Correlations between age,functional status,and the senescence-associated proteins HMGB2 and p16<Superscript>INK4a</Superscript>

Cellular senescence is a central component of the aging process. This cellular response has been found to be induced by multiple forms of molecular damage and senescent cells increase in number with age in all tissues examined to date. We have examined the correlation with age of two key proteins involved in the senescence program, p16^INK4a and HMGB2. These proteins are involved in cell cycle arrest and chromatin remodeling during senescence. Circulating levels of these markers increases with age and correlates with functional status. The levels of HMGB2 appear to be significantly correlated with functional status, whereas p16^INK4a levels are more weakly associated. Interestingly, there is a strong correlation between the two proteins independent of age. In particular, a single high-functioning individual over 90 years of age displays a disproportionately low level of HGMB2. The results suggest that with improved testing methodology, it may be possible to monitor circulating protein markers of senescence in human populations.     

Matchmaking facilitates the diagnosis of an autosomal‐recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease–gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created “matching” platforms. We describe four individuals from three unrelated families “matched” by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease‐causing gene and interprets the variants as “pathogenic.” TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder.     

Presentation of influenza hemagglutinin peptide in the presence of limited allostimulation by HLA-DR1 transfected human fibroblasts

A human fibroblast expressing HLA-DR1 antigen on its surface was generated by transfection with DR alpha and DR beta cDNAs. The ability of this transfected fibroblast line to process and to present antigens was analyzed by using human T-lymphocyte clones (TLCs) specific for HLA-DR1 alloantigen or restricted by DR1 in their recognition of influenza virus. TLC responses were measured in proliferative assays and were tested for blocking by monoclonal antibodies specific for MHC antigens. Two TLCs specific for a discrete segment (aa 306-320) of the influenza hemagglutinin molecule responded to the antigen added in peptide form but not as intact virion. The transfected fibroblast line thus appears unable to process antigen properly. A DR1-alloreactive TLC was able to respond to the transfected fibroblast. However, 24 other DR1-alloreactive TLCs and oligoclonal T-cell lines were unable to respond. These results suggest either that the conformation of the DR1 molecule on a transfected fibroblast allows peptide presentation but not allorecognition, or that self antigen processing and subsequent presentation by MHC antigens is necessary for allorecognition.     

Benefits of blood group genotyping in multi‐transfused patients from the south of Brazil

We evaluated the usefulness of blood group genotyping as a supplement to hemagglutination to determine the red blood cell (RBC) antigen profile of polytransfused patients with hematological diseases and renal failure. Seventy‐nine patients were selected. They all received more than three units of blood and eight (10%) had already clinical significant alloantibodies occurring alone or in combination against Rh, K, Fya, and Di antigens. DNA was prepared from blood samples and RHCE*E/e, KEL*01/KEL*02, FY*01/FY*02 and JK*01/JK*02 alleles were determined by using PCR‐RFLP. RHD*/RHD*Ψ and RHCE*C/c were tested using multiplex PCR. Discrepancies for Rh, Kell, Duffy, and Kidd systems were found between the phenotype and genotype‐derived phenotype in 16 of the 38 chronically transfused patients. The genotypes of these patients were confirmed by DNA array analysis (HEA Beadchip^?; Bioarray Solutions, Warren, NJ). Genotyping was very important for the determination of the true blood groups of the polytransfused patients, helped in the identification of suspected alloantibodies and in the selection of antigen‐negative RBCs for transfusion. J. Clin. Lab. Anal. 24:311–316, 2010. © 2010 Wiley‐Liss, Inc.     

Dual pathology as a result of spinal stenosis and vitamin B12 deficiency

Vitamin B12 deficiency can confound the clinical assessment of patients presenting with features of spinal disorders. Speciality practice within spinal surgery may lead the clinician to a focus upon spinal explanations for symptoms and that belief may be reinforced by supporting imaging. In the presence of mainly sensory symptoms consideration and exclusion of non surgical causes needs to occur. This study aimed at identifying the prevalence of vitamin B12 deficiency; the presence of dual pathology on imaging performed; the implementation of replacement therapy and their subsequent clinical response as perceived by patients. This was performed through a retrospective review of patients presenting to specialist spine out-patient clinics over a 4-year period via access to pathology reports followed by a telephone survey. 457 patients were investigated of which 8.5% were vitamin B12 deficient. 70% of patients had repeat levels and 31% continued to be deficient. 26% of these patients were not placed on any supplemental therapy. 72% of patients on treatment had self perceived improved outcomes as compared with 55% not on treatment. 73% of patients underwent MRI/CT imaging. 59% of which had evidence of spinal stenosis. In older patients with sensory symptoms, the coexistence of B12 deficiency should be considered. Detection of deficiency with consequent treatment results in better global outcomes than no treatment. Unless the correct blood test is done, the pathology will remain undetected, and patients may continue with their primary symptoms despite high-risk spinal surgical procedures.     

Insulin-like growth factor-I produced by seminal vesicles: relationship to intraepithelial basal cell hyperplasia in the prostate.

PURPOSE: This study examined the seminal vesicle fluid (SVF) as a potential local source of insulin-like growth factor-I (IGF-I) in the peripheral zone of the prostate. EXPERIMENTAL DESIGN: IGF-I levels in seminal fluid were measured. The levels of the IGF-I receptor (IGF-IR) in its active, phosphorylated form as well as direct downstream targets were examined in the peripheral zone of the prostate. RESULTS: In situ, we find that the IGF-IR is activated in the peripheral zone in areas of atrophy, prostatic intraepithelial hyperplasia, and cancer. In addition, immunostaining reveals preferential activation of the IGF-IR in p63-positive cells in areas of intermediate basal cell hyperplasia in the peripheral zone, indicating that prostate progenitor cells are highly sensitive to increases in local IGF-I levels. These areas of basal cell hyperplasia occur at high incidence in the peripheral zone of the prostate. Relatively high levels of IGF-I were identified in SVF. In addition, we find that SVF can stimulate the proliferation of both normal and cancer-derived prostate cells. CONCLUSIONS: These results suggest that SVF is a local source of IGF-I that provides chronic stimulation of prostate cells. This chronic stimulation could contribute to the development of prostate cancer in older men.     

Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer

From 1 September 1981 to 1 January 1987, 118 patients with FIGO Stage IB, IC, IIA, IIB, and IIC epithelial ovarian cancer were randomized to abdominal irradiation or pelvic irradiation + cyclophosphamide. There was no difference between the regimens with respect to recurrence-free survival (55%) and 4-year overall survival (63%). At routine second-look laparotomy, 16% of patients without clinical detectable tumor showed recurrence. Twenty-five percent of the patients treated with pelvic irradiation + cyclophosphamide had hemorrhagic cystitis, probably caused by radiation damage and cyclophosphamide cystitis. Eight percent had late gastrointestinal symptoms requiring surgery.     

Early identification of learning problems in neonatal intensive care graduates

Most investigators have documented a notable frequency of educational problems in children who received treatment in the neonatal intensive care unit (NICU). Seventy-four children born between 1972 and 1976 and in NICUs were followed up prospectively. At ages 3 to 6 years, preschool development was within the normal range on the McCarthy scales. A school problem, defined as grade repetition and/or special help in school, occurred in 32 (48.8%). Those with school problems had significantly lower scores on the McCarthy scales at 4 to 6 years and on the Woodcock Johnson test than the group without school problems. Children with school problems were classified correctly 60.3% of the time by duration of neonatal hospitalization, and 72% to 80.9% of the time by preschool development. If replicable, the data indicate that potential school problems can be identified sufficiently early in NICU nursery graduates that intervention could be started before they enter school.     

Pyriform sinus malformations: a cadaveric representation

Background/Purpose: The most important aspects in management of pyriform sinus malformations are awareness of the diagnosis, familiarity with the clinical manifestations, and complete surgical excision of the entire tract. Pyriform sinus anomalies are the least common branchial apparatus malformations and present anatomically as sinus tracts with or without cystic dilatation. The clinical presentations can include lateral neck mass, thyroid abscess, suppurative thyroiditis, retropharyngeal abscess, neonatal airway obstruction, and even carcinoma. Recurrent symptoms after surgery suggest incomplete identification and excision of the tract. Methods: Cadaveric dissections were performed to show both the proposed embryologic course and clinical manifestations of third and fourth branchial apparatus pyriform sinus anomalies. Results: Illustrations and digital camera images of the cadaveric models are presented to explain the course of pyriform sinus fistula tracts. Conclusions: The authors discuss 3 case presentations of pyriform sinus anomalies with emphasis on their proposed embryologic origin and anatomic basis for surgical management. Surgical excision is the mainstay of therapy. Understanding the embryologic basis for pyriform sinus malformations aids in recognition of the diagnosis despite the myriad of clinical presentations. Laryngoscopy with sinus cannulation facilitates removal of the entire sinus tract with preservation of the recurrent and superior laryngeal nerves.