Relationships between thyroid function and autoimmunity with metabolic derangement at the onset of type 1 diabetes: a cross-sectional and longitudinal study.

BACKGROUND: Type 1 diabetes (T1DM) is an autoimmune disease often associated with thyroid abnormalities. PURPOSE: We investigated the correlation between thyroid function and metabolic derangement at onset and the influence of autoimmunity on thyroid function at onset and subsequently. METHODS: We evaluated 152 patients diagnosed with T1DM between 2000 and 2012 at onset and during a mean follow-up of 5.45 ± 2.8 years. Thyroid function at onset was correlated with metabolic derangement (degree of acidosis, metabolic control and adrenal function) and compared with that of 78 healthy children. Follow-up consisted of regular evaluation of thyroid function and autoimmunity. RESULTS: Thyroid hormonal pattern was not influenced at onset by thyroid autoimmunity, but only by metabolic derangement: pH and base excess in fact were significantly lower in patients with impaired thyroid function (p < 0.0001). Patients presenting normal thyroid function at onset showed a reduced conversion from FT4 to FT3 compared to nondiabetic children (FT3/FT4 0.3 ± 0.4 in the control group, 0.24 ± 0.4 in diabetic patients, p < 0.0001). Multiple regression analysis showed the highest correlation (negative) between FT3 levels at onset and base excess (p < 0.005). Thyroid abnormalities related to metabolic derangement disappeared during follow-up. Patients with thyroid antibodies at T1DM onset were at higher risk to require levothyroxine treatment during follow-up (p < 0.05). CONCLUSIONS: Thyroid function at T1DM onset is mainly influenced by metabolic derangement, irrespective of thyroid autoimmunity. Antithyroid antibodies evaluation at T1DM onset may be helpful to define which patients are at higher risk of developing hypothyroidism.

Severe hypoglycemic episodes: a persistent threat for children with Type 1 diabetes mellitus and their families.

BACKGROUND: As lowering glycated hemoglobin (HbA1c) levels is still the main goal of insulin treatment, severe hypoglycemia (SH) remains a common experience in children with Type 1 diabetes mellitus (T1DM) and their families. AIM: This study aims to evaluate the incidence and the clinical features of SH episodes in our Centre in the last 20 yr. SUBJECTS AND METHODS: We analyzed SH incidence in 269 patients (pts) diagnosed from 1990 to 2010 (total follow-up 2212.9 pts/yr). Inclusion criteria were at least 3 visits/yr and 1-yr follow- up. SH episode was defined as any condition of low blood glucose requiring third-party assistance. RESULTS: 50.2% of patients experienced at least 1 SH episode for a total of 345 episodes. Whole incidence was 15.6/100 pts/yr, slightly different between first and second decade (12.6 vs 16.5, p=0.047). HbA1c at the time of SH was lower in the non-basal bolus group (7.4±1.3 vs 8.2±1.4; p=0.0001) and worsened 3 months later (p=0.0001). Impaired awareness was the main or only symptom in 43.5%. SH occurred at night in 32% of patients; they were significantly younger than those with SH at other times. Five SH episodes or more occurred in 8.1% of patients who presented a lower HbA1c, a younger age and shorter disease duration than the other patients. HbA1c at first SH was negatively correlated with number of SH (r=-0.20; p=0.05). CONCLUSIONS: Despite the advent of new insulin regimens, we confirm that SH still represents a relevant risk and a current threat for patients with T1DM and their families.

Low-frequency rTMS over right dorsolateral prefrontal cortex in the treatment of resistant depression: cognitive improvement is independent from clinical response, resting motor threshold is related to clinical response.

BACKGROUND: Clinical studies have shown that repetitive transcranial magnetic stimulation (rTMS) is effective in a certain percentage of treatment-resistant depression (TRD). The left dorsolateral prefrontal cortex (DLPFC) 10 Hz rTMS stimulation received FDA approval in 2008, although different rTMS protocols have also shown their effectiveness in reducing depressive symptoms. We investigated the clinical, cognitive and neurophysiologic effects of a 3 weeks' protocol of low-frequency rTMS applied over the right DLPFC in resistant depression. METHODS: Twenty-eight patients with TRD (age range 28-55) received low-frequency rTMS (1 Hz) over the right DLPFC in a 3-week open trial. Hamilton scales for depression and anxiety, Corsi block-tapping test, phonemic verbal fluency, right and left resting motor thresholds were evaluated in each subject over the trial period. RESULTS: At the end of the trial 42.9% of the subjects were considered as responders. A significant reduction of both HAMD (p < 0.001) and HAMA (p < 0.01) total scores was observed. At the 3rd week, the performances in Corsi test (p < 0.02) and phonemic verbal fluency (p = 0.065) were improved independently from depressive symptoms variation. At the end of the rTMS protocol, a significantly decreased left hemisphere resting motor threshold was registered (p < 0.01), while right hemisphere resting motor threshold did not show significant variation. CONCLUSION: Low-frequency rTMS over the right DLPFC appeared effective in 42.9% of depressive resistant subjects in this sample. A significant decrease in left hemisphere resting motor threshold was observed only in responders, while a trend for improvement in cognitive function has been found and appeared independent from clinical response.

Unilateral low frequency versus sequential bilateral repetitive transcranial magnetic stimulation: is simpler better for treatment of resistant depression?

Repetitive transcranial magnetic stimulation (rTMS) efficacy in the treatment of major depression has been shown in both low frequency right-sided and high frequency left-sided stimulation over the dorsolateral prefrontal cortex (DLPFC). The aim of the present investigation was to evaluate the hypothesis of an additive effect of bilateral stimulation compare to sequential to unilateral stimulation. Sixty patients with treatment-resistant depression were assigned to receive either low-frequency rTMS over the right DLPFC (140 s x 1 Hz) followed by controlateral sham (unilateral group, n=20), low frequency right DLPFC rTMS followed by left DLPFC high frequency rTMS (5 s x 10 Hz) (bilateral group, n=20), or bilateral sham (sham group, n=20) in a 3 weeks double-blind, randomized trial. The primary outcome variable was the score on Hamilton Depression Scale (HAM-D). Low frequency right-sided and sequential bilateral stimulation showed different antidepressant efficacy at 3 weeks and across the full duration of the study, only the unilateral method appearing significantly more effective than sham at the end of the trial, and correlated to the higher percent of remitters (30% of the group vs. 10% -bilateral- and 5% -sham). Unilateral stimulation, but not bilateral, showed higher antidepressant efficacy compared to sham stimulation. The data suggest that right-sided low frequency stimulation may be a first line treatment alternative in resistant depression. To confirm and extend these findings further studies require a longer follow-up period, supported by biological observation and replication.

Elderly and poor prognosis patients with high grade glioma: hypofractionated radiotherapy.

AIM: To evaluate efficacy of short-course radiotherapy in elderly and/or poor performance status patients with high grade glioma. MATERIALS AND METHODS: Twenty-one patients with high grade astrocytoma were selected in our Institute to receive hypofractionated radiotherapy. We considered two radiotherapy treatment arms: in arm I there were 22 patients treated with 60 Gy in 30 fractions at 5 fractions per week; in arm 2 there were 21 patients who received hypofractionated radiotherapy course of 30 Gy in 10 fractions at 5 fractions per week. RESULTS: In arm1 the median survival time was 8.2 months and the 1 year overall survival was 36%; in arm 2 the estimated median survival was 6.2 months and the 1 year overall survival was 23%. Treatment was without acute toxicity. CONCLUSIONS: In our experience, hypofractionated radiotherapy seems to be a reasonable treatment option for poor prognosis patients with high grade astrocytoma. It is well tolerated and can reduce the overall treatment time without negative effects on survival compared with conventional fractionation.

Development of ultrasound detection in American shad (Alosa sapidissima).

It has recently been shown that a few fish species, including American shad (Alosa sapidissima; Clupeiformes), are able to detect sound up to 180 kHz, an ability not found in most other fishes. Initially, it was proposed that ultrasound detection in shad involves the auditory bullae, swim bladder extensions found in all members of the Clupeiformes. However, while all clupeiformes have bullae, not all can detect ultrasound. Thus, the bullae alone are not sufficient to explain ultrasound detection. In this study, we used a developmental approach to determine when ultrasound detection begins and how the ability to detect ultrasound changes with ontogeny in American shad. We then compared changes in auditory function with morphological development to identify structures that are potentially responsible for ultrasound detection. We found that the auditory bullae and all three auditory end organs are present well before fish show ultrasound detection behaviourally and we suggest that an additional specialization in the utricle (one of the auditory end organs) forms coincident with the onset of ultrasound detection. We further show that this utricular specialization is found in two clupeiform species that can detect ultrasound but not in two clupeiform species not capable of ultrasound detection. Thus, it appears that ultrasound-detecting clupeiformes have undergone structural modification of the utricle that allows detection of ultrasonic stimulation.

Incidence of RBD and hallucination in patients affected by Parkinson's disease: 8-year follow-up.

We describe the 8-years follow-up of 80 patients affected by idiopathic, L-dopa-responsive Parkinson's disease. All patients were evaluated at baseline and during the follow-up with visual evoked potential, P300 event related potentials and polysomnography. The patients and their relatives compiled sleep and hallucination questionnaires. Statistical analysis was performed to evaluate if visual abnormalities, abnormal P300 recordings or sleep disturbances were linked to the development and hallucinations. Our results show that abnormal vision and abnormal P300 did not correlate with the incidence of hallucinations. However, the presence of REM sleep behavioral disorder (RBD) was significantly related to the development of hallucinations,independently of age, gender or duration of disease but dependent on the amount of dopaminoagonist treatment.

Characterization of the molecules involved in thymocyte thymic epithelial cell adhesion.

Cell to cell adhesion is important for mechanisms of cellular recognition, growth, and differentiation. The identification of molecules involved in these interactions is necessary in order to understand the molecular basis of these processes. We have previously described the development of two different thymic epithelial cell lines (TECS and TECL). Using an assay with radiolabeled thymocytes we found that thymocytes can adhere specifically to these thymic epithelial cells. This adhesion is trypsin sensitive, suggesting that involvement of specific cell surface proteins. In the present study we further characterize and begin identification of the molecules involved in this interaction. We found that thymocyte binding to thymic epithelial cells requires the presence of Ca2+ and Mg2+ and is mediated by a molecule greater than 10,000 MW. Also, we identified several antibodies which inhibit the adhesion of thymocytes to TECS. The membrane nature of the molecule mediating this interaction was confirmed by the ability of thymocyte membranes to block the inhibitory antibodies.

Immunoglobulins intrinsic to colorectal carcinoma: an unfavorable prognostic association with IgM.

Immunoglobulin (Ig) eluates prepared from cell membrane fractions of 50 colorectal carcinomas were found to contain significantly (P less than .001) less IgA and IgM and marginally less IgG than normal colon mucosa. IgA and IgG were present in all tumors, but IgM was present in only 20 of 50 tumors (40%). Small (less than or equal to the median vol) tumors contained significantly (P less than .05) more IgA and IgG per gram tissue than did large tumors. Tumors with a large (greater than the median) proportion of stroma contained more IgG than did those with less stroma. No associations were found between Ig and amount of viable-appearing tumor tissue, necrosis, mucin production, and staging. Patients whose tumors contained measurable amounts of IgM had a significantly (P = .012) shorter survival than did patients without intrinsic IgM (12 and 27 mo at the 75th percentile, respectively). The difference could not be explained by conventional staging.

Lymphoid hyperplasia: a major prognostic feature in 519 cases of colorectal carcinoma.

The size of the regional lymph nodes, germinal center, and paracortical areas, and the degree of perivascular lymphocyte cuffing (PLC) at the edges of 519 carcinomas of the large bowel have been analyzed microscopically and assessed quantitatively. Hyperplasia of these lymphoid areas, defined as relative or absolute size exceeding the median for the tumor stage, has been related to cancer-specific survival data for each of Dukes' Stages A, B, and C, and for disseminated disease commonly referred to as Stage D. Germinal center hyperplasia was associated with a major survival advantage in Stage B (P = 0.003) and in Stage C (P = 0.04) if present in tumor-involved lymph nodes. Paracortical hyperplasia related favorably to survival in Stages B and C; in Stage C such hyperplasia was most favorable if present in tumor-involved lymph nodes (P = 0.009). PLC related to favorable survival data only in Stage B. Lymphoid hyperplasia showed no correlation with survival in Stages A and D.

Mucinous colorectal carcinoma: immunopathology and prognosis.

A total of 519 colorectal carcinomas were examined for the presence or absence of mucinous differentiation by means of microscopical morphometry. Of these, 28% had objectively measurable amounts of mucinous tumour epithelium. Tumours with > 50% mucinous areas (14%) had significantly poorer prognosis than non-mucinous in stages A and C, while mucinous differentiation did not correlate with prognosis in stages B and D. Lymph nodes regional to mucinous tumours had significantly less paracortical response, and those with < 50% mucinous differentiation, significantly less perivascular lymphocyte cuffing at the tumour margins. These lymph node and stromal compartments are putative T-lymphocyte areas, and hence our findings suggest that mucinous tumours are either less stimulatory or perhaps inhibitory of cell-mediated immunity.

Regional lymph node and stromal immunomorphology in colorectal carcinoma and relation to tumour spread.

A quantitative morphometric study of lymphocyte patterns in the stroma and regional lymph nodes was made in 509 cases of colorectal adenocarcinoma and 17 non-invasive adenomas. An increase in the perivascular lymphocytes, and in the size of lymph nodes, germinal centres and paracortical areas was most obvious in 'localized' invasive tumours and significantly more in Dukes' stage B than in stage C. Stage C1, defined as cases where the primary tumours were confined to the wall but with lymph node spread, showed hardly any perivascular lymphocyte aggregates, although in the regional lymph nodes there was relative paracortical, i.e. T-lymphocyte, hyperplasia. It is concluded that the presence of cuffs of perivascular lymphocytes at the tumour edge, and the increased size of tumour-free regional lymph nodes together with the relative and absolute abundance of germinal centres (B-lymphocyte) and paracortical areas (T-lymphocyte), are stage dependent. This is most obvious in stage B. These morphological expressions of host immunoreactivity may well reflect favourable anti-tumour mechanisms.

Sequential antitumour immunoreactivity and carcinoembryonic antigen levels as a guide to prognosis in colorectal carcinoma.

Twenty-five patients with colorectal carcinoma were tested for blood-lymphocyte anti-tumour cytotoxicity and carcinoembryonic antigen (CEA) levels at three-monthly intervals for eighteen months or more after resection, and examined clinically every three to six months. Twelve of the patients were followed for two years and one for four years. The six patients whose tumours recurred showed positive blood lymphocyte antitumour cytotoxicity and elevated plasma CEA levels at some time from six months after operation, usually well before the recurrence was clinically detectable.

Correlation of regional lymph node in vitro antitumor immunoreactivity histology with colorectal carcinoma.

Lymph nodes from resected specimens of human colorectal carcinoma were investigated for in vitro lymphocyte cytotoxicity against primary cultures of autologous tumor cells. Regional lymph node lymphocytes were cytotoxic in 32 of 142 cases (23%). Altogether 200 nodes were examined and the cytotoxicity correlated directly with sinus histiocytosis, seen in 43 nodes from 35 cases, and with hyperplasia of B- and T-lymphocyte areas combined, seen in 92 nodes from 65 cases. Lymph nodes with combined B- and T-cell hyperplasia were significantly more common in cases of good tumor differentiation. The findings suggest that sinus histiocytosis and hyperplasia of both major lymphocyte populations are morphological expressions of in vitro antitumor immunoreactivity in the regional lymph node.