Gross and histopathologic diagnoses from North Atlantic right whale Eubalaena glacialis mortalities between 2003 and 2018.

Seventy mortalities of North Atlantic right whales Eubalaena glacialis (NARW) were documented between 2003 and 2018 from Florida, USA, to the Gulf of St. Lawrence, Canada. These included 29 adults, 14 juveniles, 10 calves, and 17 of unknown age class. Females represented 65.5% (19/29) of known-sex adults. Fourteen cases had photos only; 56 carcasses received external examinations, 44 of which were also necropsied. Cause of death was determined in 43 cases, of which 38 (88.4%) were due to anthropogenic trauma: 22 (57.9%) from entanglement, and 16 (42.1%) from vessel strike. Gross and histopathologic lesions associated with entanglement were often severe and included deep lacerations caused by constricting line wraps around the flippers, flukes, and head/mouth; baleen plate mutilation; chronic extensive bone lesions from impinging line, and traumatic scoliosis resulting in compromised mobility in a calf. Chronically entangled whales were often in poor body condition and had increased cyamid burden, reflecting compromised health. Vessel strike blunt force injuries included skull and vertebral fractures, blubber and muscle contusions, and large blood clots. Propeller-induced wounds often caused extensive damage to blubber, muscle, viscera, and bone. Overall prevalence of NARW entanglement mortalities increased from 21% (1970-2002) to 51% during this study period. This demonstrates that despite mitigation efforts, entanglements and vessel strikes continue to inflict profound physical trauma and suffering on individual NARWs. These cumulative mortalities are also unsustainable at the population level, so urgent and aggressive intervention is needed to end anthropogenic mortality in this critically endangered species.

Multimodal functional and anatomic imaging identifies preclinical microvascular abnormalities in type 1 diabetes mellitus.

Structural and functional changes in the microcirculation in type 1 diabetes mellitus predict future end-organ damage and macrovascular events. We explored the utility of novel signal processing techniques to detect and track changes in ocular hemodynamics in patients with this disease. Twenty-four patients with uncomplicated type 1 diabetes mellitus and eighteen age- and sex-matched control subjects were studied. Doppler ultrasound was used to interrogate the carotid and ophthalmic arteries, and digital photography was used to image the retinal vasculature. Frequency analysis algorithms were applied to quantify velocity waveform structure and retinal photographic data at baseline and after inhalation of 100% O2. Frequency data were compared between groups. No significant differences were found in the resistive index between groups at baseline or after inhaled O2. Frequency analysis of Doppler flow velocity waveforms identified significant differences in bands 3-7 between patients and control subjects in data captured from the ophthalmic artery (P < 0.01 for each band). In response to inhaled O2, changes in frequency band amplitudes were significantly greater in control subjects compared with patients (P < 0.05). Only control subjects demonstrated a positive correlation (R = 0.61) between changes in retinal vessel diameter and frequency band amplitudes derived from ophthalmic artery waveform data. The use of multimodal signal processing techniques applied to Doppler flow velocity waveforms and retinal photographic data identified preclinical changes in the ocular microcirculation in patients with uncomplicated diabetes mellitus. An impaired autoregulatory response of the retinal microvasculature may contribute to the future development of retinopathy in such patients.

Postcopulatory selection for dissimilar gametes maintains heterozygosity in the endangered North Atlantic right whale.

Although small populations are expected to lose genetic diversity through genetic drift and inbreeding, a number of mechanisms exist that could minimize this genetic decline. Examples include mate choice for unrelated mates and fertilization patterns biased toward genetically dissimilar gametes. Both processes have been widely documented, but the long-term implications have received little attention. Here, we combined over 25 years of field data with high-resolution genetic data to assess the long-term impacts of biased fertilization patterns in the endangered North Atlantic right whale. Offspring have higher levels of microsatellite heterozygosity than expected from this gene pool (effect size = 0.326, P < 0.011). This pattern is not due to precopulatory mate choice for genetically dissimilar mates (P < 0.600), but instead results from postcopulatory selection for gametes that are genetically dissimilar (effect size = 0.37, P < 0.003). The long-term implication is that heterozygosity has slowly increased in calves born throughout the study period, as opposed to the slight decline that was expected. Therefore, this mechanism represents a natural means through which small populations can mitigate the loss of genetic diversity over time.

Management of hyperkalaemia.

Hyperkalaemia, an elevated extracellular fluid potassium concentration, is a common electrolyte disorder and is present in 1-10% of hospitalised patients. Elevated serum potassium concentrations are usually asymptomatic but may be associated with electrocardiogram (ECG) changes. Hyperkalaemia occasionally leads to life-threatening cardiac arrhythmias. Prompt recognition of this disorder, patient risk management and administration of appropriate treatment can prevent serious cardiac complications of hyperkalaemia. Further assessment of the underlying basis for hyperkalaemia usually reveals a problem with renal potassium excretion (rather than transcellular shift of potassium or excess potassium intake). Reduced potassium excretion is typically associated with decreased potassium secretion in the aldosterone-sensitive distal nephron of the kidney. Common causes for hyperkalaemia include kidney failure, limited delivery of sodium and water to the distal nephron and drugs that inhibit the renin-angiotensin-aldosterone system. Treatment of life-threatening hyperkalaemia (particularly those patients with ECG changes) involves administration of intravenous calcium salts to stabilise the resting cardiac membrane potential. The potassium concentration can be lowered by administration of intravenous insulin combined with an infusion of glucose to stimulate intracellular uptake of potassium. Nebulised ß-2 adrenoceptor agonists can augment the effects of intravenous insulin and glucose pending more definitive management of the recurrent hyperkalaemia risk. Additional management steps include stopping further potassium intake and careful review of prescribed drugs that may be adversely affecting potassium homeostasis. Changes to prescribing systems and an agreed institutional protocol for management of hyperkalaemia can improve patient safety for this frequently encountered electrolyte disorder.

Cardiovascular risk in the young type 1 diabetes population with a low 10-year, but high lifetime risk of cardiovascular disease.

Diabetes mellitus is associated with excess cardiovascular mortality that is evident in all age groups, but is most pronounced in young people with type 1 diabetes. Cardiovascular risk estimation models generally estimate the probability of future events over a 10-year time horizon. Due to the dependency on age, children and adolescents with type 1 diabetes would be considered at low short-term risk but high life-time risk of developing a cardiovascular event. Guidelines recommend screening particularly for microvascular complications including nephropathy and retinopathy beginning around puberty. Identification of early microvascular abnormalities in children and adolescents not only predict later development of long-term microvascular complications and further end-organ damage but are associated with an increased risk for future macrovascular events. This may be because of the fact that the same glycaemic mechanisms responsible for the occurrence of microvascular disease may also apply to the development of atherosclerosis. Alternatively, interventions that reduce the development of microvascular end-organ damage may also delay the development of associated macrovascular disease. Screening for subclinical atherosclerosis, especially in the coronary and carotid vessels, has been advocated as a means of detecting early atherosclerotic disease in asymptomatic individuals with the aim of potentially reclassifying cardiovascular risk and guiding therapeutic interventions. Currently there is no randomized clinical trial evidence that additional screening using non-invasive imaging techniques alters cardiovascular disease outcomes. We do not know the best approach or combination of approaches to assess risk and reduce cardiovascular disease burden in type 1 diabetes mellitus. All screening interventions carry harms as well as benefits and until further evidence becomes available additional screening using non-invasive imaging tests for the detection of subclinical atherosclerosis cannot be currently recommended for patients with type 1 diabetes.

Comparison of rootMUSIC and discrete wavelet transform analysis of Doppler ultrasound blood flow waveforms to detect microvascular abnormalities in type I diabetes.

The earliest signs of cardiovascular disease occur in microcirculations. Changes to mechanical and structural properties of these small resistive vessels alter the impedance to flow, subsequent reflected waves, and consequently, flow waveform morphology. In this paper, we compare two frequency analysis techniques: 1) rootMUSIC and 2) the discrete wavelet transform (DWT) to extract features of flow velocity waveform morphology captured using Doppler ultrasound from the ophthalmic artery (OA) in 30 controls and 38 age and sex matched Type I diabetics. Conventional techniques for characterizing Doppler velocity waveforms, such as mean velocity, resistive index, and pulsatility index, revealed no significant differences between the groups. However, rootMUSIC and the DWT provided highly correlated results with the spectral content in bands 2-7 (30-0.8 Hz) significantly elevated in the diabetic group (p < 0.05). The spectral distinction between the groups may be attributable to manifestations of underlying pathophysiological processes in vascular impedance and consequent wave reflections, with bands 5 and 7 related to age. Spectral descriptors of OA blood velocity waveforms are better indicators of preclinical microvascular abnormalities in Type I diabetes than conventional measures. Although highly correlated DWT proved slightly more discriminatory than rootMUSIC and has the advantage of extending to subheart rate frequencies, which may be of interest.

Effect of pioglitazone on endothelial function in impaired glucose tolerance.

AIM: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT). MATERIALS AND METHODS: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated. RESULTS: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo. CONCLUSIONS: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.

Colour Doppler ultrasound of the ocular circulation in patients with systemic lupus erythematosus identifies altered microcirculatory haemodynamics.

We assessed whether quantitative analysis of Doppler flow velocity waveforms is able to identify subclinical microvascular abnormalities in SLE and whether eigenvector analysis can detect changes not detectable using the resistive index (RI). Fifty-four SLE patients with no conventional cardiovascular risk factors, major organ involvement or retinopathy were compared to 32 controls. Flow velocity waveforms were obtained from the ophthalmic artery (OA), central retinal artery (CRA) and common carotid artery (CA). The waveforms were analysed using eigenvector decomposition and compared between groups at each arterial site. The RI was also determined. The RI was comparable between groups. In the OA and CRA, there were significant differences in the lower frequency sinusoidal components (P < 0.05 for each component). No differences were apparent in the CA between groups. Eigenvector analysis of Doppler flow waveforms, recorded in proximity of the terminal vascular bed, identified altered ocular microvascular haemodynamics in SLE. Altered waveform structure could not be identified by changes in RI, the traditional measure of downstream vascular resistance. This analytical approach to waveform analysis is more sensitive in detecting preclinical microvascular abnormalities in SLE. It may hold potential as a useful tool for assessing disease activity, response to treatment, and predicting future vascular complications.

Root-MUSIC analysis of nitric oxide-mediated changes in ophthalmic artery blood flow velocity waveforms.

Clinical and experimental studies indicate that structural and functional changes in the microvasculature can predate or accompany risk factors for cardiovascular disease at the earliest stages in the disease process. In the current work, both simulated and actual Doppler ultrasound maximum blood velocity waveform envelopes recorded from the ophthalmic artery were analysed using a root-MUSIC and least squares fitting approach to determine amplitude frequency spectra. Both amplitude and frequency components of noise contaminated simulated waveforms were reliably determined indicating the robustness of the technique. The technique was then used to compare the spectral content of the ophthalmic artery blood velocity waveforms of normal controls in three test states: at baseline, following administration of GTN, a nitric oxide donor, and following administration of L-Name, a nitric oxide inhibitor. Principal components derived from root-MUSIC analysis discriminated between waveforms in baseline and non-baseline test states (p<0.00001) and between GTN and non-GTN test states (p=0.0002).

Thiazolidinediones: effects on insulin resistance and the cardiovascular system.

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.

Patterns of male reproductive success in a highly promiscuous whale species: the endangered North Atlantic right whale.

Parentage analyses of baleen whales are rare, and although mating systems have been hypothesized for some species, little data on realized male reproductive success are available and the patterns of male reproductive success have remained elusive for most species. Here we combine over 20 years of photo-identification data with high-resolution genetic data for the majority of individual North Atlantic right whales to assess paternity in this endangered species. There was significant skew in male reproductive success compared to what would be expected if mating was random (P < 0.001). The difference was due to an excess of males assigned zero paternities, a deficiency of males assigned one paternity, and an excess of males assigned as fathers for multiple calves. The variance in male reproductive success was high relative to other aquatically mating marine mammals, but was low relative to mammals where the mating system is based on resource- and/or mate-defence polygyny. These results are consistent with previous data suggesting that the right whale mating system represents one of the most intense examples of sperm competition in mammals, but that sperm competition on its own does not allow for the same degree of polygyny as systems where males can control access to resources and/or mates. The age distribution of assigned fathers was significantly biased towards older males (P < 0.05), with males not obtaining their first paternity until approximately 15 years of age, which is almost twice the average age of first fertilization in females (8 years), suggesting that mate competition is preventing younger males from reproducing. The uneven distribution of paternities results in a lower effective population size in this species that already has one of the lowest reported levels of genetic diversity, which may further inhibit reproductive success through mate incompatibility of genetically similar individuals.