Possible added value of thyroglobulin antibody (TgAb) testing in the evaluation of thyroidal status of subjects with overweight or obesity.

PURPOSE: An increase in serum TSH concentrations in the absence of thyroid disease, named isolated hyperthyrotropinemia, is frequently observed in subjects with obesity. It is directly associated with body mass index, and it is reversible following weight loss. Autoimmune hypothyroidism is frequently associated with obesity, it is usually progressive and needs replacement treatment with L-thyroxine. The aim of this study was to investigate the role of thyroglobulin antibodies (TgAb) to define the thyroidal status in subjects with overweight or obesity. METHODS: This is a retrospective study including 749 consecutive adult patients with overweight or obesity. Of those, 76 were excluded from the analysis due to hyperthyroidism, previous thyroidectomy or radioiodine therapy for hyperthyroidism, hemiagenesis or drug-induced hypothyroidism. Serum thyrotropin (TSH), free thyroxine (FT4), free 3,5,3'-triiodothyronine (FT3), TgAb and thyroperoxidase antibodies (TPOAb) were measured in all patients. RESULTS: Out of 673 patients, 408 did not have thyroid disease. Among patients with thyroid disease (n = 265), 130 had nodular disease with no humoral signs of thyroid autoimmunity and 135 (20%) had autoimmune thyroiditis, defined by the presence of TPOAb and/or TgAb. The prevalence of hyperthyrotropinemia, either directly measured or presumed based on L-thyroxine treatment at the time of data collection, was 63.9% in patients with both TgAb and TPOAb, 47.1% in those with isolated positivity of TPOAb, 42.8% in patients with isolated positivity of TgAb, and 14.5% in those with no detectable TgAb or TPOAb. CONCLUSIONS: Our results confirm a high prevalence of autoimmune thyroiditis (20%) in patients with obesity. TgAb may be associated with hypothyroidism in the absence of TPOAb. TgAb measurement may turn helpful to unravel a proportion of subjects that may have or may develop primary hypothyroidism requiring specific substitutive treatment.

Effect of aging on clinical features and metabolic complications of women with polycystic ovary syndrome.

PURPOSE: To assess the distribution of clinical features and metabolic abnormalities of polycystic ovary syndrome (PCOS) women according to their age. METHODS: Retrospective study on 602 women (mean age 23.9 ± 6.2 years), diagnosed according to International PCOS Network Guidelines criteria as having PCOS in a University-based Hospital. Anthropometric features, hormonal and metabolic parameters were measured and compared between the different age groups (group A ≤ 20 years; group B 21-30 years; group C > 30 years). RESULTS: Patients in group A were more often hyperandrogenic, while in group C hypertension, dyslipidemia, obesity, impaired fasting glucose, and insulin resistance (IR) were more prevalent. After adjusting for BMI, age correlated positively with sex hormone-binding globulin (SHBG), IR, total- and LDL-cholesterol, and negatively with DHEAS, insulin, and free androgen index (FAI). SHBG was significantly associated with IR and atherogenic dyslipidemia, while FAI levels were linked to hypertension, independently of other factors considered. Furthermore, the regression analysis showed a stronger relationship between BMI and metabolic outcomes, regardless of age. CONCLUSION: Polycystic ovarian syndrome (PCOS) phenotype changes with age. Clinical and biochemical hyperandrogenism are a major concern in young PCOS women, while metabolic burden tends to increase with aging. Some of the cardiovascular risk factors are dependent on FAI and SHBG levels, whereas BMI confirms its key role in the genesis of most of the metabolic sequelae in PCOS, independently of age.

Weight loss effect of liraglutide in real-life: the experience of a single Italian obesity center.

PURPOSE: Several randomized controlled clinical trials (RCCTs) have shown that the use of Liraglutide (L) in addition to diet and exercise in patients with obesity or overweight (OO), compared to dietary behavioral changes alone, leads to a significantly greater weight loss. This retrospective study aimed at evaluating the effectiveness of L therapy in a real-life setting. METHODS: 93 consecutive non-diabetic OO, referring to a single Obesity Center, started L therapy from October 2016 to December 2018: 21/93 OO discontinued the treatment within 90 days for various reasons. 72/93 OO (55 females, 17 males), mean ± SD age 49 ± 12.5 years (18-78) and mean body mass index 39.1 ± 5.8 (28.3-55.3) were included for further analysis. 60/72 OO reached the final dose of 3.0 mg/day. RESULTS: Mean weight loss was 7.1% in the OO who reached the dose of 3.0 mg; 68.3%, 20.0% and 10.0% of OO lost ≥ 5%, 10% and 15% of body weight, respectively. A linear correlation between early and final weight loss was found. Moreover, we observed a significant reduction of mean systolic and diastolic blood pressure and a significant increase of mean heart rate. The overall incidence of side effects was 18.3% (17/93). CONCLUSION: L treatment of OO in a real life setting yielded results comparable to those reported by the major RCCTs. Combining the results of RCCTs with the observations from real life may increase their power and overcome their respective limitations.

LDL-cholesterol lowering effect of a new dietary supplement: an open label, controlled, randomized, cross-over clinical trial in patients with mild-to-moderate hypercholesterolemia.

BACKGROUND: Hypercholesterolemia is a major risk factor for cardiovascular disorders and requires specific intervention through an adequate lifestyle (diet and physical exercise) and, if necessary, an appropriate drug treatment. Lipid-lowering drugs, although generally efficacious, may sometimes cause adverse events. A growing attention has been devoted to the correction of dyslipidemias through the use of dietary supplements. The aim of this study was to assess the lipid-lowering activity and safety of a dietary supplement containing monacolin K, L-arginine, coenzyme Q10 and ascorbic acid, named Argicolina (A), compared to a commercially available product containing monacolin K and coenzyme Q10, Normolip 5 (N). METHODS: This was a single center, controlled, randomized, open-label, cross-over clinical study enrolling 20 Caucasian outpatients aged 18-75 years with serum LDL-C between 130 and 180 mg/dL. Patients assumed two different dietary supplements (A and N) both containing monacolin K 10 mg for 8 weeks each, separated by a 4-week wash-out period. Evaluated parameters were: Total cholesterol (Tot-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting blood glucose, aspartate aminotransferase, alanine aminotransferase, creatinekinase, gamma-glutamyl-transpeptidase, brachial arterial pressure and heart rate, measured at the start and at the end of each treatment period. Safety was monitored through the study. RESULTS: LDL-C decreased by 23.3% during treatment with N (p < 0.0001) and by 25.6% during treatment with A (p < 0.0001); the LDL-C mean reduction was 36.4 (95% CI: 45,6-27,1) mg/dL during N treatment and 40.1 (95% CI: 49.2-30,9) mg/dL during A treatment. Tot-C decreased significantly (p < 0.0001) within each treatment period. HDL-C increase was negligible during A whereas it was significant during N. TG diminished markedly during A and not significantly during N. The difference between treatments was not statistically significant for all variables. No serious or severe adverse events occurred during the study. CONCLUSIONS: Our results confirm the clinically meaningful LDL-C lowering properties of monacolin K. At variance with a supplement already in the market (N), the novel association (A) of monacolin K with L-arginine, coenzime Q10 and ascorbic acid also produces a significant reduction of triglycerides without significant effects on HDL. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03425630 .

Hepatic left lobe volume is a sensitive index of metabolic improvement in obese women after gastric banding.

BACKGROUND: Nonalcoholic fatty liver disease is a common finding in obese subjects. Increasing evidence has been provided suggesting that it represents the hepatic component of the metabolic syndrome. OBJECTIVE: Aim of this longitudinal study was to evaluate the relationships between several anthropometric measures, including the hepatic left lobe volume (HLLV), and various indicators of the metabolic syndrome in a cohort of severely obese women before and after laparoscopic adjustable gastric banding (LAGB). STUDY DESIGN AND RESULTS: Seventy-five obese women (mean age 45 ± 10 years and body mass index (BMI) 42.5 ± 4.8 kg m(-2)) underwent LAGB and completed an average (± s.d.) post-surgical follow-up of 24 ± 6 months. Determination of HLLV, subcutaneous and intra-abdominal fat (IAF) was based on ultrasound. The principal component statistical analysis applied to pre-operative measurements, highlighted HLLV as a parameter that clustered with serum insulin, IAF, serum glucose and uric acid, along with triglycerides (TGs), alkaline phosphatase and high-density lipoprotein cholesterol. After LAGB, the average reduction of BMI was 23%, 12% for subcutaneous fat (SCF), 42% for HLLV and 40% for visceral fat. Among body weight, BMI, SCF, IAF and HLLV, reduction of the latter was an independent predictor of reduction of serum transaminases and γ-Glutamyltransferase, glucose, insulin and TGs. CONCLUSIONS: In severely obese women: (i) HLLV is a sensitive indicator of ectopic fat deposition, clustering with parameters defining the metabolic syndrome; (ii) weight loss achieved by LAGB is associated with a reduction of liver volume as estimated by HLLV; (iii) among various anthropometric parameters measured, reduction of HLLV that follows LAGB represents the best single predictor of improvement of various cardiometabolic risk factors.

Specific heat relaxation of an alcohol and implications for dielectric comparison.

The dynamic and the apparent specific heats of 5-methyl-2-hexanol were measured in its vitrification temperature range during its cooling and then heating at the same and exceptionally slow rates of 12 K/h and 60 K/h. The relaxation time determined from dynamic measurements is 48 s at 149.8 K. The relaxation time estimated from the onset of the apparent C(p)-endotherm measured on heating is found to be inconsistent with that determined from dynamic C(p) measurements. The fitting of a nonexponential nonlinear relaxation model to the C(p,app) data shows that beta varies slightly with the heating rate, and this is attributed to contributions to temperature-dependent energy from change in the hydrogen-bond population. The unrelaxed C(p) of the ultraviscous liquid is closer to that of its glassy state, thus showing that the vibrational part of C(p) does not increase in a sigmoid-shape manner when the glass structure kinetically unfreezes on heating. The results have implications for use of calorimetry in inferring the dielectric relaxation mechanism.

Kinetics and thermodynamics of sucrose hydrolysis from real-time enthalpy and heat capacity measurements.

We report a real time study of the enthalpy release and heat capacity during the course of HCl-catalyzed hydrolysis of sucrose to fructose and glucose. Measurements were performed during both isothermal conditions and during slow heating and then cooling at a controlled rate. The reaction rate constant of the first-order kinetics follows an Arrhenius relation with activation energy of 109.2 kJ/mol of sucrose. On hydrolysis, the enthalpy decreases by 14.4 kJ/mol of sucrose at 310 K, and the heat capacity, Cp, increases by 61 J mol-1 K-1 of sucrose in the solution. The enthalpy of hydrolysis decreases with increase in the temperature and DeltaCp on hydrolysis increases. The effects are attributed to change in the configurational and vibrational partition functions as one covalent bond in sucrose breaks to form two molecules, which then individually form additional hydrogen bonds and alter the water's structure in the solution. Cp of the solution increases with temperature less rapidly before sucrose hydrolysis than after it. This may reflect an increase in the configurational contribution to Cp as the hydrogen bond population changes.

Otologic symptoms in temporomandibular disorders patients: is there evidence of an association-relationship?

Several studies in the literature investigated the association between temporomandibular disorders (TMD) and otogenous symptoms, like vertigo, tinnitus, otalgia and muffling, although the question of the existence of a cause-effect relationship is still controversial. Epidemiological findings showed that the prevalence of ear symptomatology in the general population is variable from 10% to 31%, and increases up to 85% in TMD patients. Based on these data, many attempts have been performed to describe the physiopathological interactions between aural symptoms and TMD, as a strict anatomical link exists between the structures of the ear and those of the stomatognathic system. Unfortunately, methodological weaknesses of most studies are evident so that the comparison of results is often difficult. Considering these premises, the present study critically reviewed the literature on this debated issue, discussing the main etiopathogenetic hypotheses, the features of ear symptomatology in TMD patients and its relationship with TMD treatment in order to present current suggestions about the relationship between aural and TMD symptoms. Suggestions for future researches have been also presented, since a full understanding of this plausible interaction will be an important factor in diagnosis making and treatment planning for both pathologies.

Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes.

BACKGROUND: Aging is associated with increased cardiovascular risk and endothelial dysfunction. Since exercise can improve endothelium-dependent vasodilation, in the present study we tested whether long-term physical activity could prevent aging-related endothelial dysfunction. METHODS AND RESULTS: In 12 young and elderly (age 26.9+/-2.3 and 62.9+/-5.8 years, respectively) healthy sedentary subjects and 11 young and 14 elderly matched athletes (age 27.5+/-1.9 and 66.4+/-6.1 years, respectively), we studied (with strain-gauge plethysmography) forearm blood flow modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute), an endothelium-dependent vasodilator, at baseline, during infusion of N(G)-monomethyl-L-arginine (L-NMMA) (100 microg/100 mL forearm tissue per minute), a nitric oxide-synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), an antioxidant, and finally under simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (1, 2, and 4 microg/100 mL forearm tissue per minute) was also evaluated. In young athletes and sedentary subgroups, vasodilation to acetylcholine was inhibited by L-NMMA and was not changed by vitamin C. In elderly subjects, vasodilation to acetylcholine was blunted as compared with young subjects in both control subjects and athletes, whereas the response to sodium nitroprusside was similar. Moreover, in elderly athletes, vitamin C did not change the vasodilation to acetylcholine. In contrast, in elderly sedentary subjects, the response to acetylcholine was resistant to L-NMMA. In this subgroup, vitamin C increased the vasodilation to acetylcholine and restored the inhibiting effect of L-NMMA. CONCLUSIONS: These results suggest that regular physical activity can at least in part prevent the age-induced endothelial dysfunction, probably the restoration of nitric oxide availability consequent to prevention of production of oxidative stress.

Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension.

OBJECTIVES: We sought to evaluate whether fasting hyperhomocystinemia reduces endothelial function by oxidative stress in normotensive subjects and hypertensive patients. BACKGROUND: Subjects with hyperhomocystinemia have endothelial dysfunction. METHODS: In 23 normotensive subjects and 28 hypertensive patients, classified into normohomocystinemic and hyperhomocystinemic groups according to homocysteine plasma levels (< 8.7 and >14.6 micromol/l, respectively), we studied forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.15 to 15 microg/100 ml tissue per min) or sodium nitroprusside (1 to 4 microg/100 ml per min), an endothelium-dependent and -independent vasodilator, respectively. Acetylcholine was repeated with N(G)-monomethyl-L-arginine (L-NMMA; 100 microg/100 ml per min), vitamin C (8 mg/100 ml per min) and L-NMMA plus vitamin C. RESULTS: Normotensive hyperhomocystinemic patients showed a blunted response to acetylcholine and a lower inhibiting effect of L-NMMA on acetylcholine, as compared with normohomocystinemic patients. Although vitamin C was ineffective in normohomocystinemic subjects, it increased the response to acetylcholine and restored the inhibiting effect of L-NMMA on acetylcholine in hyperhomocystinemic patients. Hypertensive hyperhomocystinemic patients showed a reduced response to acetylcholine, as compared with normohomocystinemic subjects. In both subgroups, L-NMMA failed to blunt the response to acetylcholine. The potentiating effect of vitamin C on acetylcholine was greater in hyperhomocystinemic patients than in normohomocystinemic subjects, although it restored the inhibitory effect of L-NMMA on acetylcholine-induced vasodilation to the same extent in both groups. Hyperhomocystinemia did not change the response to sodium nitroprusside. CONCLUSIONS: In normotensive subjects and hypertensive patients, hyperhomocystinemia impairs endothelium-dependent vasodilation. It could be related to oxidant activity.

Is Hyperhomocyst(e)inemia a humoral predictor of coronary heart disease?

Elevated plasma homocyst(e)ine levels have prothrombotic and proatherosclerotic effects. Data from prospective studies indicated that plasma homocyst(e)ine acts as a modest independent predictor of coronary heart disease. At present, no conclusive data are available on the possible interaction between hyperhomocyst(e)inemia and hypertension and the occurrence of cardiovascular events. Recent longitudinal studies in high risk patients indicated that hyperhomocyst(e)inemia is strongly associated with recurrent cardiovascular events. However, this finding is not in line with the few available data from prospective studies, which failed to observe a protective role of homocyst(e)ine-lowering therapy in secondary prevention of cardiovascular events. Future results from ongoing larger trials are expected to provide more definitive answers concerning the need to support the routine use of folic acid in patients with CHD. Since the definitive impact of mild hyperhomocyst(e)inemia on coronary heart disease is still to be established, widespread determination of homocyst(e)ine levels is not needed in a general population at the present time. In contrast, knowledge of homocyst(e)inemia may be important for specific groups of individuals, such as high risk patients, and for those patients in whom traditional risk factors do not appear to account for an increased incidence of cardiovascular events.

Endothelial dysfunction in hypertension.

Endothelium can deeply influence vascular tone and structure. The main endothelium derived factor is nitric oxide, which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro and microcirculation and in renal circulation. Impaired endothelium-dependent vasodilation associated with essential hypertension seems to be a primary phenomenon, since it can be detected in the offspring of essential hypertensive patients, shows no clear correlation with blood pressure value, and is not normalized by the mere reduction of blood pressure. The phenomenon responsible for endothelial alteration in essential hypertensive patients seems to be the activation of an alternative pathway involving cyclooxygenase which reduces NO availability through production of oxidative stress. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis in essential hypertension.

Vibrational and configurational heat capacity of poly(vinyl acetate) from dynamic measurements.

The complex heat capacity C(p) (*) of poly(vinyl acetate) has been measured at 20.95 mrads modulation frequency during the cooling as well as on heating at 24, 8, and 2 Kh and during cooling at 0.5 Kh. The study is complemented with (the rate-dependent) C(p,app) measured during cooling and heating at 60, 24, and 8 Kh. At low temperatures, the real component of C(p) (*) yields the unrelaxed C(p) or C(p,vib), the vibrational part of C(p). It is found to be indistinguishable from C(p,glass) and lies on a line extrapolated to its equilibrium melt's temperature. At T near T(g),DeltaC(p)(=C(p,melt)-C(p,glass)) shows no detectable contribution from C(p,vib). The finding conflicts with a modified entropy theory calculation [E. A. DiMarzio and F. Dowell, J. Appl. Phys. 50, 6061 (1979)], which had predicted that approximately 27% of DeltaC(p) of poly(vinyl acetate) at T near T(g) is vibrational in origin and the remainder configurational. At T

Relaxation during polymerization on slow heating and the vibrational heat capacity of the polymers.

The real and imaginary components of the complex heat capacity, C(p) (') and C(p) ("), and C(p,app) have been measured in real time during the linear chain polymerization on 12 K/h heating of six different (partially) polymerized states of a stoichiometric mixture of cyclohexylamine and diglycidyl ether of bisphenol A. Their C(p,app) shows a sigmoid shape rise with different onset temperatures T(onset), which is followed by a deep exotherm as the viscosity decreases and further polymerization occurs at different rates. The rates of their enthalpy decrease on polymerization determined by subtracting C(p) (') from C(p,app) differ but C(p) (') and C(p,app) of their final states are the same. The relaxation time increases with polymerization and decreases with an increase in T. C(p) (') rises in a sigmoid shape manner, and C(p) (") shows a peak when the relaxation time of the polymerized state is equal to the inverse of the temperature modulation frequency, whether polymerization occurs or not. The unrelaxed or vibrational heat capacity C(p,vib) of the polymers at T>T(onset) is close to C(p) of their glassy state at T

Spontaneous liquifaction of isomerizable molecular crystals.

A lattice vacancy raises the energy of the neighboring (flexible) molecule in a crystal, which may be enough to isomerize it to a tautomer that does not fit the lattice site, thus creating a liquidlike local region embedding the vacancy. Similar regions may appear elsewhere in the lattice and the regions may ultimately merge. Thus a crystal may spontaneously liquefy over a period of hours to years at a temperature below its normal melting point. Simultaneous heat capacity and heat absorption measurements of several such molecular crystals show that they spontaneously liquefy at a temperature far below their reputed melting point, according to a non-exponential rate kinetics and a temperature dependent rate constant, and do not crystallize on cooling.

Composition dependence and the nature of endothermic freezing and exothermic melting.

The heat capacity, C(p), and enthalpy and entropy change of alpha-cyclodextrin, H(2)O, and 4-methylpyridine solutions have been studied during their freezing on heating, isothermal freezing, and the solid's melting on cooling. Freezing occurs in several endothermic steps on heating to 383 K and alpha-cyclodextrin rich solutions freeze in four steps. The melting rate becomes slower with decrease in temperature and its steps merge. Decreasing the amount of alpha-cyclodextrin decreases the C(p) change on freezing. The endothermic freezing phenomenon differs from freezing of a pure liquid and is attributed to formation of a solid inclusion compound and its incongruent way of exothermic melting.

Heat capacity of tetrahydrofuran clathrate hydrate and of its components, and the clathrate formation from supercooled melt.

We report a thermodynamic study of the formation of tetrahydrofuran clathrate hydrate by explosive crystallization of water-deficient, near stoichiometric, and water-rich solutions, as well as of the heat capacity, C(p), of (i) supercooled tetrahydrofuran-H2O solutions and of the clathrate hydrate, (ii) tetrathydrofuran (THF) liquid, and (iii) supercooled water and the ice formed on its explosive crystallization. In explosive freezing of supercooled solutions at a temperature below 257 K, THF clathrate hydrate formed first. The nucleation temperature depends on the cooling rate, and excess water freezes on further cooling. The clathrate hydrate melts reversibly at 277 K and C(p) increases by 770 J/mol K on melting. The enthalpy of melting is 99.5 kJ/mol and entropy is 358 J/mol K. Molar C(p) of the empty host lattice is less than that of the ice, which is inconsistent with the known lower phonon frequency of H2O in the clathrate lattice. Analysis shows that C(p) of THF and ice are not additive in the clathrate. C(p) of the supercooled THF-H2O solutions is the same as that of water at 247 K, but less at lower temperatures and more at higher temperatures. The difference tends to become constant at 283 K. The results are discussed in terms of the hydrogen-bonding changes between THF and H2O.

Heat capacity of water in nanopores.

Heat capacity of controlled amounts of water in Vycor's 2 nm radius pores has been determined in real time during the course of water's isothermal nanoconfinement from bulk state at 358 K, by using temperature-modulated calorimetry. As water transfers from bulk to nanopores via the vapor phase, its heat capacity per molecule increases asymptotically toward a limiting value of 1.4 times the heat capacity of bulk water for 1.8 wt % water in Vycor and 1.04 times for 10.0 wt %. The observations indicate that vibrational and configurational contributions to the heat capacity are highest when the amount of water is insufficient to completely cover the pore wall, and they decrease as more water is present in the nanopores and water clusters form. The heat capacity of water in completely filled nanopores approaches the value for bulk water, thus indicating that the heat capacity varies with the water molecules' position in the nanopores.

Position-dependent energy of molecules in nano-confined water.

Real time decrease in the energy (or enthalpy) measured during confinement of controlled amounts of water in 2 nm radius pores of Vycor shows that exothermic transfer of bulk water to nanopores via the vapour-phase occurred in two stages. In the first stage, at saturation pressure, H2O molecules from the vapour rapidly accumulated in the nanopore channels near the Vycor surface. In the second, at vapour pressure below saturation, the accumulation rate abruptly decreased and water (slowly) diffused and redistributed in the nanopore channels until the vapour pressure equilibrium was attained. The energy decrease per H2O molecule was highest, 14.5 kJ mol(-1), at low amounts when the pore-wall was incompletely covered by H2O. This value approached zero at higher amounts when pores were gradually filled. The results show that the vibrational and configurational contributions to the energy of H2O molecules depend upon their position in the nanopore and these contributions approach their bulk water values at high water concentration, but do not attain those values for completely filled pores.