Phenotype of Idiopathic Infantile Hypercalcemia Associated with the Heterozygous Pathogenic Variant of SLC34A1 and CYP24A1.

Idiopathic infantile hypercalcemia (IIH) is a rare genetic disease, also called hypersensitivity to vitamin D3. The molecular heterogeneity allows for the differentiation between the two forms; IIH type 1 caused by CYP24A1 genetic variants and IIH type 2 associated with SLC34A1 mutations. The affected individuals express a variety of symptoms: hypercalcemia, hypercalciuria, suppressed intact parathormone levels (PTH), nephrocalcinosis, elevated levels of serum 1,25 (OH)2-vitamin D3 or inappropriately normal levels, and kidney phosphate wasting. The present paper describes three cases of IIH with heterozygous mutations in SLC34A1 and CYP24A1 genes, respectively. The genetic diagnosis is of paramount importance for proper treatment and the prediction of long-term outcomes.

The application of pudendal nerve blockade in the treatment of pudendal neuralgia related chronic pelvic pain / Nervus pudendus idegblokád alkalmazása krónikus kismedencei fájdalmat okozó pudendusneuralgia kezelésében

Pudendal neuralgia is a rare and ­ in the absence of somatic, radiological and laboratory abnormalities ­ often unrec-ognizable problem, posing a serious challenge to therapeutic management. Our case study presents the complete diagnostic and therapeutic algorithm of a female patient with chronic pudendal pain. In addition, our paper draws attention to the role of pelvic pain workgroups ­ such as the Pelvic Pain Task Force of the Semmelweis University ­ where cases of chronic pelvic pain with no clear medical reason can be assessed and treated with higher efficiency.

Extreme Birth Weight and Metabolic Syndrome in Children.

Small and large birth weights (BWs) for gestational age (GA) represent extremes, but the correlation between extreme BW and metabolic syndrome (MetS) has not been fully elucidated. In this study, we examined this correlation in obese children based on changes in their metabolic profile from childhood to adolescence. A retrospective observational study was performed on 535 obese patients aged 0-18 years in the Clinical and Emergency Hospital for Children "Louis Turcanu" in Timisoara, Romania, based on clinical and biological data from January 2015 to December 2019. We emphasized the links between extreme BW and obesity, extreme BW and cardiometabolic risk, obesity and cardiometabolic risk, and extreme BW, obesity and MetS. Children born large for gestational age (LGA) predominated over those born small for gestational age (SGA). Our findings showed that BW has an independent effect on triglycerides and insulin resistance, whereas obesity had a direct influence on hypertension, impaired glucose metabolism and hypertriglyceridemia. The influences of BW and obesity on the development of MetS and its components are difficult to separate; therefore, large prospective studies in normal-weight patients are needed.

Predictive role of neostromal CD10 expression in breast cancer patients treated with neoadjuvant chemotherapy.

Background: The therapeutic strategy of invasive breast cancer is based on routine histopathological markers (estrogen-, progesterone receptor, HER2, Ki67) routinely evaluated in tumor cells. However, the assessment of cancer stroma could influence therapeutic strategies. Studies have shown that stromal expression of CD10, a zinc-dependent metalloproteinase, is associated with biological aggressiveness of the tumor. In the present retrospective study, we aimed to evaluate stromal CD10 expression and association between CD10 expression and response to neoadjuvant chemotherapy in invasive breast cancer. Methods: CD10 immunohistochemistry was performed on core biopsies taken before the neoadjuvant therapy. Stromal CD10 expression was determined and compared with well-known predictive and prognostic tissue markers as well as with the following groups defined according to the degree of tumor response: no regression, partial regression, and complete regression. Results: A total of 60 locally advanced invasive breast carcinomas of "no special type" were included. The proportion of CD10 positive tumors was significantly higher in the "no regression" group compared to "complete regression" group (p = 0.000). Stromal CD10 expression was found to be significantly associated with decrease in response to neoadjuvant chemotherapy. According to CD10 expression we did not find any difference in hormone receptor status, Ki67, tumor grade or neostromal area. Conclusion: Our data suggest that CD10 expression can serve as a predictive marker of the effect of neoadjuvant chemotherapy in breast cancer patients. Therefore, its inclusion into the routine assessment of biopsies to tailor tumor-specific therapeutic strategies merits consideration.

Narrow Vagina as a Predictor of Obstructive Voiding Dysfunction after Transobturator Sling Surgery.

BACKGROUND: Voiding dysfunction (VD) is a potential complication after female midurethral sling operations. OBJECTIVES: Our goal was to assess the rate of obstructive VD after -transobturator tension-free tape (TOT) procedures and to find perioperative risk factors (RFs) predicting postoperative voiding problems. METHODS: We have retrospectively evaluated the perioperative data of 397 women who underwent TOT operations. Significant post-void residual (PVR) (>50 mL) was considered as the primary (objective) end point of the study, the voiding difficulty as the secondary (subjective) 1. First univariate analysis and then multivariate logistic regression were performed, with a 5% significance level. RESULTS: Significant PVR was present in 51 (12.8%) women; catheterization was needed in 21 (5.3%) and reoperation in 3 (0.8%) cases. Seventy women (17.6%) experienced postoperative voiding difficulty. Narrow vagina (<2 cm), older age >70 years, and preoperative voiding difficulty were independent RFs for significant PVR (odds ratio: 5.07, 2.14, 5.38, respectively, p < 0.05). Preoperative overactive bladder syndrome and previous pelvic organ prolapse surgery were considered independent RFs for postoperative voiding difficulty. CONCLUSIONS: Older age, narrow vagina, or preoperative voiding difficulty increases the chance for significant postoperative PVR. These patients should be chosen and counseled appropriately.

Molecular hydrogen alleviates asphyxia-induced neuronal cyclooxygenase-2 expression in newborn pigs.

Cyclooxygenase-2 (COX-2) has an established role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE). In this study we sought to determine whether COX-2 was induced by asphyxia in newborn pigs, and whether neuronal COX-2 levels were affected by H2 treatment. Piglets were subjected to either 8 min of asphyxia or a more severe 20 min of asphyxia followed by H2 treatment (inhaling room air containing 2.1% H2 for 4 h). COX-2 immunohistochemistry was performed on brain samples from surviving piglets 24 h after asphyxia. The percentages of COX-2-immunopositive neurons were determined in cortical and subcortical areas. Only in piglets with more severe HIE, we observed significant, region-specific increases in neuronal COX-2 expression within the parietal and occipital cortices and in the CA3 hippocampal subfield. H2 treatment essentially prevented the increases in COX-2-immunopositive neurons. In the parietal cortex, the attenuation of COX-2 induction was associated with reduced 8'-hydroxy-2'-deoxyguanozine immunoreactivity and retained microglial ramifcation index, which are markers of oxidative stress and neuroinfiammation, respectively. This study demonstrates for the first time that asphyxia elevates neuronal COX-2 expression in a piglet HIE model. Neuronal COX-2 induction may play region-specific roles in brain lesion progression during HIE development, and inhibition of this response may contribute to the antioxidant/anti-infiammatory neuroprotective effects of H2 treatment.

Neuronal tumour necrosis factor-α and interleukin-1ß expression in a porcine model of intracerebral haemorrhage: Modulation by U-74389G.

Tumour necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) are important mediators of intracerebral haemorrhage (ICH) inflammatory response. Lazaroids, established antioxidants and neuroprotectants, have been studied in several brain pathologies. The present study was designed to investigate: a) TNF-α and IL-1ß changes, in neurons and b) U-74389G effects, 4 and 24h after haematoma induction in a porcine model of intracerebral haemorrhage. In twenty male landrace pigs (swines) aged 135-150 days old, autologous whole blood was injected around the right basal ganglia territory; in ten of the pigs the lazaroid compound U-74389G was administered. Brain TNF-α and IL-1ß immunopositive neurons were determined by immunoarray techniques at 4 and 24h timepoints. After the haematoma induction the number of TNF-α immunopositive neurons ipsilateral to the haematoma was significantly higher compared to the contralateral site at 4h (p<0.0005), while U-74389G significantly reduced the number of TNF-α immunopositive neurons, ipsilateral to the haematoma, at 4h (p=0.002); at 24h, TNF-α immunopositive neurons were found significantly lower in the control group ipsilateral to the haematoma in comparison to 4h timepoint(p<0.0005). The number of IL-1ß immunopositive neurons at 4h after the hematoma induction was significantly higher ipsilateral to the haematoma site (p<0.0005). U-74389G had no statistical significant effect. TNF-α and IL-1ß, increase in neurons, 4h after the haematoma induction, ipsilateral to the haematoma site. The administration of the antioxidant compound U-74389G, results in early (at 4h) decrease of TNF-α immunopositive neurons but shows no statistical significant effect to IL-1ß immunopossitive neurons.

Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs.

BACKGROUND: The neurovascular unit encompasses the functional interactions of cerebrovascular and brain parenchymal cells necessary for the metabolic homeostasis of neurons. Previous studies indicated marked but only transient (1-4 h) reactive oxygen species-dependent neurovascular dysfunction in newborn pigs after severe hypoxic/ischemic (H/I) stress contributing to the neuronal injury after birth asphyxia. OBJECTIVES: Our major purpose was to determine if neurovascular dysfunction would also occur later, at 24 h after a milder H/I stress. We also tested if the putative hydroxyl radical scavenger hydrogen (H2) exerted neurovascular protection. METHODS: Anesthetized, ventilated piglets were assigned to three groups of 9 animals: time control, asphyxia/reventilation with air, and asphyxia/reventilation with air +2.1% H2 for 4 h. Asphyxia was induced by suspending ventilation for 8 min. Cerebrovascular reactivity (CR) of pial arterioles was determined using closed cranial window/intravital microscopy 24 h after asphyxia to the endothelium-dependent cerebrovascular stimulus hypercapnia, the neuronal function-dependent stimulus N-methyl-D-aspartate (NMDA), norepinephrine, and sodium nitroprusside. The brains were subjected to histopathology. RESULTS: Hemodynamic parameters, blood gases, and core temperature did not differ significantly among the experimental groups. In the early reventilation period, the recovery of electroencephalographic activity was significantly better in H2-treated animals. Asphyxia/reventilation severely attenuated CR to hypercapnia and NMDA; however, reactivity to norepinephrine and sodium nitroprusside were unaltered. H2 fully or partially preserved CR to hypercapnia or NMDA, respectively. Histopathology revealed modest neuroprotection afforded by H2. CONCLUSIONS: Severe stimulus-selective delayed neurovascular dysfunction develops and persists even after mild H/I stress. H2 alleviates this delayed neurovascular dysfunction that can contribute to its neuroprotective effect.

Regional Differences in the Neuronal Expression of Cyclooxygenase-2 (COX-2) in the Newborn Pig Brain.

Cyclooxygenase (COX)-2 is the major constitutively expressed COX isoform in the newborn brain. COX-2 derived prostanoids and reactive oxygen species appear to play a major role in the mechanism of perinatal hypoxic-ischemic injury in the newborn piglet, an accepted animal model of the human term neonate. The study aimed to quantitatively determine COX-2 immunopositive neurons in different brain regions in piglets under normoxic conditions (n=15), and 4 hours after 10 min asphyxia (n=11). Asphyxia did not induce significant changes in neuronal COX-2 expression of any studied brain areas. In contrast, there was a marked regional difference in all experimental groups. Thus, significant difference was observed between fronto-parietal and temporo-occipital regions: 59±4% and 67±3% versus 41±2%* and 31±3%* respectively (mean±SEM, data are pooled from all subjects, n=26, *p<0.05, vs. fronto-parietal region). In the hippocampus, COX-2 immunopositivity was rare (highest expression in CA1 region: 14±2%). The studied subcortical areas showed negligible COX-2 staining. Our findings suggest that asphyxia does not significantly alter the pattern of neuronal COX-2 expression in the early reventilation period. Furthermore, based on the striking differences observed in cortical neuronal COX-2 distribution, the contribution of COX-2 mediated neuronal injury after asphyxia may also show region-specific differences.

Evaluation of laser-speckle contrast image analysis techniques in the cortical microcirculation of piglets.

A new laser speckle-contrast analysis (LASCA) technique based on multi-exposure imaging was employed to simultaneously study pial arteriolar responses with cerebrocortical perfusion changes to various vasodilator (5-10% CO(2) ventilation, bradykinin (1-10 µM), N-methyl-D-aspartate (100 µM)) vasoconstrictor (10-100 µM noradrenaline, 1M KCl), or neutral (2.1% H(2) ventilation) stimuli as well as to asphyxia in the newborn piglet. Anesthetized, ventilated animals (n=20) were fitted with closed cranial windows. Multiple exposure laser-speckle image series (1-100 ms) were obtained using a near infrared diode laser (λ=808 nm). The autocorrelation decay time (τ) of speckle fluctuations was determined over pial arterioles and parenchymal areas to express 1/τ being proportional to blood flow velocity by two different LASCA techniques: our novel multi-exposure or a single exposure (2 and 20 ms) approach. 1/τ values yielded by different LASCA techniques were not significantly different at most points. LASCA easily detected both increases and decreases in cortical blood flow (CoBF). Cortical 1/τ changes to hypercapnia closely matched quantitative CoBF data determined previously, and were also in accordance with increases of pial arteriolar blood flow, calculated from arteriolar flow velocity and cross sectional area changes. In summary, LASCA emerges as an appealing method to simultaneously study microvascular reactivity and cortical perfusion changes in the piglet.

[Ultrasonography in the diagnosis of ovarian and endometrial carcinoma]. / Az ultrahangvizsgálat szerepe a méhtest és a petefészek rosszindulatú daganatainak diagnosztikájában.

Transvaginal sonography has become a crucial part of the routine gynecologic examination. It offers now a great help in the diagnosis of almost all gynecological diseases. Transvaginal ultrasound means the first step in the diagnosis of the first two most common gynecological malignancies, and in many cases we are able to set up a diagnosis of its own. The purpose of this article is to emphasize the significant role of transvaginal ultrasonography in the diagnosis of these two dieseases mentioned above, with summarizing the latest developments regarding the capabilities of sonography (Doppler-technique, three-dimensional ultrasonograpy).

Hydrogen is neuroprotective and preserves cerebrovascular reactivity in asphyxiated newborn pigs.

Hydrogen (H2) has been reported to neutralize toxic reactive oxygen species. Oxidative stress is an important mechanism of neuronal damage after perinatal asphyxia. We examined whether 2.1% H2-supplemented room air (H2-RA) ventilation would preserve cerebrovascular reactivity (CR) and brain morphology after asphyxia/reventilation (A/R) in newborn pigs. Anesthetized, ventilated piglets were assigned to one of the following groups: A/R with RA or H2-RA ventilation (A/R-RA and A/R-H2-RA; n = 8 and 7, respectively) and respective time control groups (n = 9 and 7). Asphyxia was induced by suspending ventilation for 10 min, followed by reventilation with the respective gases for 4 h. After euthanasia, the brains were processed for neuropathological examination. Pial arteriolar diameter changes to graded hypercapnia (5-10% CO2 inhalation), and NMDA (10(-4) M) were determined using the closed cranial window/intravital microscopy before and 1 h after asphyxia. Neuropathology revealed that H2-RA ventilation significantly reduced neuronal injury induced by A/R in virtually all examined brain regions including the cerebral cortex, the hippocampus, basal ganglia, cerebellum, and the brainstem. Furthermore, H2-RA ventilation significantly increased CR to hypercapnia after A/R (% vasodilation was 23 ± 4% versus 41 ± 9%, p < 0.05). H2-RA ventilation did not affect reactive oxygen species-dependent CR to NMDA. In summary, H2-RA could be a promising approach to reduce the neurologic deficits after perinatal asphyxia.

PACAP and VIP differentially preserve neurovascular reactivity after global cerebral ischemia in newborn pigs.

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective in numerous models. Impairment of cerebrovascular reactivity (CR) contributes to ischemia/reperfusion (I/R)-induced neuronal damage. We tested whether PACAP and/or VIP preserve CR to I/R-sensitive dilator responses dependent on endothelial and/or neuronal function. Accordingly, changes in pial arteriolar diameters in response to hypercapnia (5-10% CO(2) ventilation) or topical N-methyl-d-aspartate (NMDA, 10(-4) M) were determined before and after I/R via intravital microscopy in anesthetized/ventilated piglets. Local pretreatment with non-vasoactive doses of PACAP (10(-8) M) and VIP (10(-9) M) prevented the attenuation of postischemic CR to hypercapnia; to 10% CO(2), the CR values were 27+/-8% vs 92+/-5% vs 88+/-13% (vehicle vs PACAP38 vs VIP, CR expressed as a percentage of the response before I/R, mean+/-SEM, n=8-8, p<0.05). PACAP, but not VIP, preserved CR to NMDA after I/R, with CR values of 31+/-10% vs 87+/-8% vs 35+/-12% (vehicle vs PACAP38 vs VIP, n=6-6). Unlike PACAP, VIP-induced vasodilation has not yet been investigated in the piglet. We tested whether VIP-induced arteriolar dilation was sensitive to inhibitors of cyclooxygenase (COX)-1 (SC-560, 1 mg/kg), COX-2 (NS-398, 1 mg/kg), indomethacin (5 mg/kg), and nitric oxide synthase (L-NAME, 15 mg/kg). VIP (10(-8)-10(-7)-10(-6) M, n=8) induced reproducible, dose-dependent vasodilation of 16+/-3%, 33+/-6%, and 70+/-8%. The response was unaffected by all drugs, except that the vasodilation to 10(-8) M VIP was abolished by SC-560 and indomethacin. In conclusion, PACAP and VIP differentially preserve postischemic CR; independent of their vasodilatory effect.