Neuropeptide Y polymorphism and alcohol consumption in middle‐aged men

Neuropeptide Y (NPY) plays an important role in the hypothalamic regulation of food intake and energy balance. According to recent findings in animals, NPY also seems to be a potent regulator of alcohol consumption. We used the recently identified Leu(7) to Pro(7) polymorphism in the signal peptide part of NPY to investigate whether the NPY system is associated with alcohol consumption in humans. The subjects (N = 889) were an ethnically homogenous, nonselected population sample of middle‐aged men from Eastern Finland. The gene variant producing Pro(7) substitution was associated with a 34% higher average alcohol consumption, even after adjustment for a number of covariates (P = 0.03). The proportion of heavy drinkers (over 230 g of ethanol/week) was also somewhat higher in this group (13.1% vs. 8.2%, P = 0.10). Our study provides the first evidence that alcohol preference in humans is likely to be regulated by the NPY system. Am. J. Med. Genet. 93:117–121, 2000. © 2000 Wiley‐Liss, Inc.     

Prognostic value of MMP-2 immunoreactive protein (72 kD type IV collagenase) in primary skin melanoma

The penetration of the subepithelial basement membrane is the first critical step in the dissemination of melanoma. In vitro studies have suggested that the 72 kD type IV collagenase (MMP-2) may be important in melanoma invasion. It has recently been demonstrated that the expression of MMP-2 immunoreactive protein increased with increasing atypia in melanocytic tumours and was associated with later haematogenous metastases in melanoma. This paper investigates the value of MMP-2 as a possible prognostic marker in melanoma. The expression of MMP-2 immunoreactive protein was studied with immunoperoxidase staining in paraffin-embedded sections of 50 cases of primary skin melanoma by using specific, affinity purified antibodies. Positive immunostaining was quantified by counting the percentage of positive cancer cells and was compared with clinical patient characteristics and survival. Sixty-four per cent of the primary melanoma cases displayed positive cytoplasmic immunostaining for MMP-2 in tumour cells. Marked overexpression of MMP-2 protein (≥34 per cent of melanoma cells positive) correlated with the 5-year survival of the patients when compared with patients with lower MMP-2 positivity, 55 per cent vs. 85 per cent, respectively (P<0·05). Male patients displayed positive staining more often than females (75 per cent vs. 54 per cent, respectively). There was no correlation between MMP-2 positivity and Clark level or Breslow classification. A distinct group with unfavourable prognosis was identified. The 10-year survival for MMP-2-positive male melanoma patients was 39 per cent as opposed to 79 per cent with the other melanoma patients (P<0·05). In the hierarchic Cox regression model for survival, MMP-2 immunoreactive protein was found to be independent of Clark level and Breslow classification. Overexpression of MMP-2 protein indicated a 4·5-fold relative risk of dying from melanoma. It is concluded that MMP-2 immunoreactive protein in melanoma cells is an independent prognostic factor for survival. High MMP-2 expression in male melanoma patients indicates an unfavourable prognosis. © 1998 John Wiley & Sons, Ltd.     

Molecular genetics of the long QT syndrome: Two novel mutations of the KVLQT1 gene and phenotypic expression of the mutant gene in a large kindred

At least three different gene loci were recently shown to account for the long QT syndrome (LQTS), a monogenic disorder with altered myocardial repolarization and occurrence of life-threatening cardiac arrhythmias. We screened 44 unrelated probands for mutations of the gene encoding the cardiac potassium channel KVLQT1 using single-strand conformational polymorphism (SSCP) and subsequent DNA sequencing. Two different mutations, T182I and D188N, were identified in two separate pedigrees. Cosegregation of the mutation with the disease phenotype was evident in both families. No mutations were identified at codon 212, previously suggested to represent a mutational hot spot of the KVLQT1 channel, in any of the 44 probands. The large pedigree with the D188N mutation (30 affected and 43 nonaffected individuals) permitted an analysis of expression of the mutant gene in its documented carriers. Although the mean (± SD) Qtc interval was markedly longer in affected (484 ± 38 ms) than in nonaffected individuals (406 ± 27 ms, P < 0.001), there was a marked overlapping of individual values in these two groups. QTc values in symptomatic and asymptomatic carriers of the mutant gene were not significantly different. In conclusion, we have identified two novel mutations of the KVLQT1 component of a cardiac potassium channel. Our data support the functional significance of the pore-S6 domain of this membrane protein and emphasize the diagnostic usefulness of DNA analyses in families with LQTS. Hum Mutat 11:158–165, 1998. © 1998 Wiley-Liss, Inc.     

Favorable change in mammographic parenchymal patterns and breast cancer risk factors

The aim of our study was to estimate the incidence of favorable mammographic patterns and to assess the incidence by risk factors of breast cancer. Data relate to 1,947 women aged 40–47 years who were screened by mammography every second year and whose mammographic parenchymal pattern at initial screening was either P2 or DY (Wolfe's classification). The pattern was assessed at each screening round. The incidence of N1,P1 parenchymal pattern by risk factors was estimated. The Cox proportional hazards model was applied in univariate and multivariate analyses of the data. The incidence of N1,P1 pattern was 12.5/100 woman years among women with P2,DY pattern at the beginning of follow-up. The relative risk of N1,P1 pattern adjusted for th eother risk factors for women aged 45 years or more was 1.7 [95% confidence interval (CI) 1.5–1.9] compared with younger women. The adjusted relative risk of N1,P1 pattern among women with a body mass index (BMI) of 25 or more was 2.1 (95% CI 1.6–2.8) compared with women with a BMI of less than 20; women with more than 2 pregnancies had a 30% higher adjusted relative risk (RR = 1.3, 95% CI 1.1–1.6) than women with no pregnancies. The incidence of favorable mammographic parenchymal pattern was significantly related to old age, large BMI and multiparity. The effects of age and BMI on incidences of favorable and unfavorable change potentiate each other but not that of parity. Int. J. Cancer 78:410–414, 1998. © 1998 Wiley-Liss, Inc.     

One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma

We investigated the 1-year outcome of children hospitalized for wheezing, paying special attention to the effect of early anti-inflammatory therapy. In addition, we identified risk factors for recurrent wheezing and asthma. Eighty-eight children under 2 years old treated in the hospital for wheezing were followed for 1 year. Nebulized anti-inflammatory therapy was given for 16 weeks: 31 patients received budesonide, 29 patients cromolyn sodium, and 28 control patients received no therapy. The number of subsequent physician-diagnosed wheezing episodes was recorded. Four months of anti-inflammatory therapy did not significantly decrease the occurrence of asthma 1 year later; 45% of patients in the cromolyn group, 42% in the budesonide group, and 61% in the control group had asthma, defined as at least two bronchial obstruction episodes during the 1-year period after the original hospitalization for wheezing. An age over 12 months at the time of the initial bronchial obstructing episode [P = 0.009, risk ratio (RR) = 5.4, 95% confidence interval (CI) = 1.53–19.31], failure to identify a viral cause (P = 0.0003, RR = 12.0, CI = 3.16–45.40), history of wheezing (P = 0.02, RR = 14.6, CI = 1.59–132.10), the presence of atopy (P = 0.01, RR = 5.3, CI = 1.47–19.21), a family history of atopy (P = 0.03, RR = 3.6, CI = 1.15–11.12), and serum eosinophil cationic protein (ECP) ≥ 16 μg/L (P = 0.005) were significant risk factors for asthma. We conclude that early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma during the period of 1 year following hospitalization for the original episode of wheezing. Young children requiring hospital admission for wheezing during a respiratory tract infection are at increased risk of having subsequent asthma if they have wheezed previously, if they have atopy or a family history of atopy, if they have elevated serum ECP, if they are over 12 months of age at the original bronchial obstructive episode, and especially when viral studies are negative. Pediatr Pulmonol. 1998; 26:113–119. © 1998 Wiley-Liss, Inc.     

Nasopharyngeal eosinophil cationic protein in bronchiolitis

A prospective 4-month follow-up of children hospitalized with bronchiolitis revealed that high concentrations of eosinophil cationic protein (ECP) in nasopharyngeal aspirates (NPA) are predictive of wheezing after bronchiolitis. In the 29 patients who received no anti-inflammatory therapy the median concentration of NPA ECP was 882 ng/g in those with physician-diagnosed wheezing and 154 ng/g in those without subsequent physician-diagnosed wheezing (P = 0.02). The NPA ECP concentrations of the whole study group of 88 children with and without subsequent hospital admissions for wheezing were 531 and 299 ng/g, respectively (P = 0.02). At entry the children with negative viral findings had significantly higher concentrations of respiratory tract ECP than those with positive viral findings (515 vs. 240 ng/g; P = 0.01). The concentration of ECP in respiratory secretions decreased significantly after bronchiolitis (P = 0.01) provided that no new viral or mycoplasmal infection occurred. NPA ECP values decreased in relation to time regardless of whether anti-inflammatory therapy was used or not. Children with high concentrations of respiratory tract ECP seemed to benefit from anti-inflammatory therapy with nebulized cromolyn sodium or budesonide; both drugs significantly decreased the number of subsequent physician-diagnosed bronchial obstructions (P = 0.0006), and they tended to decrease the number of hospital admissions for wheezing (P = 0.08). Our results suggest that high concentrations of ECP in respiratory tract secretions in children with bronchiolitis reflect the presence of eosinophilic inflammation also seen in asthma. Pediatr. Pulmonol. 1997;24:35–41. © 1997 Wiley-Liss, Inc.     

Matrix metalloproteinase-2 (MMP-2) immunoreactive protein—a new prognostic marker in uveal melanoma?

Uveal melanoma is the most common primary intraocular tumour. Once haematogenous metastasis has occurred, there is no cure for the disease and there is an obvious need for new biological prognostic markers to estimate the risk of metastasis. In this study, the expression of matrix metalloproteinase-2 (MMP-2) was characterized immunohistochemically in 29 human uveal melanomas. Enzyme-linked immunoassays and gelatin zymographies were assessed in order to quantify the expression of gelatinases A and B, as well as the tissue inhibitor of metalloproteinases (TIMPs), in the vitreous body. A total of 49 per cent of the uveal melanomas displayed a positive immunoreaction for MMP-2 in melanoma cells, the epithelioid cells showing the most frequent staining. There was no correlation between the positivity of MMP-2 staining and the size of the primary tumour, gender or age. The expression of MMP-2 was associated with a dismal prognosis: the 5-year overall survival rate for MMP-2-positive cases was significantly inferior to that of the MMP-2 negative cases, 49 per cent vs. 86 per cent, respectively (p=0·02). A patient group at high risk of metastatic disease was identified; only 38 per cent of patients with a MMP-2-positive non-spindle cell uveal melanoma survived for 5 years. The analyses of MMPs or TIMPs in the vitreous body had no prognostic value. Positive immunostaining for MMP-2 was observed in the retinal pigment epithelium, corneal epithelium, and fibroblasts in the ciliary body and choroid. It is concluded that immunohistochemical analysis of MMP-2 may help to predict a risk of metastasis in uveal melanoma. Copyright © 1999 John Wiley & Sons, Ltd.     

Symptoms of depression and anxiety in relation to dental health behavior and self-perceived dental treatment need

The purpose of this study was to investigate the dental health behavior and self-perceived dental treatment need, in relation to depressive symptoms and symptoms of anxiety, among a general population drawn from a sample of 31-yr-old-men and women born in Northern Finland in 1966 (n = 8463). The dental health behavior included toothbrushing frequency and the frequency of dental check-ups. Depressive symptoms, as well as symptoms of anxiety, were determined on the basis of the Symptom Checklist-25 (SCL-25). The participants were also asked about their education and family income. Subjects with a high number of depressive symptoms had lower toothbrushing frequency as well as a lower frequency of dental visits than subjects with no or only a few depressive symptoms. Morover, the self-perceived dental treatment need was more common among those with a high number of depressive symptoms. Symptoms of anxiety were significantly associated with lower toothbrushing frequency. The results support the view that there is an increased risk for impaired dental health among subjects with depressive symptoms or symptoms of anxiety.     

Education is the strongest socio‐economic predictor of smoking in pregnancy

Aims

To investigate socio‐economic disparities in smoking in pregnancy (SIP) by the mother's education, occupational class and current economic conditions.

Design

Cross‐sectional analysis with linked survey and register data.

Setting

South‐western Finland.

Participants

A total of 2667 pregnant women [70% of the original sample (n = 3808)] from FinnBrain, a prospective pregnancy cohort study.

Measurements

The outcome was smoking during the first pregnancy trimester, measured from the Finnish Medical Birth Register. Education and occupational class were linked from population registers. Income support recipiency and subjective economic wellbeing were questionnaire‐based measures of current economic conditions. These were adjusted for age, partnership status, residential area type, parental separation, parity, childhood socio‐economic background, childhood adversities (the Trauma and Distressing Events During Childhood scale) and antenatal stress (Edinburgh Postnatal Depression Scale). Logistic regressions and attributable fractions (AF) were estimated.

Findings

Mother's education was the strongest socio‐economic predictor of SIP. Compared with university education, adjusted odds ratios (aORs) of SIP were: 2.2 [95% confidence interval (CI) = 1.2–3.9; P = 0.011] for tertiary vocational education, 4.4 (95% CI = 2.1–9.0; P < 0.001) for combined general and vocational secondary education, 2.9 (95% CI = 1.4–6.1; P = 0.006) for general secondary education, 9.5 (95% CI 5.0–18.2; P < 0.001) for vocational secondary education and 14.4 (95% CI = 6.3–33.0; P < 0.001) for compulsory schooling. The total AF of education was 0.5. Adjusted for the other variables, occupational class and subjective economic wellbeing did not predict SIP. Income support recipiency was associated positively with SIP (aOR = 1.8; 95% CI = 1.1–3.1; P = 0.022). Antenatal stress predicted SIP (aOR = 2.0; 95% CI = 1.4–2.8; P < 0.001), but did not attenuate its socio‐economic disparities.

Conclusions

In Finland, socio‐economic disparities in smoking in pregnancy are attributable primarily to differences in the mother's educational level (low versus high) and orientation (vocational versus general).     

Clinical guidance for radioiodine refractory differentiated thyroid cancer

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression‐free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as “redifferentiation” agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.