Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss-of-function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b-B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b^−/−) mice. Although male and female Mpig6b^−/− mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b^−/− mice developed progressive splenomegaly starting at 8 weeks of age. Micro–computed tomography (μCT) of femurs showed that female Mpig6b^−/− mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b^−/− mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10-week-old female Mpig6b^−/− mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b^−/− mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b^−/− mice also demonstrated improvement in spleen weight compared to sham-operated Mpig6b^−/− mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte-driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Stone extraction with loop ureteral catheter versus ureteroscopy in small distal ureteral stones—retrospective comparison of 547 consecutive patients

BackgroundTo evaluate whether stone extraction with a loop ureteral catheter (LUC) in distal ureteral stones is associated with a higher frequency of ureteral strictures compared to treatment with primary ureteroscopic stone removal (p-URS) or ureteroscopic laser lithotripsy (l-URS).MethodsFive hundred and forty-seven consecutive patients were primarily endourologically treated for distal ureteral stones in our department between 2005 and 2019 and included in the study protocol. Data was retrospectively obtained from the patients’ charts and medical reports as well as from office-based urologists. Data analysis was performed using Fisher’s exact test, Mann-Whitney test or Student’s t-test as appropriate. A level of P<0.05 was assigned statistical significance.ResultsFour hundred and twelve patients were treated by URS (p-URS n=304, l-URS n=108) and another 135 by LUC stone extraction. Median follow-up was 41 [2–159] months. There was no difference between the groups concerning age, gender, proportion of patients with ureteral stenting, operating time, hospitalization or readmission rates. The number of ureteric strictures was small in all procedures [n=3 (1.0%) in p-URS, n=2 (1.9%) in l-URS and n=2 (1.5%) in LUC] and there was no difference between the groups concerning this serious complication (p-URS vs. LUC: P=0.6465; l-URS vs. LUC: P=0.9999).ConclusionsIn small distal stones, LUC stone extraction still is an alternative to URS procedures in stone management with comparable results concerning postinterventional ureteral strictures. In experienced hands, it still has its value in accurately selected patients.     

Analyzing the learning curves of a novice and an experienced urologist for transrectal magnetic resonance imaging-ultrasound fusion prostate biopsy

BackgroundThe aim of the current study was to evaluate and compare the learning curves of transrectal magnetic resonance imaging-ultrasound fusion biopsy for two urologists with different backgrounds (Operator 1: experienced, self-trained and Operator 2: novice, trained by a mentor/MRI reading courses).MethodsA cohort of 400 patients who underwent fusion prostate biopsy in our department was analyzed. The learning curves were assessed in terms of overall and clinically significant prostate cancer (PCa) detection rates, percentage of positive biopsy cores/targeted and the percentage of PCa tissue on positive targeted cores.ResultsIncreasing trends were observed for both urologists in terms of all biopsy outcomes during the study time. For the novice urologist, a significant increase was observed for overall PCa detection rate, but not for clinically significant disease (25.44%, P=0.04/15%, P=0.145). Operator 1 showed an increasing diagnosis yield of clinically significant disease up to 104 cases. Similar cancer detection rates were observed when comparing the first and last biopsies performed by both operators. Multivariate analysis adjusted for age, PSA, prostate volume, lesion diameter and PIRADS score showed an increase of PCa detection with 51% for every 52 biopsies performed (P=0.022).ConclusionsWhen starting with magnetic resonance imaging-ultrasound fusion prostate biopsy, mentoring and prostate magnetic resonance imaging reading training allow a novice urologist to demonstrate a good initial PCa detection rate. After about 52 cases, he reached a stable PCa and clinically significant PCa detection rate, that was similar to that of an experienced urologist.     

Involvement of Fusarium spp. in fungal keratitis

Members of the filamentous fungal genus Fusarium are among the agents most frequently causing keratomycosis in humans. Fusarium keratitis is most common among agricultural workers in geographical regions with hot, humid, tropical or semi-tropical climates, but can occur more rarely in countries with temperate climates, such as Hungary. Keratitis is usually treated with a topical antifungal agent, sometimes in combination with sub-conjunctival injections and/or antimycotic agents, but therapeutic keratoplasty may be needed for patients whose corneal infection does not resolve. Early and accurate diagnosis, coupled with appropriate antifungal therapy, is crucial for improving the chances of complete recovery.     

Intracytoplasmic sperm injection in the mouse

Intracytoplasmic sperm injection (ICSI) into mouse oocytes involvesa very low survival rate. This study was designed to determinewhy ICSI frequently fails in mice. Metaphase II oocytes wereobtained from superovulated 4–6 week old F₁ hybrid mice.Spermatozoa were retrieved from the epididymis of 12–14week old F₁ hybrid mice. The spiked microinjection pipette usedto inject a spermatozoon into the ooplasm had outer and innerdiameters of 10 and 8 µm respectively. The oocytes usedin the first part of the study were not activated (group 1).Some oocytes were incubated with calcium ionophore for 5 min(group 2). The injected oocytes were evaluated 6, 20, 48 and72 h after injection. A total of 143 eggs in each group underwentICSI. In group 1, sperm heads escaped into the perivitellinespace. In all, 63 (47%) of the remaining oocytes were damagedduring the injection or had degenerated by the first evaluation.The survival rate was 53%, but fertilization did not occur.In group 2, 31 oocytes (22%) were damaged during microinjectionor soon degenerated. Two oocytes underwent accidental subzonalinsemination. Six oocytes were fertilized (4.2%) among the 78%of survivors. After injection, the sperm tail was found in thecytoplasm (27 and 31% in groups 1 and 2 respectively), the perivitellinespace (45% in both groups) or protruding through the zona pellucida(28 and 23% respectively). More oocytes degenerated when thetail remained in the cytoplasm, i.e. 78% in group 1 and 36%in group 2.     

Impact of a physical fitness program in a blue-collar workforce

The purpose of this study was to examine the impact of participation in the Wellness--Paths to Health Physical Fitness Program on selected physiological and personal health variables including blood pressure, pulse, body weight, trunk flexibility, cardiovascular endurance, abdominal strength, percent body fat and a cumulative fitness score. The subjects (N = 129) of this study were divided into four levels of adherence to this exercise-based health program. Data analysis examined relationships between adherence levels and changes in the selected physiological and personal health variables across two measures. In addition, data from high-risk participants were analyzed. The results of the study found statistical significant changes in the selected variables between repeated assessment measures. In addition, statistically significant relationships were found between levels of adherence to the program and six of the dependent variables.     

Total sleep deprivation decreases saliva ghrelin levels in adolescents

Ghrelin, a regulator of food intake and energy expenditure, has been shown to be associated with insufficient sleep. The goal of the present study was to investigate the effect of a single night of total sleep deprivation on fasting saliva ghrelin and on nocturnal variation of saliva ghrelin concentration. A further aim of the study was to investigate the influence of body mass index on changes in saliva ghrelin levels. Altogether 35 adolescents (18 boys; age: 13.8 ± 1.14 years) were studied on two subsequent days (sleep and total sleep deprivation). Saliva samples were collected during the two experimental nights at 21:00 hours, 01:00 hours and 06:00 hours. Total-ghrelin concentration showed a continuous increase from the evening until 06:00 hours. This increase was blunted significantly (p = 0.003) by total sleep deprivation. Total-ghrelin level was significantly lower (p = 0.02) during total sleep deprivation at 06:00 hours (median 403.6 pg ml⁻¹; 95% confidence interval: 343.1–468.9 pg ml⁻¹) as compared with values during the sleep condition (median 471.2 pg ml⁻¹; 95% confidence interval: 205.4–1578.7 pg ml⁻¹). Acyl-ghrelin levels did not present any change at the three time points, and were not affected by total sleep deprivation. Stratifying the study population according to body mass index (normal weight and overweight/obese groups), the blunting effect of total sleep deprivation was more pronounced in the obese/overweight group (sleep: median 428.2 pg ml⁻¹; 95% confidence interval: 331.3–606.9 pg ml⁻¹ versus total sleep deprivation: median 333.1 pg ml⁻¹; 95% confidence interval: 261.5–412.9 pg ml⁻¹; p = 0.0479). Saliva total-ghrelin concentrations gradually increased during the night, and total sleep deprivation significantly blunted this increase. This blunting effect was mainly observed in subjects with overweight/obesity. The physiological and clinical implications of the present observation are to be clarified by further studies.     

Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2-pyrrolinodoxorubicin

The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate carcinomas. AN-207 consists of the agonist [D-Lys(6)]LH-RH linked to 2-pyrrolino-doxorubicin, an intensely potent derivative of doxorubicin. In the first experiment, 2-pyrrolinodoxorubicin was administered at a concentration of 50 nmol/kg, as a single drug (AN-201) and as an unconjugated mixture with [D-Lys(6)]LH-RH or conjugated to the carrier [D-Lys(6)]LH-RH (AN-207). Following the second administration of radical AN-201 alone or mixed with the carrier, all rats died with signs of general toxicity, but all animals treated with the conjugate AN-207, survived. After 5 weeks of treatment with a total dose of 150 nmol/kg AN-207, the tumors regressed from an initial volume of 8.35 +/- 1.7 cm(3) to 4.47 +/- 0.8 cm(3), while tumors in the control group measured 17.84 +/- 2.2 cm(3). The therapy with AN-207 also significantly reduced tumor weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was between 3.9 and 4.5 cm(3). After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 +/- 0.51 cm(3), whereas 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 +/- 1.4 cm(3) and 6.74 +/- 1 cm(3), respectively), as compared to 15.6 +/- 2.2 cm(3) for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treatment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is an effective antitumor agent. Our work indicates that the cytotoxic analog AN-207 is much less toxic than the antineoplastic radical (AN-201) incorporated, and significantly more active in inhibiting tumor growth. Further development of approaches based on targeted cytotoxic analog AN-207 may lead to major improvements in current palliative therapy of prostate cancer.     

Importance of platelet functions in Alzheimer's disease

The function of platelets of patients with Alzheimer's disease has been characterized. The shape of platelets is more spherical and the initial rate of platelet aggregation caused by different agonists measured in plasma is faster in the case of Alzheimer's disease and senile dementia of the Alzheimer-type than that of other demented patients: multi infarct dementia and probable vascular dementia. Although fast aggregation is characteristic of activated platelets but the Alzheimer platelets are not hypersensitive. The activation of Alzheimer platelets makes the velocity of ADP induced aggregation slower and it is different than the behaviour of normal activated platelets. The shape-associated parameter and the initial rate of 50 microM ADP-induced aggregation of platelets non-activated and activated by cytochrome C are recommended for establishing the diagnosis of Alzheimer's disease and senile dementia of the Alzheimer-type. The evaluation of these parameters has been discussed. The cytochrome C may be useful to normalize the function of Alzheimer platelets in plasma, not only in vitro.     

Surgical management of villous and tubulovillous adenomas of the rectum]

One hundred four cases of middle and low rectal villous and tubulovillous adenomas have been operated on with transanal polypectomy (8), transanal endoscopic microsurgery--TEM (80), anterior rectum resection with double stapled straight sigmoideorectosomy (7), and deep rectum resection, bi-directional mucosectomy and hand sutured straight sigmoideoanostomy (9). The option of the authors to remove the tumours in 5 cm to the dentate line are the transanal polypectomy or transanal mucosectomy corresponding to their size. The transanal endoscopic microsurgical technic is recommended to manage the polyps smaller than 4 to 5 cm in the middle rectum. The best radicallity in removal of the circular, extended villous adenomas could be achieved with deep rectum resection, bi-directional mucosectomy and transanal straight, hand sewn sigmoideoanostomy.