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1.
J Natl Cancer Inst ; 115(11): 1278-1293, 2023 11 08.
Article in English | MEDLINE | ID: mdl-37348864

ABSTRACT

Immunotherapy combinations are being investigated to expand the benefit of immune checkpoint blockade across many cancer types. Radiation combinations, in particular using stereotactic body radiotherapy, are of keen interest because of underlying mechanistic rationale, safety, and availability as a standard of care in certain cancers. In addition to direct tumor cytotoxicity, radiation therapy has immunomodulatory effects such as induction of immunogenic cell death, enhancement of antigen presentation, and expansion of the T-cell receptor repertoire as well as recruitment and increased activity of tumor-specific effector CD8+ cells. Combinations of radiation with cytokines and/or chemokines and anti-programmed death 1 and anticytotoxic T-lymphocyte antigen 4 therapies have demonstrated safety and feasibility, as well as the potential to improve long-term outcomes and possibly induce out of irradiated field or abscopal responses. Novel immunoradiotherapy combinations represent a promising therapeutic approach to overcome radioresistance and further enhance systemic immunotherapy. Potential benefits include reversing CD8+ T-cell exhaustion, inhibiting myeloid-derived suppressor cells, and reversing M2 macrophage polarization as well as decreasing levels of colony-stimulating factor-1 and transforming growth factor-ß. Here, we discuss current data and mechanistic rationale for combining novel immunotherapy agents with radiation therapy.


Subject(s)
Neoplasms , Radioimmunotherapy , Humans , Combined Modality Therapy , Neoplasms/radiotherapy , Neoplasms/drug therapy , Immunotherapy , Radiation Dosage
2.
JPRAS Open ; 37: 42-51, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37360978

ABSTRACT

Background/Aim: NovoSorbⓇ Biodegradable Temporizing Matrix (BTM) is a relatively novel, biodegradable polyurethane-based dermal regeneration template. The aim of this study was to evaluate the long-term scarring outcomes and safety of BTM in patients who underwent dermal reconstruction involving ≥5% of the total body surface area. Methods: This was a postmarket, multicenter, observational cohort study involving evaluation of long-term outcomes in patients treated with BTM. A total of 55 patients (35 from Royal Adelaide Hospital, South Australia, and 20 from Victoria Adult Burns Service, The Alfred, Victoria) who underwent dermal repair with BTM between 2011 and 2017 were screened for inclusion in this study. All patients had BTM implanted for ≥18 months. Results: Fifteen eligible patients with a mean (SD) age of 49.1 (14.3) years completed study assessments. These patients had a total of 39 areas treated with BTM. Using the Patient and Observer Scar Assessment Scale, scar quality was reported to be good by both observers and patients, with a mean (SD) observer score across all lesions of 3.6 (1.2) and mean (SD) overall opinion of 3.8 (1.2) as well as a mean (SD) patient score of 3.5 (1.2) and overall opinion of 5.0 (2.2). No adverse events or adverse device effects were reported or identified. Conclusion: The long-term scar quality is comparable to published studies. BTM is safe in the long term with no additional risks or adverse consequences being identified.

3.
Orphanet J Rare Dis ; 17(1): 98, 2022 03 03.
Article in English | MEDLINE | ID: mdl-35241128

ABSTRACT

BACKGROUND: Hypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5'-phosphate-PLP-and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP. RESULTS: The study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (-GT) of pathogenic ALPL variants: 40 +GT and 37 -GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP < 25 UI/L (model 1), the area under curve (AUC) and the 95% confidence intervals (CI) was 0.68 (95% CI 0.63-0.72) and it improved to 0.87 (95% CI 0.8-0.9), when PEA or PLP threshold levels were added (models 2 and 3), reaching 0.94 (0.91-0.97) when both substrates were included (model 4). The internal validation showed that the addition of serum PLP threshold levels to the model just including ALP improved significantly sensitivity (S) and negative predictive value (NPV) - 100%, respectively- with an accuracy (AC) of 93% in comparison to the inclusion of urinary PEA (S: 71%; NPV 75% and AC: 79%) and similar diagnostic utility measures as those observed in model 3 were detected when both substrates were added. CONCLUSIONS: In this study, we propose a biochemical predictive model based on the threshold levels of the main biochemical markers of HPP (ALP < 25 IU/L and PLP > 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variants.


Subject(s)
Alkaline Phosphatase , Hypophosphatasia , Machine Learning , Adult , Alkaline Phosphatase/genetics , Bone and Bones , Humans , Hypophosphatasia/diagnosis , Hypophosphatasia/epidemiology , Hypophosphatasia/genetics , Pyridoxal Phosphate
4.
Orphanet J Rare Dis ; 15(1): 51, 2020 02 17.
Article in English | MEDLINE | ID: mdl-32066479

ABSTRACT

BACKGROUND: Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase-ALP-measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. RESULTS: Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9-30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9-13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively. CONCLUSIONS: In subjects with persistent hypophosphatasaemia -secondary causes excluded- one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.


Subject(s)
Alkaline Phosphatase , Hypophosphatasia , Adult , Alkaline Phosphatase/genetics , Cross-Sectional Studies , Humans , Hypophosphatasia/diagnosis , Hypophosphatasia/genetics
5.
Andrology ; 5(5): 923-930, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28914499

ABSTRACT

Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty-nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs.


Subject(s)
Cryptorchidism/genetics , Gene Dosage , MAP Kinase Signaling System/genetics , Adolescent , Child , Child, Preschool , Comparative Genomic Hybridization , Gene Duplication , Genes, ras , Humans , Infant , Male , Pedigree , Testosterone/blood
6.
Clin Genet ; 92(1): 91-98, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28067412

ABSTRACT

Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease-mitochondrial RNA processing (RNase-MRP) and RNase-P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage-hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1-dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Dwarfism/genetics , Genetic Predisposition to Disease , Musculoskeletal Abnormalities/genetics , Osteochondrodysplasias/genetics , Ribonucleoproteins/genetics , Child , Child, Preschool , Dwarfism/diagnostic imaging , Dwarfism/physiopathology , Female , Homozygote , Humans , Male , Musculoskeletal Abnormalities/diagnostic imaging , Musculoskeletal Abnormalities/physiopathology , Mutation, Missense/genetics , Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/physiopathology , Phenotype , RNA, Long Noncoding/genetics
7.
Clin Genet ; 88(6): 579-83, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25512148

ABSTRACT

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.


Subject(s)
Familial Primary Pulmonary Hypertension/genetics , Genetic Predisposition to Disease/genetics , Mutation , Protein Serine-Threonine Kinases/genetics , Roma/genetics , Adolescent , Adult , Base Sequence , Familial Primary Pulmonary Hypertension/ethnology , Female , Founder Effect , Genetic Predisposition to Disease/ethnology , Homozygote , Humans , Male , Pedigree , Portugal , Sequence Analysis, DNA , Spain
10.
AJR Am J Roentgenol ; 196(2): 462-7, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21257901

ABSTRACT

OBJECTIVE: The purpose of this study was to determine the percentage of patients referred to an interventional radiology (IR) practice who need palliative care and to examine the training required for a diplomate of the American Board of Radiology (ABR) to qualify for the hospice and palliative medicine certifying examination. MATERIALS AND METHODS: This retrospective study reviewed all patient referrals to an academic vascular and IR practice during the month of August 2009. The demographics, underlying diagnosis, and the type of procedures performed were ascertained from the electronic medical record. The requirements for a diplomate of the ABR to obtain certification as a hospice and palliative medicine subspecialist were evaluated and summarized. RESULTS: Two-hundred eighty-two patients were referred to the IR service and underwent a total of 332 interventional procedures. Most of the patients (229 [81.2%]) had underlying diagnoses that would warrant consultation with a hospice and palliative medicine subspecialist; these patients were significantly older (58.5 vs 44.7 years; p < 0.01) and underwent more procedures (1.21 vs 1.02; p < 0.01). To obtain a subspecialty certification in hospice and palliative medicine, a radiologist needs certification by the ABR, an unrestricted medical license, 2 years of subspecialty training in hospice and palliative medicine, 100 hours of interdisciplinary hospice and palliative medicine team participation, active care of 50 terminally ill adult patients, and successful performance on the certification examination. CONCLUSION: Procedures related to palliative care currently compose the majority of our IR cases. Certification in hospice and palliative medicine can be achieved with a modest investment of time and clinical training.


Subject(s)
Palliative Care/methods , Radiology, Interventional/education , Radiology, Interventional/statistics & numerical data , Referral and Consultation/statistics & numerical data , Adult , Aged, 80 and over , Certification , Education, Medical, Continuing , Female , Hospice Care , Humans , Male , Middle Aged , Physician's Role , Radiology , Retrospective Studies , Terminal Care , United States
11.
J Clin Endocrinol Metab ; 96(2): E404-12, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21147883

ABSTRACT

CONTEXT: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity. OBJECTIVE: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS. DESIGN AND METHODS: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications. RESULTS: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. CONCLUSION: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.


Subject(s)
Body Height/genetics , Homeodomain Proteins/genetics , Cohort Studies , DNA/genetics , Databases, Nucleic Acid , Dwarfism/genetics , Female , Gene Dosage , Gene Duplication , Growth Disorders/genetics , Humans , In Situ Hybridization, Fluorescence , Male , Microsatellite Repeats , Nucleic Acid Amplification Techniques , Osteochondrodysplasias/genetics , Pedigree , Reverse Transcriptase Polymerase Chain Reaction , Short Stature Homeobox Protein , Spain
12.
J Evol Biol ; 23(11): 2494-500, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20825525

ABSTRACT

The evolution of mutualisms under novel selective pressures will play a key role in ecosystem responses to environmental change. Because fixed nitrogen is traded in plant­rhizobium mutualisms, increasing N availability in the soil is predicted to alter coevolution of these interactions. Legumes typically decrease the number of associations (nodules) with rhizobia in response to nitrate, but the evolutionary dynamics of this response remain unknown. We grew plant and rhizobium genotype combinations in three N environments to assess the coevolutionary potential of the nodule nitrate response in natural communities of plants and rhizobia. We found evidence for coevolutionary genetic variation for nodulation in response to nitrate (G × G × E interaction), suggesting that the mutualism response to N deposition will depend on the combination of partner genotypes. Thus, the nitrate response is not a fixed mechanism in plant­rhizobium symbioses, but instead is potentially subject to natural selection and dynamic coevolution.


Subject(s)
Biological Evolution , Genetic Variation , Medicago truncatula/metabolism , Nitrates/metabolism , Plant Root Nodulation/genetics , Sinorhizobium/metabolism , Symbiosis , Genotype , Linear Models , Medicago truncatula/genetics , Sinorhizobium/genetics
13.
Placenta ; 30(6): 551-4, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19386358

ABSTRACT

Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is a severe form of preeclampsia with high rates of neonatal and maternal morbidity. In recent years, loss of function of cdkn1c (a tight-binding inhibitor of G1 cyclin/cyclin-dependent kinase complexes and a negative regulator of cell proliferation) has been observed in several mouse models of preeclampsia. In this paper, we report on three women with HELLP/preeclampsia who had children with Beckwith Wiedemann syndrome, a complex genetic disorder characterised, among other findings, by overgrowth, omphalocele and macroglossia. All three children displayed mutations in CDKN1C predicted to generate truncated proteins. Two of the mutations were maternally inherited while the third was de novo. This finding suggests a fetal contribution to the maternal disease. To the best of our knowledge this is the first report of CDKN1C mutations in children born to women with preeclampsia/HELLP syndrome, thus suggesting the involvement of an imprinted gene in the pathophysiology of preeclampsia.


Subject(s)
Beckwith-Wiedemann Syndrome/genetics , Cyclin-Dependent Kinase Inhibitor p57/genetics , HELLP Syndrome/genetics , Pre-Eclampsia/genetics , Base Sequence , Beckwith-Wiedemann Syndrome/complications , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , HELLP Syndrome/etiology , Humans , Infant, Newborn , Mutation/physiology , Pre-Eclampsia/etiology , Pregnancy
14.
Int J Sports Med ; 29(9): 738-45, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18213535

ABSTRACT

This study investigated fatigue-induced changes in neuromuscular and stride characteristics during and immediately after the 5-km running time trial. Eighteen well-trained male distance runners performed a maximal 20-m sprint test and maximal voluntary contraction (MVC) in a leg press machine before and immediately after the 5-km running time trial. In all the tests the EMG of five lower limb muscles was measured. The results of the present study showed that muscle fatigue measured in maximal exercises like 20-m sprint and MVC are not related to the fatigue induced changes during the 5-km time trial. The fatigue in the 20-m sprint test was related to the maximal 20-m pretest velocity (r=0.58, p<0.05), but the velocity loss during the 5-km time trial was inversely related to 5-km performance (r= - 0.60, p<0.05) and training volume (r= - 0.58, p<0.05). It was concluded that the fatigue in 5-km running measured pre- and postexercise at maximal effort is more related to sprint performance rather than endurance performance, but the fatigue measured during the 5-km running is related to endurance performance and factors affecting pacing strategy.


Subject(s)
Exercise Tolerance , Fatigue/etiology , Leg , Muscle Contraction , Muscle, Skeletal/physiopathology , Running , Adult , Electromyography , Exercise Test , Fatigue/physiopathology , Humans , Male , Time Factors
15.
J Vasc Surg ; 40(2): 279-86, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15297821

ABSTRACT

OBJECTIVES: Hemispheric neurologic symptoms, amaurosis fugax, and Hollenhorst plaques at eye examination are standard indications for carotid imaging to identify carotid artery occlusive disease (CAOD). Previous reports have suggested that other ocular findings, such as retinal artery occlusion and anterior ischemic optic neuropathy, are associated with CAOD. However, the predictive value of ocular findings for the presence of CAOD is controversial. The purpose of this study was to define the predictive value of ocular symptoms and ophthalmologic examination in identifying significant CAOD. METHODS: Over 3 years 145 patients were referred for carotid imaging on the basis of ocular indications in 160 eyes. Forty patients were excluded because of concurrent non-ocular indications for carotid imaging, leaving 105 patients referred exclusively for ocular indications to evaluate. Ophthalmologic history and eye examination were correlated with carotid duplex ultrasound findings. RESULTS: Amaurosis fugax was associated with a positive scan in 20.0% of carotid arteries (P =.022). Hollenhorst plaques at fundoscopic examination were associated with a positive scan in 18.2% of carotid arteries (P =.02). Ocular findings exclusive of Hollenhorst plaques were particularly poor predictors of CAOD, inasmuch as only 1 of 64 arteries (1.6%) had significant ipsilateral internal carotid artery stenosis (P =.022). Venous stasis retinopathy was the only ocular finding other than Hollenhorst plaques with any predictive value (1 of 5 scans positive; positive predictive value, 20.0%). CONCLUSIONS: Ocular symptoms and findings are poor predictors of CAOD. Amaurosis fugax, Hollenhorst plaques, and venous stasis retinopathy demonstrated moderate predictive value, whereas all other ocular findings demonstrated no predictive value in identifying CAOD.


Subject(s)
Carotid Stenosis/complications , Carotid Stenosis/diagnostic imaging , Eye Diseases/complications , Eye Diseases/diagnosis , Adult , Aged , Aged, 80 and over , Amaurosis Fugax/complications , Amaurosis Fugax/diagnosis , Female , Humans , Male , Middle Aged , Ophthalmoscopy , Predictive Value of Tests , Retinal Diseases/complications , Retinal Diseases/diagnosis , Ultrasonography, Doppler, Duplex
16.
Curr Drug Targets ; 4(1): 13-22, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12528986

ABSTRACT

To provide an overview of the epidemiologic parameters of emerging adverse effects associated with antiretroviral therapy for human immunodeficiency virus (HIV) disease. All available antiretroviral agents are associated with significant adverse drug effects. Of particular interest are newly emerging suspected adverse drug effects which were not generally noted in pre-marketing trials nor captured under current standard clinical care practices. Suspected antiretroviral toxicities meeting these criteria include: HIV-associated lipodystrophy which can include peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities; hyperlactatemia and lactic acidosis; and metabolic bone abnormalities such as decreased bone mineral density, osteoporosis and osteonecrosis. Results of prospective and observational studies reported to date suggest that these abnormalities, while aetiologically complex, are likely attributable to treatment factors and may be intricately interrelated. The medical management of these symptoms remains unsatisfactory given the unexplored efficacy of traditional approaches in the HIV positive population. While the pathogenic mechanism of these disorders remains obscure, a theory of tissue-specific mitochondrial toxicity has been proposed. With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.


Subject(s)
Antiretroviral Therapy, Highly Active/adverse effects , HIV Infections/drug therapy , Acidosis, Lactic/chemically induced , Bone Diseases, Metabolic/chemically induced , DNA, Mitochondrial/metabolism , HIV Infections/metabolism , Humans , Lactic Acid/blood , Lipodystrophy/chemically induced , Metabolic Diseases/chemically induced
17.
Science ; 294(5551): 2563-6, 2001 Dec 21.
Article in English | MEDLINE | ID: mdl-11752579

ABSTRACT

Kruppel-like factor 6 (KLF6) is a zinc finger transcription factor of unknown function. Here, we show that the KLF6 gene is mutated in a subset of human prostate cancer. Loss-of-heterozygosity analysis revealed that one KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirm that whereas wild-type KLF6 up-regulates p21 (WAF1/CIP1) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. Our data suggest that KLF6 is a tumor suppressor gene involved in human prostate cancer.


Subject(s)
Genes, Tumor Suppressor , Mutation , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins , Trans-Activators/genetics , Alleles , Amino Acid Substitution , Animals , Cell Division , Cell Line , Chromosome Mapping , Chromosomes, Human, Pair 10/genetics , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/genetics , Cyclins/metabolism , Genetic Heterogeneity , Humans , Kruppel-Like Factor 6 , Kruppel-Like Transcription Factors , Loss of Heterozygosity , Male , Mice , Microsatellite Repeats , Mutation, Missense , Proliferating Cell Nuclear Antigen/metabolism , Promoter Regions, Genetic , Trans-Activators/chemistry , Trans-Activators/physiology , Transcriptional Activation , Tumor Cells, Cultured , Up-Regulation , Zinc Fingers
18.
Am J Hum Genet ; 69(5): 1033-45, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11590545

ABSTRACT

May-Hegglin anomaly (MHA) and Fechtner (FTNS) and Sebastian (SBS) syndromes are autosomal dominant platelet disorders that share macrothrombocytopenia and characteristic leukocyte inclusions. FTNS has the additional clinical features of nephritis, deafness, and cataracts. Previously, mutations in the nonmuscle myosin heavy chain 9 gene (MYH9), which encodes nonmuscle myosin heavy chain IIA (MYHIIA), were identified in all three disorders. The spectrum of mutations and the genotype-phenotype and structure-function relationships in a large cohort of affected individuals (n=27) has now been examined. Moreover, it is demonstrated that MYH9 mutations also result in two other FTNS-like macrothrombocytopenia syndromes: Epstein syndrome (EPS) and Alport syndrome with macrothrombocytopenia (APSM). In all five disorders, MYH9 mutations were identified in 20/27 (74%) affected individuals. Four mutations, R702C, D1424N, E1841K, and R1933X, were most frequent. R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness. The E1841K, D1424N, and R1933X coiled-coil domain mutations were common to both MHA and FTNS. Haplotype analysis using three novel microsatellite markers revealed that three E1841K carriers--one with MHA and two with FTNS--shared a common haplotype around the MYH9 gene, suggesting a common ancestor. The two new globular-head mutations, K371N and R702H, as well as the recently identified MYH9 mutation, R705H, which results in DFNA17, were modeled on the basis of X-ray crystallographic data. Altogether, our data suggest that MHA, SBS, FTNS, EPS, and APSM comprise a phenotypic spectrum of disorders, all caused by MYH9 mutations. On the basis of our genetic analyses, the name "MYHIIA syndrome" is proposed to encompass all of these disorders.


Subject(s)
Genes, Dominant/genetics , Molecular Motor Proteins , Mutation/genetics , Myosin Heavy Chains/genetics , Nonmuscle Myosin Type IIA/genetics , Thrombocytopenia/genetics , Amino Acid Sequence , Chromosomes/genetics , DNA Mutational Analysis , Evolution, Molecular , Exons/genetics , Haplotypes/genetics , Humans , Microsatellite Repeats/genetics , Models, Molecular , Molecular Sequence Data , Myosin Heavy Chains/chemistry , Nephritis, Hereditary/genetics , Nephritis, Hereditary/physiopathology , Nonmuscle Myosin Type IIA/chemistry , Phenotype , Physical Chromosome Mapping , Protein Conformation , Sequence Alignment , Structure-Activity Relationship , Syndrome , Terminology as Topic , Thrombocytopenia/physiopathology
19.
Aust Dent J ; 46(1): 24-31, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11355237

ABSTRACT

A variety of topical fluorides is now used clinically for the prevention and control of dental caries. It is essential for the dental profession to be fully aware of the relative retention rates of fluoride in saliva and thus its contact with the teeth. These may vary following the use of the different categories and concentrations of agents available and with different methods of use. It is also important to be aware of the amounts of fluoride ion ingested following use of the more concentrated forms and of the resultant elevation in total blood fluoride levels. These parameters were investigated in a series of experiments involving human volunteer subjects using a variety of topical fluoride materials commercially available in Australia. Fluoride mouthrinses appeared to provide the highest salivary retention rates per dose of all forms of topical fluoride. Ingestion rates from concentrated gels were acceptable when effective evacuation methods were applied. The use of custom-made trays resulted in a reduction in amounts of fluoride ion ingested, though simple self-application by toothbrush of smaller quantities proved to be an effective alternative in terms of amount of fluoride ion retained in saliva per amount applied and ingested. None of the concentrated gels used resulted in elevations in total blood fluoride levels which were of concern in adults. It is acknowledged that salivary retention rates of fluoride ion do not necessarily reflect the caries inhibitory effects of topical fluorides. However, these data provide some indication of possible advantages of some products and methods of application over others.


Subject(s)
Fluorides, Topical/pharmacokinetics , Adult , Deglutition , Dentifrices , Fluorides/blood , Fluorides, Topical/administration & dosage , Gels , Humans , Mouthwashes , Saliva/metabolism
20.
Eur J Hum Genet ; 9(4): 244-52, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11313767

ABSTRACT

A genetic diagnostic service for familial hypercholesterolaemia (FH) has been established over the last 4 years in the Clinical Molecular Genetics Laboratory at Great Ormond Street Hospital for Children NHS Trust (GOSH), London. In total there have been 368 referrals; 227 probands and 141 family members, which have come from a number of lipid clinics and from general practitioners. FH is caused by mutations in the low-density lipoprotein receptor gene (LDLR) and these are analysed by SSCP, DNA sequencing and direct assays. The clinically indistinguishable disorder, familial defective apolipoprotein B100 (FDB) is caused by one of three mutations in the apolipoprotein B100 gene (APOB) which are analysed by direct assays. Mutations predicted to be pathogenic were found in 76 probands, 67 in LDLR (23 previously undescribed) and nine in APOB. The mutation detection rate was 53% in paediatric probands, 32% in adults with a 'definite' FH diagnosis (tendon xanthoma positive) and 14% in adults with a 'possible' FH diagnosis (tendon xanthoma negative). The predicted loss of sensitivity that would result from reducing the number of exons tested has been assessed, and a molecular screening strategy suitable for UK patients is proposed. A similar strategy may be useful for other countries where genetic heterogeneity results in a wide mutation spectrum for FH.


Subject(s)
Apolipoproteins B/genetics , Hyperlipoproteinemia Type II/genetics , Receptors, LDL/genetics , Adult , Apolipoprotein B-100 , Child , Genetic Testing , Humans , Hyperlipoproteinemia Type II/diagnosis , Molecular Biology , Mutation , Polymorphism, Single-Stranded Conformational , United Kingdom
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