Sexual Dimorphism of Digit‐Length Ratio in a Viviparous Lizard: Influence of Age,but not Preservation State or Sex of Interuterine Twin

The existence of sex differences in digit‐length ratio (especially between the second and fourth digits, 2D:4D) is well established for humans from fetal life onwards, and has been linked with later performance. In rodents, the ratio is affected prenatally by exposure to androgens and estrogens, with some research suggesting an influence from sex of the neighbouring intrauterine fetus. However, the ubiquity and ontogenetic development of sexual dimorphism in digit ratios is not well established among wild amniotes. We report the first digit ratios for a gekkotan lizard, representing a speciose lineage in which viviparity has evolved independently from mammals and other reptiles. For the gecko Woodworthia “Otago/Southland”, in which up to two embryos develop in separate uteri, we found: (1) significant sexual dimorphism in adults in 2D:3D of the right hindlimb only (larger in males), but not in 2D:4D for any limb; (2) no dimorphism in ratios for young juveniles, with no influence of sex of the interuterine twin, and no relationship with sprint speed; (3) in preserved tissues of the same juveniles, no sexual dimorphism in ratios, but a change in relative lengths of some digits with preservation. The ontogenetic pattern might be explained by altered sex–steroid exposure at the transition to adulthood rather than during prenatal development. Our results support a phylogenetic hypothesis that sauropsids (birds and reptiles) differ from mammals in the direction of sex difference, if present. Experiments are needed to establish the roles of androgens and estrogens in establishing these sex differences in lizards. Anat Rec, 301:1169–1178, 2018. © 2018 Wiley Periodicals, Inc.     

Intraoperative hyperthermia and chemoradiotherapy for inoperable pancreatic carcinoma

The aim of this study was to evaluate the tolerability and the possible clinical benefit of intraoperative hyperthermia combined with multischedule chemotherapy and bypass surgery for the palliative treatment of inoperable pancreatic cancer. Ten patients with unresectable adenocarcinoma of the pancreas received preoperative chemotherapy [5-fluorouracil (5-FU)], bypass surgery and postoperative chemotherapy (5-FU, doxorubicin and cisplatin) plus sandostatin and radiotherapy (45 Gy, 25 fractions, 5 days a week). A single session of intraoperative hyperthermia was performed, by using a waveguide-type applicator (433 MHz). The tumour region was heated to 43-45 degrees C for up to 60 min, while 500 mg 5-FU was infused simultaneously through the gastroduodenal into the splenic artery. Postoperative recovery was uneventful for all patients. A brief instrument was developed for evaluating patients' quality of life. Chemotherapy-related toxicity included myelosuppression, vomiting, alopecia and increase in blood urea nitrogen (BUN), creatinine, SGOT and SGPT. Glucose and amylase determinations remained within normal limits throughout the whole treatment. There was a significant improvement before and 1 month after combined treatment in Eastern Cooperative Oncology Group (ECOG) status (1.8 +/- 0.4), Scott-Huskinsson pain scale (3.2 +/- 0.8) and quality of life score (30.5 +/- 6.7). No progressive disease was noticed and the median overall survival was 11 (SE = 2.4) months. There was also a significant (P = 0.002, Wilcoxon test) decrease in values of both serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), from 7.6 +/- 1.3 ng/mL and 875.7 +/- 104.8 U/mL to 3.5 +/- 0.7 ng/mL and 65.3 +/- 14.1 U/mL respectively. The first clinical results suggest a potential advantage of using combined intraoperative hyperthermia, chemotherapy and postoperative radiotherapy in the palliative treatment of the adenocarcinoma of the pancreas. The whole procedure seems to be free of perioperative morbidity, while the chemotherapy toxicity was rather moderate. However, the preliminary nature limits the general applicability of our results.     

Gender as a risk factor for contrast nephropathy: effects of hydration and N-acetylcysteine

BACKGROUND: In a few studies, N-acetylcysteine has been shown to prevent contrast-induced nephropathy in patients with chronic, stable renal failure undergoing elective procedures. Other studies have shown variable outcomes. Furthermore, the majority of prior studies have mainly studied men, and gender as a risk factor has not been studied. HYPOTHESIS: The study sought to evaluate the effectiveness of N-acetylcysteine and hydration in unselected patients with both acute and stable renal insufficiency (RI) undergoing urgent or elective cardiac or peripheral angiography. METHODS: We evaluated records of 146 patients with RI undergoing angiography. We compared patients receiving periprocedure hydration and acetylcysteine with patients who were only hydrated or received no pretreatment. We evaluated the 48-h change in serum creatinine between groups and further analyzed the effect of hydration and gender on outcomes. RESULTS: Demographics and baseline creatinine were similar between groups. Post procedure, the creatinine increased significantly in both groups, but less so in the acetylcysteine group (control: 0.35 +/- 0.08 mg/dl; acetylcysteine: 0.14 +/- 0.04 mg/dl, p < 0.05). When the control group was further stratified by hydration, the increase in creatinine for the hydrated patients was only 0.17 +/- 0.10 mg/dl compared with 0.54 +/- 0.12 mg/dl in patients with inadequate hydration. In the control group, women were more likely to receive no preprocedural hydration (59 vs. 40%), had a bigger rise in creatinine, received less protection from hydration alone, but were equally well protected by hydration plus acetylcysteine. In the acetylcysteine group, change in creatinine for women was minimal (+ 0.14 +/- 0.07 mg/dl) and not different from men (+ 0.15 +/- 0.05). CONCLUSION: Unselected patients with acute and chronic RI had no benefit from acetylcysteine beyond that seen with hydration alone. Gender may be a risk factor for contrast-induced nephropathy, with hydration offering less protection in women. Acetylcysteine (with hydration) seems to minimize the gender difference.     

Tissue oxygen monitoring during hemorrhagic shock and resuscitation: a comparison of lactated Ringer's solution,hypertonic saline dextran,and HBOC-201

BACKGROUND: The ideal resuscitation fluid for the trauma patient would be readily available to prehospital personnel, universally compatible, effective when given in small volumes, and capable of reversing tissue hypoxia in critical organ beds. Recently developed hemoglobin-based oxygen-carrying solutions possess many of these properties, but their ability to restore tissue oxygen after hemorrhagic shock has not been established. We postulated that a small-volume resuscitation with HBOC-201 (Biopure) would be more effective than either lactated Ringer's (LR) solution or hypertonic saline dextran (HSD) in restoring baseline tissue oxygen tension levels in selected tissue beds after hemorrhagic shock. We further hypothesized that changes in tissue oxygen tension measurements in the deltoid muscle would reflect the changes seen in the liver and could thus be used as a monitor of splanchnic resuscitation. METHODS: This study was a prospective, blinded, randomized resuscitation protocol using anesthetized swine (n = 30), and was modeled to approximate an urban prehospital clinical time course. After instrumentation and splenectomy, polarographic tissue oxygen probes were placed into the liver (liver PO2) and deltoid muscle (muscle PO2) for continuous tissue oxygen monitoring. Swine were hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg over 20 minutes, shock was maintained for another 20 minutes, and then 100% oxygen was administered. Animals were then randomized to receive one of three solutions: LR (12 mL/kg), HSD (4 mL/kg), or HBOC-201 (6 mL/kg). Physiologic variables were monitored continuously during all phases of the experiment and for 2 hours postresuscitation. RESULTS: At a MAP of 40 mm Hg, tissue PO2 was 20 mm Hg or less in both the liver and muscle beds. There were no significant differences in measured liver or muscle PO2 values after resuscitation with any of the three solutions in this model of hemorrhagic shock. When comparing the hemodynamic effects of resuscitation, the cardiac output was increased from shock values in all three animal groups with resuscitation, but was significantly higher in the animals resuscitated with HSD. Similarly, MAP was increased by all solutions during resuscitation, but remained significantly below baseline except in the group of animals receiving HBOC-201 (p < 0.01). HBOC-201 was most effective in both restoring and sustaining MAP and systolic blood pressure. There was excellent correlation between liver and deltoid muscle tissue oxygen values (r = 0.8, p < 0.0001). CONCLUSION: HBOC-201 can be administered safely in small doses and compared favorably to resuscitation with HSD and LR solution in this prehospital model of hemorrhagic shock. HBOC-201 is significantly more effective than HSD and LR solution in restoring MAP and systolic blood pressure to normal values. Deltoid muscle PO2 reflects liver PO2 and thus may serve as an index of the adequacy of resuscitation in critical tissue beds.     

Metabolomic fingerprinting of porcine lung tissue during pre-clinical prolonged ex vivo lung perfusion using in vivo SPME coupled with LC-HRMS

Normothermic ex vivo lung perfusion (NEVLP) has emerged as a modernized organ preservation technique that allows for detailed assessment of donor lung function prior to transplantation. The main goal of this study was to identify potential biomarkers of lung function and/or injury during a prolonged (19 h) NEVLP procedure using in vivo solid-phase microextraction (SPME) technology followed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The use of minimally invasive in vivo SPME fibers for repeated sampling of biological tissue permits the monitoring and evaluation of biochemical changes and alterations in the metabolomic profile of the lung. These in vivo SPME fibers were directly introduced into the lung and were also used to extract metabolites (on-site SPME) from fresh perfusate samples collected alongside lung samplings. A subsequent goal of the study was to assess the feasibility of SPME as an in vivo method in metabolomics studies, in comparison to the traditional in-lab metabolomics workflow. Several upregulated biochemical pathways involved in pro- and anti-inflammatory responses, as well as lipid metabolism, were observed during extended lung perfusion, especially between the 11th and 12th hours of the procedure, in both lung and perfusate samples. However, several unstable and/or short-lived metabolites, such as neuroprostanes, have been extracted from lung tissue in vivo using SPME fibers. On-site monitoring of the metabolomic profiles of both lung tissues through in vivo SPME and perfusate samples on site throughout the prolonged NEVLP procedure can be effectively performed using in vivo SPME technology.     

Cyclooxygenase-2 mRNA expression is associated with c-fos mRNA expression and transient water ADC reduction detected with diffusion MRI during acute focal ischemia in rats

Cyclooxygenase-2 (COX-2) plays an important role in the development of injury during cerebral ischemia and inhibition of its activity can reduce infarct size. COX-2 expression during acute ischemia is caused by activation of post-synaptic glutamate receptors, which occurs during spreading depression and ischemic depolarization. Both of these phenomena cause a reduction in the apparent diffusion coefficient of water (ADC), which can be detected with diffusion-weighted magnetic resonance imaging. The reduction is believed to be caused by cellular swelling that occurs as cells depolarize. The goal of this work was to determine the spatial relationship between cyclooxygenase-2 mRNA (cox-2) expression, c-fos mRNA expression and ADC reduction during acute focal cerebral ischemia. Adult rats were subjected to either 30- or 60-min permanent occlusion of the middle cerebral artery. A 2-Tesla scanner was used to acquire diffusion-weighted echo-planar images throughout the ischemic period, which were used to calculate ADC maps. Cox-2 and c-fos mRNA were detected with (35)S in situ hybridization. The results indicate that, for rats subjected to 60-min ischemia, cox-2 was observed in superficial layers of cortex, where transient ADC reduction and c-fos expression were observed. The same was true for most rats subjected to 30-min ischemia. However, in a small number of rats of the 30-min group, cox-2 mRNA expression was observed in regions exhibiting transient and persistent ADC reduction with no c-fos expression. The results suggest that cox-2 mRNA expression during acute MCA occlusion is caused by either or both spreading depression and transient ischemic depolarization.     

Mild hypothermia decreases the incidence of transient ADC reduction detected with diffusion MRI and expression of c-fos and hsp70 mRNA during acute focal ischemia in rats

The effects of mild hypothermia on the apparent diffusion coefficient of water (ADC) and expression of c-fos and hsp70 mRNA were examined during acute focal cerebral ischemia. Young adult rats were subjected to 60-min middle cerebral artery occlusion under either normothermia (37.5°C) or hypothermia (33°C). Diffusion-weighted echo-planar magnetic resonance imaging was used to monitor changes in ADC throughout the ischemic period. Perfusion MRI with dysprosium contrast was used at the end of the ischemic period to verify that the occlusion was successful. C-fos and hsp70 mRNA expression were examined with in situ hybridization at the end of the ischemic period. The results indicate that the size of the region that exhibited reduced ADC was smaller during hypothermia than during normothermia. Hypothermia also decreased the frequency of occurrence of transient ADC reductions, especially in dorsal aspects of cortex. Expression of both c-fos and hsp70 mRNA were markedly reduced by hypothermia. Transient ADC reduction and c-fos expression are associated with spreading depression, which is believed to contribute to lesion expansion during acute focal ischemia. The results suggest that part of the neuroprotective effect of hypothermia may be due to a reduced incidence of spreading depression.     

Prognostic Value of Computed Tomography Versus Echocardiography Derived Right to Left Ventricular Diameter Ratio in Acute Pulmonary Embolism

BackgroundComputed Tomography (CT) Pulmonary Angiography is the most commonly used diagnostic study for acute pulmonary embolism (PE). Echocardiogram (ECHO) is also used for risk stratification in acute PE, however the diagnostic performance of CT versus ECHO for risk stratification remains unclear.MethodsCT and ECHO right ventricle (RV) and left ventricle (LV) diameters were measured in a retrospective cohort of patients with acute PE. RV:LV diameter ratios were calculated and correlation between CT and ECHO RV:LV ratio was assessed. Sensitivity and specificity for the composite adverse events endpoint of mortality, respiratory failure requiring intubation, cardiac arrest, or shock requiring vasopressors within 30 days of admission were assessed for CT or ECHO derived RV:LV ratio alone and in combination with biomarkers (troponin or B-type natriuretic peptide).ResultsA total of 74 subjects met the inclusion criteria and had a mean age of 62±18 years. The proportion of patients with RV:LV >1 was similar when comparing CT (37.8%) versus ECHO (33.8%) (P = 0.61). A statistically significant correlation was found between CT derived and ECHO derived RV:LV diameter ratio (r = 0.832, P < 0.001). The sensitivity and specificity to predict 30-day composite adverse events for CT versus ECHO derived RV:LV diameter ratio >1 together with positive biomarker status was similar with sensitivity and specificity of 87% and 41% versus 87% and 42%, respectively.ConclusionsIn patients with acute PE, CT and ECHO RV:LV diameter ratio correlate well and identify similar proportion of PE patients at risk for early adverse events. These findings may streamline risk stratification of patients with acute PE.     

Transient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats

Cerebral ischemia induces immediate early genes such as c-fos and stress genes such as hsp70. In this study, the spatial relationships between c-fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion magnetic resonance (MR) imaging were examined. The middle cerebral artery (MCA) of young adult rats was occluded for 30 or 60 min. Diffusion MR (D-MR) images were acquired continuously during the ischemic period and dysprosium-contrast perfusion (P-MR) images were acquired at the end of the ischemic period. C-fos and hsp70 mRNA expression were examined with in situ hybridization. The most significant finding of this work was that for both durations of ischemia, c-fos induction was observed in cortical and sub-cortical regions exhibiting a transient reduction in the apparent diffusion coefficient of water (ADC). Transients which occurred on a time scale of 3 min may have been caused by spreading depression. Those occurring on a 10-min time scale may have been caused by an initial reduction in blood flow with occlusion that was followed by an ischemia-induced increase in collateral blood flow. P-MR imaging showed that perfusion in c-fos positive regions was higher than in regions with persistently reduced ADC. Hsp70 induction did not correlate with transient ADC reduction. It was induced in the MCA territory in regions showing persistent ADC changes, with induction being greatest at the periphery of these regions. It was also induced in regions that exhibited both spontaneous reversal of the diffusion changes and decreased perfusion.