MRI-based screening for structural definition of eligibility in clinical DMOAD trials: Rapid OsteoArthritis MRI Eligibility Score (ROAMES).

PURPOSE: Our aim was to introduce a simplified MRI instrument, Rapid OsteoArthritis MRI Eligibility Score (ROAMES), for defining structural eligibility of patients for inclusion in disease-modifying osteoarthritis drug trials using a tri-compartmental anatomic approach that enables stratification of knees into different structural phenotypes and includes diagnoses of exclusion. We also aimed to define overlap between phenotypes and determine reliability. METHODS: 50 knees from the Foundation for National Institutes of Health Osteoarthritis Biomarkers study, a nested case-control study within the Osteoarthritis Initiative, were selected within pre-defined definitions of phenotypes as either inflammatory, subchondral bone, meniscus/cartilage, atrophic or hypertrophic. A focused scoring instrument was developed covering cartilage, meniscal damage, inflammation and osteophytes. Diagnoses of exclusion were meniscal root tears, osteonecrosis, subchondral insufficiency fracture, tumors, malignant marrow infiltration and acute traumatic changes. Reliability was determined using weighted kappa statistics. Descriptive statistics were used for determining concordance between the a priori phenotypic definition and ROAMES and overlap between phenotypes. RESULTS: ROAMES identified 43 of 50 (86%) pre-defined phenotypes correctly. Of the 50 participants, 27 (54%) had no additional phenotypes other than the pre-defined phenotype. 18 (36%) had one and 5 (10%) had two additional phenotypes. None had three or four additional phenotypes. All features of ROAMES showed almost perfect agreement. One case with osteonecrosis and one with a tumor were detected. CONCLUSIONS: ROAMES is able to screen and stratify potentially eligible knees into different structural phenotypes and record relevant diagnoses of exclusion. Reliability of the instrument showed almost perfect agreement.

Clinical outcomes following unilateral adrenalectomy in patients with primary aldosteronism.

BACKGROUND: In approximately half of cases of primary aldosteronism (PA), the cause is a surgically-resectable unilateral aldosterone-producing adrenal adenoma. However, long-term data on surgical outcomes are sparse. AIM: We report on clinical outcomes post-adrenalectomy in a cohort of patients with PA who underwent surgery. DESIGN: Retrospective review of patients treated for PA in a single UK tertiary centre. METHODS: Of 120 consecutive patients investigated for PA, 52 (30 male, median age 54, range 30-74) underwent unilateral complete adrenalectomy. Blood pressure, number of antihypertensive medications, and serum potassium were recorded before adrenalectomy, and after a median follow-up period of 50 months (range 7-115). Recumbent renin and aldosterone were measured, in the absence of interfering antihypertensive medication, ≥3months after surgery, to determine if PA had been biochemically cured. RESULTS: Overall, blood pressure improved from a median (range) 160/95 mmHg (120/80-250/150) pre-operatively to 130/80 mmHg (110/70-160/93), P < 0.0001. 24/52 patients (46.2%) had cured hypertension, with a normal blood pressure post-operatively on no medication. 26/52 (50%) had improved hypertension. 2/52 patients (3.8%) showed no improvement in blood pressure post-operatively. Median (range) serum potassium level increased from 3.2 (2.3-4.7) mmol/l pre-operatively to 4.4 mmol/l (3.3-5.3) post-operatively, P < 0.0001). Median (range) number of antihypertensive medications used fell from 3 (0-6) pre- to 1 post-operatively (range 0-4), P < 0.0001. CONCLUSIONS: Unilateral adrenalectomy provides excellent long-term improvements in blood pressure control, polypharmacy and hypokalaemia in patients with lateralizing PA. These data may help inform discussions with patients contemplating surgery.

Heterogenous patterns of recovery of thirst in adult patients with adipsic diabetes insipidus.

BACKGROUND: The natural history of adipsic diabetes insipidus (ADI) is not well described, and reports of recovery of thirst are rare. DESIGN AND METHODS: Case histories presentation. ADI was identified by demonstrating absent thirst and arginine vasopressin (AVP) responses to hypertonic saline infusion. RESULTS: Twelve patients with ADI were identified (craniopharyngioma 5, anterior communicating artery aneurysm (ACOM) repair 4, congenital 1, neurosarcoidosis 1, prolactinoma 1). Three patients died. Six patients had permanent ADI. Three patients had recovery of thirst, with a heterogenous pattern of recovery. In the first case, ADI had developed after clipping of an ACOM aneurysm. Ten years after surgery; he sensed the return of thirst; repeated hypertonic saline infusion showed recovery of thirst and AVP secretion. In the second case, a 41-year-old female with an intrasellar craniopharyngioma developed post-operative ADI with persistent hypernatremia. Two years post-operatively, she complained of thirst, and hypertonic saline infusion showed normalization of thirst but absent AVP responses, confirming recovery of thirst, but with persistent diabetes insipidus (DI). In the third case, a 29-year-old Caucasian had craniotomy and radiotherapy for craniopharyngioma and developed ADI post-operatively. Eight years post-op, she presented with thirst, seizures and pNa of 112 mmol/l. Hypertonic saline infusion showed persistent DI but thirst responses typical of compulsive water drinking; she has had recurrent hyponatraemia since then. CONCLUSIONS: We report that 3/12 patients with ADI recovered thirst after longstanding adipsia with heterogenous pattern of recovery. Both the mortality of 25% and the recovery rate of 25% should be considered when planning long-term surveillance.

Chronic hypopituitarism is uncommon in survivors of aneurysmal subarachnoid haemorrhage.

OBJECTIVE: The incidence of hypopituitarism after aneurysmal subarachnoid haemorrhage (SAH) is unclear from the conflicting reports in the literature. As routine neuroendocrine screening for hypopituitarism for all patients would be costly and logistically difficult, there is a need for precise data on the frequency of hypopituitarism and on factors which might predict the later development of pituitary dysfunction. We aimed to: (i) Establish the incidence of long-term hypopituitarism in patients with aneurysmal SAH. (ii) Determine whether data from patients' acute admission with SAH could predict the occurrence of long-term hypopituitarism. DESIGN: One hundred patients were studied prospectively from the time of presentation with acute SAH. Plasma cortisol, plasma sodium and a variety of clinical and haemodynamic parameters were sequentially measured for the first 12 days of their acute admission. Forty-one patients then underwent dynamic pituitary testing at median 15 months following SAH (range 7-30 months), with insulin tolerance test (ITT) or, if contraindicated, a glucagon stimulation test (GST) plus short synacthen test (SST). If symptoms of cranial diabetes insipidus (CDI) were present, a water deprivation test was also performed. RESULTS: Forty-one patients attended for follow-up dynamic pituitary testing. Although 14 of 100 had acute glucocorticoid deficiency immediately following SAH, only two of 41 had long-term adrenocorticotrophic hormone (ACTH) deficiency and four of 41 had growth hormone (GH) deficiency. None were hypothyroid or gonadotrophin deficient. None had chronic CDI or hyponatraemia. There was no association between acute glucocorticoid deficiency, acute CDI or acute hyponatraemia and long-term pituitary dysfunction. CONCLUSION: Both anterior and posterior hypopituitarism are very uncommon following SAH and are not predicted by acute clinical, haemodynamic or endocrinological parameters. Routine neuroendocrine screening is not justified in SAH patients.

Susceptibility artifacts detected on 3T MRI of the knee: frequency, change over time and associations with radiographic findings: data from the joints on glucosamine study.

OBJECTIVE: To determine the prevalence of intraarticular susceptibility artifacts and to detect longitudinal changes in the artifacts, on 3T magnetic resonance imaging (MRI) of the knee in a cohort of patients with knee pain, and to assess the association of susceptibility artifacts with radiographic intraarticular calcifications. DESIGN: Three hundred and forty-six knees of 177 subjects aged 35-65 were included. 3T MRI was performed at baseline and at 6 months. Baseline radiographs were assessed for presence/absence of linear/punctate calcifications within the tibiofemoral joint (TFJ) space. Corresponding MRIs were assessed for susceptibility artifacts (i.e., linear/punctate hypointensities) in the TFJ space on coronal dual-echo steady-state (DESS) sequences. Kappa statistics were applied to determine agreement between findings on baseline DESS and radiography. Changes in artifacts over time were recorded. RESULTS: In the medial compartment, 13 (4%) of the knees showed susceptibility artifacts at baseline. Six knees had persistent artifacts and six knees had incident artifacts at follow-up. Agreement between DESS and radiography was κ = 0.18 (-0.15, 0.51) in the medial compartment. Frequency of artifacts in the lateral compartment was low (2%). CONCLUSION: Susceptibility artifacts detected on knee MRI are not frequent, and likely correspond to vacuum phenomena as they commonly change over time and are not associated with intraarticular calcifications. Radiologists should be aware of these artifacts as they can interfere with cartilage segmentation.

Trajectory of cartilage loss within 4 years of knee replacement--a nested case-control study from the osteoarthritis initiative.

OBJECTIVE: Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior to KR vs non-replaced controls. METHODS: A nested case-control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence (T0), and at 1-4 years prior to T0 (T-1 to T-4). Cartilage loss between cases and controls was compared using paired t-tests and conditional logistic regression. RESULTS: One hundred and eighty-nine knees of 164 OAI participants [55% women; age 64 ± 8.7; body mass index (BMI) 29 ± 4.5] had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls [94 ± 137 vs 55 ± 104 µm; P = 0.0017 (paired t); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08-1.70)]. The discrimination was stronger for T-2 → T0 [OR 1.61 (1.33-1.95), n = 127] than for T-1 → T0, and was not statistically significant for intervals prior to T-2 [i.e., T-4 → T-2, OR 0.97 (0.67-1.41), n = 60]. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI. CONCLUSIONS: In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined.

Acute glucocorticoid deficiency and diabetes insipidus are common after acute traumatic brain injury and predict mortality.

CONTEXT: Published data demonstrates that hypopituitarism is common after traumatic brain injury (TBI). Hormone deficiencies are transient in many, but the natural history of the acute changes after TBI has not been documented. In addition, it is not clear whether there are any early parameters that accurately predict the development of permanent hypopituitarism. OBJECTIVES: There were 3 main objectives of this study: 1) to describe the natural history of plasma cortisol (PC) changes and sodium balance after TBI; 2) to identify whether acute hypocortisolemia or cranial diabetes insipidus (CDI) predict mortality; and 3) to identify whether the acute pituitary dysfunction predicts the development of chronic anterior hypopituitarism. DESIGN: Each TBI patient underwent sequential measurement of PC, plasma sodium, urine osmolality, and fluid balance after TBI. All other anterior pituitary hormones were measured on day 10 after TBI. The results from 15 surgical comparisons defined a PC less than 300 nmol/L as inappropriately low for an acutely ill patient. CDI was diagnosed according to standard criteria. Surviving TBI patients underwent dynamic anterior pituitary testing at least 6 months after TBI. SETTING: The patients were recruited from the Irish National Neurosurgery Centre. PATIENTS: One hundred sequential TBI patients were recruited. Fifteen patients admitted to Intensive Therapy Unit (ITU) after major surgery were recruited as comparison patients. MAIN OUTCOME MEASURES: PC in TBI patients was compared with that of comparison patients. The mortality rate was compared between TBI patients with and without acute hypocortisolemia. Results of follow-up dynamic pituitary testing were compared between those with and without acute hypocortisolemia. RESULTS: Most of the TBI patients (78%) developed inappropriately low PC after TBI. Low PC and CDI were predictive of mortality. Thirty-nine percent of the patients who had follow-up testing had at least 1 pituitary hormone deficit, all of whom had had previous acute hypocortisolemia or CDI. CONCLUSIONS: Acute hypocortisolemia and CDI are predictive of mortality and long-term pituitary deficits in TBI.

Anterior hypopituitarism is rare and autoimmune disease is common in adults with idiopathic central diabetes insipidus.

OBJECTIVE: Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood-onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. DESIGN AND PATIENTS: We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function. RESULTS: One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty-three percent had at least one autoimmune disease in addition to central diabetes insipidus. CONCLUSIONS: Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.

Pituitary dysfunction following traumatic brain injury or subarachnoid haemorrhage - in "Endocrine Management in the Intensive Care Unit".

Traumatic brain injury and subarachnoid haemorrhage are important causes of morbidity and mortality in the developed world. There is a large body of evidence that demonstrates that both conditions may adversely affect pituitary function in both the acute and chronic phases of recovery. Diagnosis of hypopituitarism and accurate treatment of pituitary disorders offers the opportunity to improve mortality and outcome in both traumatic brain injury and subarachnoid haemorrhage. In this article, we will review the history and pathophysiology of pituitary function in the acute phase following traumatic brain injury and subarachnoid haemorrhage, and we will discuss in detail three key aspects of pituitary dysfunction which occur in the early course of TBI; acute cortisol deficiency, diabetes insipidus and SIAD.

The association of osteoarthritis risk factors with localized, regional and diffuse knee pain.

OBJECTIVE: To identify determinants of different patterns of knee pain with a focus on risk factors for knee osteoarthritis (OA). DESIGN: The Knee Pain Map is an interviewer-administered assessment that asks subjects to characterize their knee pain as localized, regional, or diffuse. A total of 2677 participants from the Osteoarthritis Initiative were studied. We used multinomial logistic regression to examine the relationship between risk factors for OA and knee pain patterns. We examined the bivariate and multivariate relationships of knee pain pattern with age, body mass index (BMI), sex, race, family history of total joint replacement, knee injury, knee surgery, and hand OA. RESULTS: We compared 2462 knees with pain to 1805 knees without pain. In the bivariate analysis, age, sex, BMI, injury, surgery, and hand OA were associated with at least one pain pattern. In the multivariate model, all of these variables remained significantly associated with at least one pattern. When compared to knees without pain, higher BMI, injury, and surgery were associated with all patterns. BMI had its strongest association with diffuse pain. Older age was less likely to be associated with localized pain while female sex was associated with regional pain. CONCLUSIONS: We have shown that specific OA risk factors are associated with different knee pain patterns. Better understanding of the relationship between OA risk factors and knee pain patterns may help to characterize the heterogeneous subsets of knee OA.

Thyrotoxic periodic paralysis due to excessive L-thyroxine replacement in a Caucasian man.

Thyrotoxic periodic paralysis is a potentially fatal complication of hyperthyroidism, more common in Asian races, which is defined by a massive intracellular flux of potassium. This leads to profound hypokalaemia and muscle paralysis. Although the paralysis is temporary, it may be lethal if not diagnosed and treated rapidly, as profound hypokalaemia may induce respiratory muscle paralysis or cardiac arrest. The condition is often misdiagnosed in the west due to its comparative rarity in Caucasians; however it is now increasingly described in Caucasians and is also being seen with increasing frequency in western hospitals due to increasing immigration and population mobility. Here we describe the case of a patient with panhypopituitarism due to a craniopharyngioma, who developed thyrotoxic periodic paralysis due to excessive L-thyroxine replacement. This disorder has been described in Asian subjects but, to our knowledge, thyrotoxic periodic paralysis secondary to excessive L-thyroxine replacement has never been described in Caucasians.

Estrogen-derived steroidal metal complexes: agents for cellular delivery of metal centers to estrogen receptor-positive cells.

Targeted cellular delivery of drugs to specific tissues is an important goal in biomedical chemistry. Achieving this requires harnessing and applying molecular-level recognition events prevalent in (or specific to) the desired tissue type. Tissues rich in estrogen receptors (ERs), which include many types of breast cancer, accumulate molecules that have high binding affinities for these receptors. Therefore, molecules that (i) bind to the ER, (ii) have favorable cellular transport properties, and (iii) contain a second functionality (such as a center that may be used for diagnostic imaging or medical therapy) are exciting synthetic targets in the field of drug delivery. To this end, we have prepared a range of metallo-estrogens based on 17alpha-ethynylestradiol and examined their binding to the ER both as isolated receptor and in whole cell assays (ER positive MCF-7 cells). Estrogens functionalized with metal binding units are prepared by palladium-catalyzed cross-coupling reactions and a wide range of metal centers introduced readily. All the compounds prepared and tested exhibit effective binding to the estrogen receptor and are delivered across the cell membrane into MCF-7 cells. In the whole cell assays, despite their monocationic nature, the palladium and platinum complexes prepared exhibit similar (and even enhanced) receptor binding affinities compared to their corresponding neutral free ligands. It is unprecedented for a higher ER binding affinity to be observed for a cationic complex than for its metal-free ligand.