Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience

Postoperative serum cortisol is used as an indicator of Cushing’s disease (CD) remission following transsphenoidal surgery (TSS) and guides (controversially) the need for immediate adjuvant treatment for CD. We investigated postoperative cortisol and adrenocorticotropic hormone (ACTH) levels as predictors of remission/recurrence in CD in a large retrospective cohort of patients with pathologically confirmed CD, over 6 years at a single institution. Midnight and morning cortisol, and ACTH at 24–48 h postoperatively (>24 h after last hydrocortisone dose) were measured. Remission was defined as normal 24-h urine free cortisol, normal midnight salivary cortisol, a normal dexamethasone-corticotropin releasing hormone (CRH) test or continued need for hydrocortisone, assessed periodically. Statistical analysis was performed using PASW 18. Follow up data was available for 52 patients (38 females and 14 males), median follow up was 16.5 month (range 2–143 months), median age was 45 years (range 21–72 years), 28 tumors were microadenomas and 16 were macroadenomas, and in eight cases no tumor was observed on magnetic resonance imaging. No patient with postoperative cortisol levels >10 mcg/dl were found to be in remission. Ten of the 52 patients with cortisol >10 mcg/dl by postoperative day 1–2 underwent a second TSS within 7 days. Forty-three patients (82.7 %) achieved CD remission (36 after one TSS and 7 after a second early TSS) and six patients suffered disease recurrence (mean 39.2 ± 52.4 months). An immediate second TSS induced additional hormonal deficiencies (diabetes insipidus) in three patients with no surgical complications. Persistent disease was noted in nine patients despite three patients having an immediate second TSS. Positive predictive value for remission of cortisol <2 mcg/dl and ACTH <5 pg/ml was 100 %. Cortisol and ACTH levels (at all postoperative time points and at 2 months) were correlated (r = 0.37, P < 0.001). Nadir serum cortisol of ≤2 mcg/dl and ACTH <5 pg/ml predicted remission (P < 0.005), but no level predicted lack of recurrence. Immediate postoperative ACTH/cortisol did not predict length of remission. No patients with postoperative cortisol >10 mcg/dl were observed to have delayed remission; all required additional treatment. There was no significant difference in age, body mass index, tumor size and length of follow-up between postoperative cortisol groups: cortisol ≤2 mcg/dl, cortisol >5 mcg/dl and cortisol >10 mcg/dl. Immediate postoperative cortisol levels should routinely be obtained in CD patients post TSS, until better tools to identify early remission are available. Immediate repeat TSS could be beneficial in patients with cortisol >10 mcg/dl and positive CD pathology: our combined (micro- and macroadenomas) remission rate with this approach was 82.7 %. ACTH measurements correlate well with cortisol. However, because no single cortisol or ACTH cutoff value excludes all recurrences, patients require long-term clinical and biochemical follow-up. Further research is needed in this area.     

Prevalence of gastric varices and results of sclerotherapy with N-butyl 2 cyanoacrylate for controlling acute gastric variceal bleeding

AIM: To study the prevalence, predictors and control of bleeding following N-butyl 2 cyanoacrylate (NBC) sclerotherapy of gastric varix (GV). METHODS: We analyzed case records of 1436 patients with portal hypertension, who underwent endoscopy during the past five years for variceal screening or upper gastrointestinal (GI) bleeding. Fifty patients with bleeding GV underwent sclerotherapy with a mean of 2 mL NBC for control of bleeding. Outcome parameters were primary hemostasis (bleeding control within the first 48 h), recurrent bleeding (after 48 h of esophago- gastro-duodenoscopy) and in-hospital mortality were analyzed. RESULTS: The prevalence of GV in patients with portal hypertension was 15% (220/1436) and the incidence of bleeding was 22.7% (50/220). Out of the 50 bleeding GV patients, isolated gastric varices (IGV-I) were seen in 22 (44%), gastro-oesophageal varices (GOV) on lesser curvature (GOV-Ⅰ) in 16 (32%), and GOV on greater curvature (GOV-Ⅱ) in 15 (30%). IGV-Ⅰ was seen in 44% (22/50) patients who had bleeding as compared to 23% (39/170) who did not have bleeding (P < 0.003). Primary hemostasis was achieved with NBC in all patients. Re-bleeding occurred in 7 (14%) patients after 48 h of initial sclerotherapy. Secondary hemostasis was achieved with repeat NBC sclerotherapy in 4/7 (57%). Three patients died after repeat sclerotherapy, one during transjugular intrahepatic portosystemic stem shunt (TIPSS), one during surgery and one due to uncontrolled bleeding. Treatment failure-related mortality rate was 6% (3/50). CONCLUSION: GV can be seen in 15% of patients withportal hypertension and the incidence of bleeding is 22.7%. NBC is highly effective in controlling GV bleeding. In hospital mortality of patients with bleeding GV is 6%.     

A systematic review and meta-analysis of cold in situ perfusion and preservation for pancreas transplantation

Background

This study aimed to identify the most effective solution for in situ perfusion/preservation of the pancreas in donation after brain death donors, in addition to optimal in situ flush volume(s) and route(s) during pancreas procurement.

Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors

N-methyl-d-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. Reducing copper availability by specific chelators (bathocuproine disulfonate, cuprizone) induced nondesensitizing NMDAR currents even at physiologically low glycine concentrations. This effect was mimicked by, and was not additive with, genetic ablation of cellular prion protein (PrP(C)), a key copper-binding protein in the CNS. Acute ablation of PrP(C) by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrP(C) interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aβ(1-42) (10 nM-5 μM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aβ(1-42), copper chelators, or PrP(C) inactivation all enhance the activity of glycine at the NMDAR, giving rise to pathologically large nondesensitizing steady-state NMDAR currents and neurotoxicity. We propose a physiological role for PrP(C), one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ(1-42) might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrP(C)-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor.     

A comparison of the presence of Theileria ovis by PCR amplification of their SSU rRNA gene in small ruminants from two provinces of Pakistan

ObjectiveTo compare the presence of Theileria ovis in small ruminants from two provinces of Pakistan and to determine the risk factors associated with the spread of theileriosis.MethodsIn present study, a total of 210 blood samples were collected from sheep (n=99) and goats (n=111) from 5 sampling sites in Punjab (Dera Ghazi Khan, Layyah, Multan and Rahim Yar Khan districts) and Khyber Pukhtoon Khwa (district Kohat) provinces, in Pakistan, from randomly selected herds. Data on the characteristics of the animals (species, gender, age, tick presence or absence, prior treatment for babesiosis) and the herd (location, size, species of animals, dogs associated with the herds, tick burden of dogs associated with the herds) was collected through questionnaires.ResultsTwelve blood samples (6% of total), 11 from district Kohat, produced the 520 base pairs DNA fragment specific for small subunit ribosomal RNA (ssu rRNA) gene of Theileria ovis, by PCR amplification, of which 11 were sheep and 1 was goat indicating that sheep are more significantly (P=0.001) prone to this parasite. On the other hand parasite was detected only in 2 out of 210 samples (1%) by blood smear screening confirming PCR as the reliable detection tool.ConclusionsPCR is more sensitive and reliable diagnostic tool for detection of Theileria sp. as compared to blood smear screening. Incidence of Theileria ovis is very high in Khyber Pukhtoon Khwa as compared to Punjab province. It was also observed that presence of ticks on animals was the only significant risk factor associated with the theileriosis in small ruminants.     

From the Cover: Ecosystem responses in the southern Caribbean Sea to global climate change

Over the last few decades, rising greenhouse gas emissions have promoted poleward expansion of the large-scale atmospheric Hadley circulation that dominates the Tropics, thereby affecting behavior of the Intertropical Convergence Zone (ITCZ) and North Atlantic Oscillation (NAO). Expression of these changes in tropical marine ecosystems is poorly understood because of sparse observational datasets. We link contemporary ecological changes in the southern Caribbean Sea to global climate change indices. Monthly observations from the CARIACO Ocean Time-Series between 1996 and 2010 document significant decadal scale trends, including a net sea surface temperature (SST) rise of ∼1.0 ± 0.14 °C (±SE), intensified stratification, reduced delivery of upwelled nutrients to surface waters, and diminished phytoplankton bloom intensities evident as overall declines in chlorophyll a concentrations (ΔChla = −2.8 ± 0.5%⋅y⁻¹) and net primary production (ΔNPP = −1.5 ± 0.3%⋅y⁻¹). Additionally, phytoplankton taxon dominance shifted from diatoms, dinoflagellates, and coccolithophorids to smaller taxa after 2004, whereas mesozooplankton biomass increased and commercial landings of planktivorous sardines collapsed. Collectively, our results reveal an ecological state change in this planktonic system. The weakening trend in Trade Winds (−1.9 ± 0.3%⋅y⁻¹) and dependent local variables are largely explained by trends in two climatic indices, namely the northward migration of the Azores High pressure center (descending branch of Hadley cell) by 1.12 ± 0.42°N latitude and the northeasterly progression of the ITCZ Atlantic centroid (ascending branch of Hadley cell), the March position of which shifted by about 800 km between 1996 and 2009.     

Tumour necrosis factor-related apoptosis-inducing ligand is a novel therapeutic target in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension is a fatal disease characterised by progressive narrowing of pulmonary arterioles, driven by aberrant cellular proliferation. Identification of key pathways in disease pathogenesis is required for the development of new-targeted therapies. We have previously reported tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic pulmonary arterial hypertension and animal models. Since TRAIL induces endothelial cell apoptosis and smooth muscle cell proliferation, we hypothesised that TRAIL is an important driver of disease in pulmonary arterial hypertension.MethodsWe characterised the expression of TRAIL in human and rodent pulmonary arterial hypertension and determined the effects of TRAIL on pulmonary artery smooth muscle cells (PASMCs) in vitro. Using genetic deletion, pharmacological overexpression, antibody blockade, and bone marrow transplant (BMT) chimera experiments we determined the direct pathogenic role of TRAIL in three independent rodent models of pulmonary arterial hypertension. We then tested the efficacy of inhibiting TRAIL in halting or regressing established disease in two preclinical models. Terminal phenotyping included cardiac catheterisation, echocardiography, and pulmonary vascular immunohistochemistry.FindingsTRAIL mRNA and protein expression was upregulated in PASMCs from patients with pulmonary arterial hypertension. In vitro, TRAIL was a mitogen for PASMCs. TRAIL-deficient mice were protected from both hypoxia-induced and diet-induced pulmonary arterial hypertension. Antibody blockade prevented rats from developing toxin-induced disease. In BMT chimeras, only mice with expression of TRAIL restricted to tissue developed pulmonary arterial hypertension. In rodents with established pulmonary arterial hypertension, an anti-TRAIL antibody reversed pulmonary vascular remodelling, through reducing proliferation and inducing apoptosis, improved pulmonary haemodynamics, and significantly improved survival.InterpretationOur studies are the first to determine the importance of TRAIL in the pathogenesis of pulmonary arterial hypertension and demonstrate its potential for translation into a novel therapeutic targetFundingBritish Heart Foundation.     

ProSeal laryngeal mask airway and endotracheal tube in elderly hypertensive patients undergoing routine surgical procedures: A comparison of hemodynamic parameters

Background/PurposeThe effects of ProSeal laryngeal mask airway (PLMA) removal and tracheal extubation on cardiovascular responses were studied in elderly hypertensive patients in a randomized double-blind study.MethodsA total of 60 elderly hypertensive American Society of Anesthesiologists I–II patients were randomly allocated to two groups (n = 30 of each) for PLMA insertion or endotracheal intubation. A standardized anesthetic sequence was used for induction and maintenance of anesthesia. The two groups were then compared for pressor response at the time of extubation/PLMA removal.ResultsIn PLMA group, heart rate and rate pressure product increased during PLMA removal but remained elevated for only 3 minutes while mean arterial pressure remained elevated for only 2 minutes. The elevations of heart rate, mean arterial pressure, and rate pressure product were exaggerated in the extubation group and persisted for more than 5 minutes. No complication was observed in any patient and no difficulty was encountered in insertion of PLMA in any patient.ConclusionElderly hypertensive patients are at risk of exaggerated pressor response at the time of extubation. PLMA removal is associated with fewer hemodynamic changes than tracheal extubation and should be preferred wherever possible.     

The possible role of the age of the human host in determining the localization of hydatid cysts

Cystic hydatid disease or cystic echinococcosis (CE) is a cyclozoonotic infection distributed world-wide. The morbidity attributable to the infection depends on the size of the cyst(s) and the organ(s) involved. The cysts are most commonly found in the liver and lungs but certain locations have been reported to be more prevalent in children and/or young adults than in older subjects. In order to identify the relationship, if any, between the age of the patient and the site of involvement, the age and cyst distribution of 92 cases of CE were analysed. Lung, brain, spinal and orbital hydatid cysts were more commonly seen in younger patients whereas other sites were preferentially involved in older patients. The factors that determine the final localization of the cysts are discussed. It is concluded that age somehow alters the host-parasite relationship and thus affects the organ distribution of the cysts.     

Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia.

Typically glands of prostatic adenocarcinoma have a single cell lining, although stratification can be seen in invasive carcinomas with a cribriform architecture, including ductal carcinoma. The presence and diagnostic significance of stratified cells within non-cribriform carcinomatous prostatic glands has not been well addressed. The histomorphological features and immunohistochemical profile of cases of non-cribriform prostatic adenocarcinoma with stratified malignant glandular epithelium were analyzed. These cases were identified from needle biopsy cases from the consultation files of one of the authors and from a review of 150 consecutive in-house needle biopsy cases of prostatic adenocarcinoma. Immunohistochemistry was performed utilizing antibodies reactive against high molecular weight cytokeratin (34betaE12), p63 and alpha-methylacyl-coenzyme-A racemase (AMACR). A total of 8 cases were identified, including 2 from the 150 consecutive in-house cases (1.3%). In 4 cases, the focus with glands having stratified epithelium was the sole carcinomatous component in the biopsy, while such a component represented 5-30% of the invasive carcinoma seen elsewhere in the remaining cases. The main attribute in all these foci was the presence of glandular profiles lined by several layers of epithelial cells with cytological and architectural features resembling flat or tufted high-grade prostatic intraepithelial neoplasia, but lacking basal cells as confirmed by negative 34betaE12 and/or p63 immunostains in all cases. The AMACR staining profile of the stratified foci was variable, with 4 foci showing positivity, and 3 foci being negative, including two cases that displayed AMACR positivity in adjacent non-stratified prostatic adenocarcinoma. Prostatic adenocarcinoma with stratified malignant glandular epithelium can be identified in prostate needle biopsy samples harboring non-cribriform prostatic adenocarcinoma and resembles glands with high-grade prostatic intraepithelial neoplasia. These 'PIN-like' carcinomas can present in pure form. Recognition of this pattern of prostatic adenocarcinoma is necessary to correctly diagnose such cases as invasive carcinoma.