transcript 1 (PCAT-1) expression level of patients with multiple myeloma (MM) and clinical value.Methods 72 cases of patients with MM treated in the Second People's Hospital of Zhaoqing City were selected as the study objects,and 60 cases of normal subjects undergoing physical examination in the same period were as the control group.Serum lncRNA PCAT-1 expression was detected by RT-PCR method.The relationship between lncRNA PCAT 1 expression and clinical pathological parameters,treatment effect was analyzed,and 5 years survival was analyzed by using Kaplan-Meier,and survival difference was detected by using Log-Rank method.Results Serum PCAT-1mRNA expression in MM group (2.65 ± 0.64) was significantly higher than that in the control group (1.06 ± 0.23,t=18.276,P=0.000).There were no significant differences in sex,clinical stage and pathological types of hemoglobin,plasma cells,platelets,albumin,β2-MG and CRP between PCAT 1 mRNA high expression group and low expression group (x2 =0.001 ～ 3.345,all P ＞ 0.05).Ca2+ ≥ 10 mg/dl in the PCAT-1 high expression group (57.14％) was significantly higher than that in the low expression group (27.27％,x2 =5.229,P=0.022).There was no significant difference in treatment effect between PCAT-1 mRNA high expression group and low expression group (88.64 ％ vs 75.00％,x2 =2.291,P=0.130).PFS and OS expression in PCAT-1 high expression group were lower than that in the low expression group (x2 =7.269,P =0.007;x2 =9.190,P =0.002).COX risk regression multiple factor analysis showed that age and PCAT-1mRNA expression were independent prognostic factors influencing patients (OR =3.275,P =0.025,95％CI:2.691～3.761;OR=2.136,P=0.046,95％CI:2.034～2.685).Conclusion LncRNA PCAT-1 is highly expressed in serum of patients with multiple myeloma,and correlated with the prognosis of patients.

Juvenile myoclonic epilepsy: Challenges on its 60th anniversary.

PURPOSE: Since its initial 1957 description, juvenile myoclonic epilepsy (JME) has been recognized as a common epileptic syndrome worldwide. METHODS: We reviewed a series of articles on JME to clarify challenges in clinical and pathophysiological findings, treatment and outcome. RESULTS: Typical JME characteristics include: 1) the age at seizure onset between 10 and 25 years; 2) the triad of myoclonia, generalized tonic-clonic seizures, and absences, of which only myoclonia is a mandatory criterion; 3) cognitive dysfunction that may have impact on interpersonal relationships and social outcome; 4) possibility of seizure control in up to 80% of individuals, in particular with the use of sodium valproate; 5) a tendency for lifelong seizures with an early morning preponderance; 6) after decades from the clinical onset, a possibility to be off medications for a third of the patients, and 7) several prognostic factors. CONCLUSION: After 60 years, several challenges remain in this complex epileptic syndrome.

Depression and anxiety in patients with and without same-sex attraction: differences in clinical expression, lifestyle factors, and vulnerability indicators.

BACKGROUND: The aim of this study was to compare clinical expressions (severity and loneliness), lifestyle factors (substance use), and vulnerability indicators (stressful childhood experiences) in patients with any same-sex attraction versus heterosexual patients diagnosed with depression and/or anxiety disorder. Little is known about this, even though it is now well documented that depression and anxiety are more prevalent among persons with same-sex attraction. METHOD: Data, derived from the Netherlands Study of Depression and Anxiety (NESDA), allowed us to compare patients with a same-sex (n = 122) and an exclusively opposite-sex (n = 1658) attraction. Persons with same-sex attraction included persons who were attracted to both sexes. Data were collected by means of the Composite International Diagnostic Interview and paper-and pencil questionnaires. RESULTS: Seven percent of the patients reported any same-sex orientation. Clinical expression of depression and anxiety did not differ in relation to sexual attraction. Regarding substance use, same-sex attracted women reported more drug use than heterosexual women (drug use: 16.2% vs. 6.6%, P = 0.003). Regarding stressful childhood experiences, men with any same-sex attraction reported more sexual abuse during childhood than men with a heterosexual orientation (20.4% vs. 8.5%, P = 0.005). CONCLUSIONS: For women with same-sex attraction substance use (especially illicit drug use) might be a coping mechanism to deal with existing symptoms or with the minority stressors they have to deal with; for same-sex attracted men stressful childhood experiences might reflect an aspect of etiology.

Association of TGFB1 -509C/T polymorphism gene with clinical variability in cystic fibrosis patients: A case-control study.

PURPOSE: In this work, we are interested to study the implication of -509C/T polymorphism, located in the promoter region of TGFB1 (transforming growth factor ß1), in the phenotypic variability of CF patients. PATIENTS AND METHODS: The present study enrolled 111 CF patients and 100 healthy control subjects. The study of the -509C/T polymorphism was performed using PCR-RFLP method. RESULTS: We found that patients carried non-F508del homozygous mutation with TT genotype was associated to lung symptoms (P=0.04). This association was not found in the sub-groups of patients with F508del at homozygous state P=0.145. No association was found between this polymorphism and the variability of digestive, pancreatic and ileus meconial symptoms. CONCLUSION: On the basis of our results, the -509C/T polymorphism of the TGFB1 gene seems to be a modulator factor of cystic fibrosis.

Relation between HLA typing and clinical presentations in Systemic Lupus Erythematosus patients in Al-Qassim region, Saudi Arabia.

BACKGROUND: Systemic lupus erythematosus (SLE) is a disease with diverse clinical presentations due to interaction between genetic and environmental factors. SLE is associated worldwide with polymorphisms at various loci, including the major histocompatibility complex (MHC), although inconsistencies exist among these studies. AIMS: This study was carried out to investigate, the association of HLA-DRB1, DRB3, DRB4, DRB5, and DQB1 alleles in SLE patients and clinical presentations at Qassim, Saudi Arabia. METHODS: Fifty one patients with SLE-84.3% of whom had kidney involvement were studied in a case control study for HLA-DRB1, DRB3, DRB4, DRB5, and DQB1. RESULTS: It was found that DRB3 is a protective gene among Saudi's against SLE, HLA DRB3, HLA DRB1*11 frequency was increased in patients with serositis with a p value of (0.004), (0.047) respectively, increased frequency of HLA DQB1*3 among SLE patients with skin manifestations with a p value of (0.041), the frequency of HLA DRB1*15 alleles was increased among SLE patients with nephritis with a p value of (0.029), the frequency of HLA DRB1*11 among those with hematological manifestations with a p value of (0.03) and the frequency DRB1*10 was found to be increased among SLE patients with neurological manifestations with a p value of (0.002). CONCLUSION: In contradistinction to what have been found among other populations DRB3 is a protective gene among Saudi's against SLE. No evidence for a role of the HLA-DRB1, DRB4, DRB5, DQB1 alleles. There was an increased HLA DRB3 frequency with serositis, DQB1*3 skin manifestations, HLA DRB1*15 with nephritis, DRB1*10 with hematological manifestations and DRB1*11 with neurological manifestations.

Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.

Cenani-Lenz syndrome (CLS) is a rare autosomal recessive developmental disorder of the limbs. The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis. The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement. CLS was recently associated with mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling. We have identified a large consanguineous Pakistani pedigree with 9 members affected by CLS. The affected individuals present with a consistent expression of the syndrome restricted to the limbs and kidneys. Symptoms from the lower limb are mild or absent and there were no radioulnar synostosis or craniofacial involvement. Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T > C (p.L953P) in the LRP4 gene. The mutation is located in a region encoding the highly conserved low-density lipoprotein receptor repeat class B domain of LRP4. Our findings add to the genotype-phenotype correlations in CLS and support kidney anomalies as a frequent associated feature.

Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation

Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype-phenotype correlation has been established. In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype-phenotype correlation.

Expresión clínica del síndrome de muerte súbita cardíaca / Clinical expression of cardiac sudden death syndrome

Objetivo: Describir la expresión clínica del síndrome de muerte súbita cardíaca en poblaciones de Ciudad de La Habana, Cuba, durante el período 2000-2004. Diseño: Observacional, descriptivo, prospectivo, transversal. Métodos: Se estudiaron las muertes naturales atribuibles a causas cardíacas, durante 5 años, y se determinaron cuáles de estas fueron súbitas. El estudio SUCADES I (SUdden CArdiac DEath Study I) fue realizado en la municipalidad de Arroyo Naranjo con una población de 210 000 hab, incluyó 5 098 decesos por muerte natural, de los cuales, 474 fueron por muerte súbita. Se documentó la expresión clínica del síndrome a partir del tiempo de aparición, tiempo de inicio de los síntomas y síntomas premonitorios en los sucesos instantáneos y los no instantáneos. El lugar de presentación incluyó el medio extrahospitalario y el intrahospitalario. Resultados: El 45,4 por ciento de las muertes súbitas fueron instantáneas, el 38,2 por ciento ocurrió en la primera hora del inicio de los síntomas, en el horario de 06:00-11:59 a.m. (30,0 por ciento). La pérdida de la conciencia (72,4 por ciento) y la disnea (36,9 por ciento) fueron los síntomas premonitorios de muerte instantánea y no instantánea más frecuentes, respectivamente. El 66,2 por ciento de las paradas cardíacas se iniciaron en el ámbito extrahospitalario, predominó el domicilio de las víctimas (35,0 por ciento). Conclusiones: Clínicamente la muerte súbita se manifestó por pérdida de la conciencia (instantánea), durante la primera hora del inicio de los síntomas, en el domicilio de las víctimas, en el período de 06:00-11:59 a.m(AU)

Objective: To describe the clinical expression of cardiac sudden death syndrome in populations from Ciudad de La Habana over 2000-2004. Design: Observational, descriptive, prospective and cross-sectional. Methods: The natural deaths attributable to cardiac causes over 5 years determining which of them were sudden. The SUCADES I study (Sudden Cardiac Death Syndrome) was conducted in the Arroyo Naranjo municipality with a population of 210 000 inhabitants and included 5 098 deceases from natural death, from which 474 were sudden deaths. The clinical expression of the syndrome was documented from the time of appearance, time of onset of the premonitory symptoms and warning symptoms in instantaneous and non-instantaneous events. The place of presentation included the outside hospital environment. Results: The 45,4 percent of sudden events were instantaneous, the 38,2 percent occurred during the first hour of the onset of symptoms at 06.00-11.59 hours (30 percent). The consciousness loss (72,4 percent) and dyspnea (36,9 percent) were the more frequent premonitory symptoms of instantaneous ad non-instantaneous death, respectively. The 66,2 percent of cardiac arrest occurred outside the hospital mainly at home of victims (35,0 percent). Conclusions: Clinically, the sudden death is characterized by the consciousness loss (instantaneous) during the first hour of symptoms onset, at home and at 06.00-11.59 hours(AU)

Expresión clínica del síndrome de muerte súbita cardíaca / Clinical expression of cardiac sudden death syndrome

Objetivo: Describir la expresión clínica del síndrome de muerte súbita cardíaca en poblaciones de Ciudad de La Habana, Cuba, durante el período 2000-2004. Diseño: Observacional, descriptivo, prospectivo, transversal. Métodos: Se estudiaron las muertes naturales atribuibles a causas cardíacas, durante 5 años, y se determinaron cuáles de estas fueron súbitas. El estudio SUCADES I (SUdden CArdiac DEath Study I) fue realizado en la municipalidad de Arroyo Naranjo con una población de 210 000 hab, incluyó 5 098 decesos por muerte natural, de los cuales, 474 fueron por muerte súbita. Se documentó la expresión clínica del síndrome a partir del tiempo de aparición, tiempo de inicio de los síntomas y síntomas premonitorios en los sucesos instantáneos y los no instantáneos. El lugar de presentación incluyó el medio extrahospitalario y el intrahospitalario. Resultados: El 45,4 por ciento de las muertes súbitas fueron instantáneas, el 38,2 por ciento ocurrió en la primera hora del inicio de los síntomas, en el horario de 06:00-11:59 a.m. (30,0 por ciento). La pérdida de la conciencia (72,4 por ciento) y la disnea (36,9 por ciento) fueron los síntomas premonitorios de muerte instantánea y no instantánea más frecuentes, respectivamente. El 66,2 por ciento de las paradas cardíacas se iniciaron en el ámbito extrahospitalario, predominó el domicilio de las víctimas (35,0 por ciento). Conclusiones: Clínicamente la muerte súbita se manifestó por pérdida de la conciencia (instantánea), durante la primera hora del inicio de los síntomas, en el domicilio de las víctimas, en el período de 06:00-11:59 a.m

Objective: To describe the clinical expression of cardiac sudden death syndrome in populations from Ciudad de La Habana over 2000-2004. Design: Observational, descriptive, prospective and cross-sectional. Methods: The natural deaths attributable to cardiac causes over 5 years determining which of them were sudden. The SUCADES I study (Sudden Cardiac Death Syndrome) was conducted in the Arroyo Naranjo municipality with a population of 210 000 inhabitants and included 5 098 deceases from natural death, from which 474 were sudden deaths. The clinical expression of the syndrome was documented from the time of appearance, time of onset of the premonitory symptoms and warning symptoms in instantaneous and non-instantaneous events. The place of presentation included the outside hospital environment. Results: The 45,4 percent of sudden events were instantaneous, the 38,2 percent occurred during the first hour of the onset of symptoms at 06.00-11.59 hours (30 percent). The consciousness loss (72,4 percent) and dyspnea (36,9 percent) were the more frequent premonitory symptoms of instantaneous ad non-instantaneous death, respectively. The 66,2 percent of cardiac arrest occurred outside the hospital mainly at home of victims (35,0 percent). Conclusions: Clinically, the sudden death is characterized by the consciousness loss (instantaneous) during the first hour of symptoms onset, at home and at 06.00-11.59 hours