Autoimmune thyroid diseases are more common in patients with prolactinomas: a retrospective case-control study in an Italian cohort.

BACKGROUND: Prolactin may exert immunological effects. Over the years, a higher prevalence of autoimmune thyroid diseases (ATD) has been reported in patients with prolactinomas (PRLs) in areas with sufficient iodine intake. PURPOSE: The aim of our study was to evaluate the prevalence of ATD [Graves' disease (GD) and chronic autoimmune thyroiditis (AIT)] in a retrospective cohort of Italian patients with PRLs compared to a sex-matched control group, represented by subjects with non-functioning pituitary adenoma (NFPA) or empty sella (ES). MATERIALS AND METHODS: We enrolled 149 patients (108 F/41 M) with PRLs (110 micro/39 macro) and 143 subjects (100 F/43 M) with NFPA (n = 96, 56 micro/40 macro) or ES (n = 47), with normal serum prolactin. Neck ultrasound and thyroid function tests (anti-thyroid antibodies, TSH, FT3 and FT4) were performed in all patients. RESULTS: In PRLs, median serum prolactin was significantly higher (98.3 vs. 8.9 ng/ml, p ≤ 0.0001), while age was lower (34 vs. 46 years, p ≤ 0.001) compared to controls. The prevalence of ATD was 13.4% (20/149) in PRLs (1 GD and 19 AIT) compared to 6.3% (9/143) in the controls (p = 0.042). At the multivariate analysis, serum prolactin was the only independent factor predicting ATD. Thyroid volume (12.5 ± 5.9 ml vs. 12.8 ± 10 ml, p = 0.47) and the presence of uni- or multinodular goiter (29.5% vs. 35%, p = 0.35) did not differ between PRLs and control groups. CONCLUSIONS: Our data in an area with mild iodine deficiency confirm a higher prevalence of ATD in patients with prolactinomas.

Chronic lymphocytic thyroiditis (CLT) has a positive prognostic value in papillary thyroid cancer (PTC) patients: the potential key role of Foxp3+ T lymphocytes.

BACKGROUND: An impact of chronic lymphocytic thyroiditis (CLT) on papillary thyroid cancer (PTC) outcome has long been advocated but it is still controversial. PURPOSE: The aim of this study was to evaluate the prognostic value of CLT in a retrospective cohort of PTC patients and to characterize the lymphocytic subpopulations and infiltrate (LI). MATERIALS AND METHODS: We assessed 375 PTC patients, aged 45.2 ± 16.4 years, and treated with thyroidectomy and radioiodine remnant ablation, with a mean follow-up of 6.28 ± 3.86 years. In a subgroup of patients (n = 81) tissue sections were reviewed for the presence of CLT or lymphocytes associated with tumor in absence of background thyroiditis (TAL); cytotoxic CD8+/regulatory Foxp3+ T lymphocyte (CD8+/Foxp3+) ratio was characterized by immunohistochemistry: a low ratio is suggestive of a less effective anti tumor immune response. RESULTS: Seventy-five/375 patients (20%) had a histological diagnosis of CLT and showed at the last follow-up a significantly better outcome compared to those with no CLT (cure rate: 91.8 versus 76.3%, p = 0.003). LI was characterized in 81 PTC patients (24 with CLT and 57 with TAL): the peri-tumoral CD8+/Foxp3+ ratio was lower in patients not cured at the final evaluation. CONCLUSIONS: Our data suggest that concurrent CLT has a protective effect on PTC outcome and that the imbalance between cytotoxic and regulatory T lymphocytes in the peri-tumoral TAL may affect the tumor-specific immune response favoring a more aggressive behavior of cancer.

Genome-wide analysis of E. coli cell-gene interactions.

BACKGROUND: The pursuit of standardization and reliability in synthetic biology has achieved, in recent years, a number of advances in the design of more predictable genetic parts for biological circuits. However, even with the development of high-throughput screening methods and whole-cell models, it is still not possible to predict reliably how a synthetic genetic construct interacts with all cellular endogenous systems. This study presents a genome-wide analysis of how the expression of synthetic genes is affected by systematic perturbations of cellular functions. We found that most perturbations modulate expression indirectly through an effect on cell size, putting forward the existence of a generic Size-Expression interaction in the model prokaryote Escherichia coli. RESULTS: The Size-Expression interaction was quantified by inserting a dual fluorescent reporter gene construct into each of the 3822 single-gene deletion strains comprised in the KEIO collection. Cellular size was measured for single cells via flow cytometry. Regression analyses were used to discriminate between expression-specific and gene-specific effects. Functions of the deleted genes broadly mapped onto three systems with distinct primary influence on the Size-Expression map. Perturbations in the Division and Biosynthesis (DB) system led to a large-cell and high-expression phenotype. In contrast, disruptions of the Membrane and Motility (MM) system caused small-cell and low-expression phenotypes. The Energy, Protein synthesis and Ribosome (EPR) system was predominantly associated with smaller cells and positive feedback on ribosome function. CONCLUSIONS: Feedback between cell growth and gene expression is widespread across cell systems. Even though most gene disruptions proximally affect one component of the Size-Expression interaction, the effect therefore ultimately propagates to both. More specifically, we describe the dual impact of growth on cell size and gene expression through cell division and ribosomal content. Finally, we elucidate aspects of the tight control between swarming, gene expression and cell growth. This work provides foundations for a systematic understanding of feedbacks between genetic and physiological systems.

Insect melanogenesis. III. Metabolon formation in the melanogenic pathway-regulation of phenoloxidase activityy by endogenous dopachrome isomerase (decarboxylating) from Manduca sexta.

Tyrosinase initiates melanogenesis in a variety of organisms. The nature of melanin formed is modified subsequently by dopachrome isomerase and other melanogenic proteins. Earlier, we reported the partial purification of dopachrome isomerase (decarboxylating) from the hemolymph of Manduca sexta and demonstrated the generation of a new quinone methide intermediate during melanogenesis (Sugumaran, M., and Semensi, V. (1991) J. Biol. Chem. 266, 6073-6078). In this paper, we report the purification of this enzyme to homogeneity and a novel inhibition mechanism for regulation of phenoloxidase activity. The activity of phenoloxidase isolated from M. sexta was markedly inhibited by purified dopachrome isomerase. In turn, phenoloxidase also reciprocated by inhibiting the isomerase activity. Preformed dopaminechrome did not serve as the substrate for the isomerase; but dopaminechrome that generated in situ by phenoloxidase was readily converted to melanin pigment by the phenoloxidase/isomerase mixture. Furthermore, the isomerase, which has a molecular weight of about 40,000 in native state, exhibited retardation during affinity electrophoresis on sodium dodeyl sulfate (SDS)-polyacrylamide gel electrophoresis gel copolymerized with tyrosinase and migrated with a molecular weight of 50,000, indicating complex formation with phenoloxidase. Electrophoresis of pupal cuticular extract on polyacrylamide gel, followed by activity staining revealed the presence of a protein band carrying both phenoloxidase and isomerase activity. Accordingly, a high-molecular-weight melanogenic complex was isolated from the pharate cuticle of M. sexta. The complex catalyzed the generation of melanochrome from dopa, while the free phenoloxidase produced only dopachrome from the same substrate. When the complex was treated with trace amounts of SDS, which inhibited the activity of dopachrome isomerase present in the complex, then only the conversion of dopa to dopachrome was observed. These studies confirm the formation of a melanogenic complex between phenoloxidase and dopachrome isomerase. By forming a complex and regulating each other's activity, these two enzymes seem to control the levels of endogenous quinones.

Relating speech and swallow function to dropout in a longitudinal study of head and neck cancer.

The relation between functional outcome and dropout from a 12-month follow-up period was examined in a longitudinal study whose objective was to define and quantify the functional effects of oral surgical resection and reconstruction on speech and swallowing in patients with head and neck cancer. In a group of 150 patients recruited to a surgical study in the Cancer Control Science Program in Head and Neck Cancer Rehabilitation, dropout from all causes and dropout from specific causes (medical, patient, and administrative specific) were assessed in relation to longitudinal speech and swallow function. In univariate analysis, better speech articulation was associated with decreased risk of dropout from all causes and from medical-specific causes. Better swallow performance was associated with decreased risk of medical-specific dropout. Multivariate analysis revealed the following: (1) only articulation function was associated with dropout from all causes; (2) the association of speech articulation function with medical dropout was diminished after adjusting for advanced age and surgical resection variables; (3) the association of speech articulation function became significant for patient-specific dropout after adjusting for advanced age and surgical resection variables and indicated that better function decreased the risk of this type of dropout; and (4) swallowing function was not related to dropout. Patients treated for oral or oropharyngeal cancer who have poorer speech outcomes are more likely to drop out from a longitudinal study. Basing study results on only patients who complete a longitudinal study will understate the level of dysfunction experienced.

Factors related to dropout in a study of head and neck cancer patients after surgery.

The extent and nature of dropout was assessed in a longitudinal study whose objective was to define and quantify the functional effects of oral surgical resection and reconstruction on speech and swallowing function in patients with head and neck cancer. Of 150 patients who were enrolled to be followed up with speech and swallow assessments for 1 year after surgery, 113 (75%) dropped out and 37 (25%) returned to complete the study at the final 12-month evaluation point. In general, those completing the study had a smaller resection than the patients who dropped out before the 12-month evaluation. Fifty percent of the dropout was accounted for by medical reasons, 23% by administrative reasons, and 27% by patient-specific reasons (i.e., reasons known only to the patient). Analysis of the dropout categories revealed that higher cancer stage, larger volume of resection, and having a flap surgical closure versus a primary closure or skin graft increased a patient's chance of dropping out. A larger volume of resection was also related to an increased chance of being a patient-specific dropout. Patients who reported no or low alcohol usage had a greater chance of completing follow-up than being a patient-specific dropout.

Surgical variables affecting speech in treated patients with oral and oropharyngeal cancer.

Postoperative speech function may be influenced by a number of treatment variables. The objective of this study was to examine the relationships among various treatment factors to determine the impact of these measures on speech function. Speech function was tested prospectively in 142 patients with surgically treated oral and oropharyngeal cancer 3 months after treatment. Each patient's speech was recorded during a 6- to 7-minute conversation and while performing a standard articulation test, producing speech outcome measures of percent correct consonant phonemes and percent conversational understandability. Correlational analyses were used to determine the relationships among the speech outcome measures and 14 treatment parameters. Speech function was mildly to moderately negatively correlated with most surgical resection variables, indicating that larger amounts of tissue resected were associated with worse speech function. Overall measures of conversational understandability and percent correct consonant phonemes were related to extent of oral tongue resection, floor of mouth resection, soft palate resection, and total volume of tissue resected. These relationships varied depending on the method of surgical closure. Method of surgical reconstruction had a profound impact on postoperative speech function 3 months after treatment and was an important factor in determining how oral tongue resection influenced articulation and intelligibility. The combination of closure type, percent oral tongue resected, and percent soft palate resected had the strongest relationship with overall speech function for patients with surgically treated oral and oropharyngeal cancer 3 months after treatment.

Characterization of a defense complex consisting of interleukin 1 and phenol oxidase from the hemolymph of the tobacco hornworm, Manduca sexta.

Hemolymph of fifth instar Manduca sexta larvae collected under non-sterile conditions exhibited the presence of a novel high molecular weight protein complex, which was absent from the hemolymph collected aseptically. The high molecular weight complex consisted of, at least prophenol oxidase, phenol oxidase, and an interleukin 1-like molecule, thereby demonstrating the generation of this complex as a consequence of a host defense response. While the native phenol oxidase and the interleukin 1-like molecule possessed molecular weights of about 80,000 and 17,000, respectively, the complex had a molecular weight of about 400,000. Apart from prophenol oxidase, phenol oxidase, and interleukin 1, dopachrome isomerase and other, as of yet unidentified, proteins may be part of the complex as judged by the presence of additional bands observed during SDS-polyacrylamide gel electrophoresis. The significance of the assembly of this defense complex for insect host defense strategies is discussed.

Speech and swallowing function after oral and oropharyngeal resections: one-year follow-up.

BACKGROUND: The purpose of this study was to determine whether the speech and swallowing function of surgically treated oral cancer patients improves between 1 month and 1 year after surgery. METHODS: Speech and swallowing performances were assessed for 28 men and 10 women preoperatively and at 1, 3, 6, and 12 months postoperatively following a standardized protocol. Speech tasks included an audio recording of a brief conversation and of a standard articulation test; swallowing function was examined using videofluoroscopy. Data were also collected on the number and duration of speech/swallowing therapy sessions, as well as the amount and duration of radiotherapy. RESULTS: Statistical analyses revealed that the speech and swallowing function of surgically treated oral and oropharyngeal cancer patients did not improve progressively between 1 and 12 months postsurgery; the level of functioning that these patients demonstrated at the 1- and 3-month posthealing evaluations was characteristic of their status at 1 year after surgery. CONCLUSION: The lack of improvement between 1 and 12 months postsurgery may be related to the relatively small amount of therapy that these patients received during that period. Several outcome variables worsened significantly at the 6-month evaluation; the reversal of function at the 6-month evaluation point could be the effect of postoperative radiotherapy, because irradiated and nonirradiated patients differed in their pattern of recovery on oropharyngeal swallow efficiency and several speech variables.

Surgical variables affecting postoperative swallowing efficiency in oral cancer patients: a pilot study.

This study examined the correlation between swallow function at 3 months postoperatively and surgical variables including volume resected, flap volume, ratio of flap volume to volume resected, percentage of oral tongue, tongue base, and anterior and lateral floor of mouth resected, and whether or not the mandible was preserved in 30 surgically treated oral cancer patients. Swallows of measured amounts of liquid and paste (pudding) materials were examined videofluoroscopically. Nine measures of swallow function were completed for each swallow. A factor analysis of all swallow variables was done for liquid and for paste consistencies to determine whether one measure was statistically representative of all swallow measures. This analysis indicated that oral pharyngeal swallow efficiency (OPSE) represented all measures for both liquid and paste consistencies. Then the correlation between OPSE and surgical variables was defined. Only percentage of oral tongue and percentage of tongue base resected were significantly negatively correlated with OPSE. That is, OPSE decreased for both liquid and paste as percentage of oral tongue or percentage of tongue base resected increased. Results are discussed in terms of diet choices and surgical management.

Speech and swallow function after tonsil/base of tongue resection with primary closure.

Speech and swallowing function was examined in 11 patients who underwent surgical resection of greater than 1 cm of tongue base, tonsil, and faucial arch with mandible resected on the side of the tumor and reconstruction by primary closure. Preoperatively and 1 and 3 months post-healing, high fidelity audio recordings were made of a 6- to 7-minute conversational speech sample, the sentence version of The Fisher Logemann Test of Articulation Competence was administered, and videofluoroscopic assessment of oropharyngeal swallow was conducted. All subjects exhibited changes in speech and swallowing function postoperatively, with little improvement during the study. Patients exhibited greatest difficulty on stop and fricative consonants and bolus propulsion. Comparison with patients who received anterior tongue and floor of mouth resections and distal flap reconstruction revealed consistently better speech performance by the tonsil/base of tongue patients, although the same phonemes were affected. Swallow function was equally affected in the two groups. Results are discussed in terms of locus of surgical resection, nature of reconstruction, and need for swallowing therapy.

Speech and swallowing function after anterior tongue and floor of mouth resection with distal flap reconstruction.

The purpose of this study was to assess the postoperative functioning of oral cancer patients with resections of the anterior tongue and floor of mouth, reconstructed with distal flap closure. Speech and swallowing performance was assessed for 11 men and 5 women preoperatively and at 1 and 3 months postoperatively following a standardized protocol. Speech tasks included an audio recording of a brief conversation and of a standard articulation test; swallowing function was examined using videofluoroscopy. Data were also collected on the number and duration of speech/swallowing treatment sessions, as well as the amount and duration of radiation therapy. Statistical analyses revealed that patients demonstrated a significant and severe impairment in speech and swallow functioning after surgery, with no recovery of function by 3 months post-healing. The degree of impairment in these patients may be related to the adynamic character of the distal flap used for reconstruction. Lack of improvement at the 3-month evaluation may be related to either the timing of postoperative radiation therapy or the low rate (44%) and amount of speech/swallowing treatment provided to these patients.