Targeting G protein-coupled receptor kinases (GRKs) in Heart Failure

In the human body, over 1000 different G protein-coupled receptors (GPCRs) mediate a broad spectrum of extracellular signals at the plasma membrane, transmitting vital physiological features such as pain, sight, smell, inflammation, heart rate and contractility of muscle cells. Signaling through these receptors is primarily controlled and regulated by a group of kinases, the GPCR kinases (GRKs), of which only seven are known and thus, interference with these common downstream GPCR regulators suggests a powerful therapeutic strategy. Molecular modulation of the kinases that are ubiquitously expressed in the heart has proven GRK2, and also GRK5, to be promising targets for prevention and reversal of one of the most severe pathologies in man, chronic heart failure (HF). In this article we will focus on the structural aspects of these GRKs important for their physiological and pathological regulation as well as well known and novel therapeutic approaches that target these GRKs in order to overcome the development of cardiac injury and progression of HF.

In vivo assessment of HCN channel current (I(h)) in human motor axons

The "Trond" protocol of nerve excitability tests has been used widely to assess axonal function in peripheral nerve. In this study, the routine Trond protocol was expanded to refine assessment of cAMP-dependent, hyperpolarization-activated current (I(h)) activity. I(h) activity is generated by hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels in response to hyperpolarization. It limits activity-dependent hyperpolarization, contributes to neuronal automaticity, and is implicated in chronic pain states. Published data regarding I(h) activity in motor nerve are scant. We used additional strong, prolonged hyperpolarizing conditioning stimuli in the threshold electrotonus component of the Trond protocol to demonstrate the time-course of activation of I(h) in motor axons. Fifteen healthy volunteers were tested on four occasions during 1 week. I(h) action was revealed in the threshold electrotonus by the limiting and often reversal, after about 100 ms, of the threshold increase caused by strong hyperpolarizing currents. Statistical analysis by repeated-measures analysis of variance enabled confidence limits to be established for variation between subjects and within subjects. The results demonstrate that, of all the excitability parameters, those dependent on I(h) were the most characteristic of an individual, because variance between subjects was more than four times the variance within subjects. This study demonstrates a reliable method for in vivo assessment of I(h,) and also serves to document the normal variability in nerve excitability properties within subjects.

Community Genetics Reveal Elevated Levels of Sympatric Gene Flow among Morphologically Similar but Not among Morphologically Dissimilar Species of Lake Victoria Cichlid Fish

We examined genetic structure among five species of Lake Victoria haplochromine cichlids in four island communities, using a full factorial sampling design that compared genetic differentiation between pairs of species and populations of varying morphological similarity and geographical proximity. We found that allopatric conspecific populations were on average significantly more strongly differentiated than sympatric heterospecific populations of morphologically similar species. Allopatric heterospecific populations of morphologically dissimilar species were most differentiated. Our work demonstrates that phenotypic divergence can be maintained and perhaps even evolve in sympatry despite considerable gene flow between species. Conversely, phenotypic resemblance among conspecific populations can be maintained despite geographical isolation. Additionally we show that anthropogenically increased hybridization does not affect all sympatric species evenly but predominantly affects morphologically similar and closely related species. This has important implications for the evolution of reproductive isolation between species These findings are also consistent with the hypothesis of speciation reversal due to weakening of divergent selection and reproductive isolation as a consequence of habitat homogenization and offers an evolutionary mechanistic explanation for the observation that species poor assemblages in turbid areas of the lake are characterized by just one or two species in each of a few morphologically distinct genera.

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

Mucormycosis is an emerging cause of infectious morbidity and mortality in patients with hematologic malignancies. However, there are no recommendations to guide diagnosis and management. The European Conference on Infections in Leukemia assigned experts in hematology and infectious diseases to develop evidence-based recommendations for the diagnosis and treatment of mucormycosis. The guidelines were developed using the evidence criteria set forth by the American Infectious Diseases Society and the key recommendations are summarized here. In the absence of validated biomarkers, the diagnosis of mucormycosis relies on histology and/or detection of the organism by culture from involved sites with identification of the isolate at the species level (no grading). Antifungal chemotherapy, control of the underlying predisposing condition, and surgery are the cornerstones of management (level A II). Options for first-line chemotherapy of mucormycosis include liposomal amphotericin B and amphotericin B lipid complex (level B II). Posaconazole and combination therapy of liposomal amphotericin B or amphotericin B lipid complex with caspofungin are the options for second line-treatment (level B II). Surgery is recommended for rhinocerebral and skin and soft tissue disease (level A II). Reversal of underlying risk factors (diabetes control, reversal of neutropenia, discontinuation/taper of glucocorticosteroids, reduction of immunosuppressants, discontinuation of deferroxamine) is important in the treatment of mucormycosis (level A II). The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings (no grading). Maintenance therapy/secondary prophylaxis must be considered in persistently immunocompromised patients (no grading).

Transient rhythmic network activity in the somatosensory cortex evoked by distributed input in vitro

The initiation and maintenance of physiological and pathophysiological oscillatory activity depends on the synaptic interactions within neuronal networks. We studied the mechanisms underlying evoked transient network oscillation in acute slices of the adolescent rat somatosensory cortex and modeled its underpinning mechanisms. Oscillations were evoked by brief spatially distributed noisy extracellular stimulation, delivered via bipolar electrodes. Evoked transient network oscillation was detected with multi-neuron patch-clamp recordings under different pharmacological conditions. The observed oscillations are in the frequency range of 2-5 Hz and consist of 4-12 mV large, 40-150 ms wide compound synaptic events with rare overlying action potentials. This evoked transient network oscillation is only weakly expressed in the somatosensory cortex and requires increased [K+]o of 6.25 mM and decreased [Ca2+]o of 1.5 mM and [Mg2+]o of 0.5 mM. A peak in the cross-correlation among membrane potential in layers II/III, IV and V neurons reflects the underlying network-driven basis of the evoked transient network oscillation. The initiation of the evoked transient network oscillation is accompanied by an increased [K+]o and can be prevented by the K+ channel blocker quinidine. In addition, a shift of the chloride reversal potential takes place during stimulation, resulting in a depolarizing type A GABA (GABAA) receptor response. Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate (AMPA), N-methyl-D-aspartate (NMDA), or GABA(A) receptors as well as gap junctions prevents evoked transient network oscillation while a reduction of AMPA or GABA(A) receptor desensitization increases its duration and amplitude. The apparent reversal potential of -27 mV of the evoked transient network oscillation, its pharmacological profile, as well as the modeling results suggest a mixed contribution of glutamatergic, excitatory GABAergic, and gap junctional conductances in initiation and maintenance of this oscillatory activity. With these properties, evoked transient network oscillation resembles epileptic afterdischarges more than any other form of physiological or pathophysiological neocortical oscillatory activity.

The functional relationship between yawning and vigilance

BACKGROUND: Although yawning is a ubiquitous and phylogenetically old phenomenon, its origin and purpose remain unclear. The study aimed at testing the widely held hypothesis that yawning is triggered by drowsiness and brings about a reversal or suspension of the process of falling asleep. METHODS: Subjects complaining of excessive sleepiness were spontaneously yawning while trying to stay awake in a quiet and darkened room. Changes in their electroencephalogram (EEG) and heart rate variability (HRV) associated with yawning were compared to changes associated with isolated voluntary body movements. Special care was taken to remove eye blink- and movement-artefacts from the recorded signals. RESULTS: Yawns were preceded and followed by a significantly greater delta activity in EEG than movements (p< or =0.008). After yawning, alpha rhythms were attenuated, decelerated, and shifted towards central brain regions (p< or =0.01), whereas after movements, they were attenuated and accelerated (p<0.02). A significant transient increase of HRV occurred after the onset of yawning and movements, which was followed by a significant slow decrease peaking 17s after onset (p<0.0001). No difference in HRV changes was found between yawns and movements. CONCLUSIONS: Yawning occurred during periods with increased drowsiness and sleep pressure, but was not followed by a measurable increase of the arousal level of the brain. It was neither triggered nor followed by a specific autonomic activation. Our results therefore confirm that yawns occur due to sleepiness, but do not provide evidence for an arousing effect of yawning.

When left becomes right and vice versa: mirrored vision after cerebral hypoxia

The combination of acquired mirror writing and reading is an extremely rare neurological disorder. It is encountered when brain damaged patients prefer horizontally mirrored over normal script in writing and reading. Previous theories have related this pathology to a disinhibition of mirrored engrams in the non-dominant hemisphere, possibly accompanied by a reversal of the preferred scanning direction. Here, we report the experimental investigation of PR, a patient who developed pronounced mirror writing and reading following septic shock that caused hypoxic brain damage. A series of five oculomotor experiments revealed that the patient's preferred scanning direction was indeed reversed. However, PR showed striking scanpath abnormalities and mirror reversals that cannot be explained by previous theories. Considered together with mirror phenomena she displayed in neuropsychological tasks and everyday activities, our findings suggest a horizontal reversal of visual information on a perceptual level. In addition, a systematic manipulation of visual variables within two further experiments had dramatic effects on her mirror phenomena. When confronted with moving, flickering or briefly presented stimuli, PR showed hardly any left-right reversals. Not only do these findings underline the perceptual nature of her disorder, but also allow interpretation of the pathology in terms of a dissociation between visual subsystems. We speculate that early visual cortices are crucially involved in this dissociation. More generally, her mirrored vision may represent an extreme clinical manifestation of the relative instability of the horizontal axis in spatial vision.

Safety of inferior vena cava filter retrieval in anticoagulated patients

PURPOSES: To evaluate the safety of inferior vena cava (IVC) filter retrieval in therapeutically anticoagulated patients in comparison to prophylactically or not therapeutically anticoagulated patients with respect to retrieval-related hemorrhagic complications. MATERIALS AND METHODS: This was a retrospective study of 115 consecutive attempted IVC filter retrievals in 110 patients. Filter retrievals were stratified as performed in patients who were therapeutically anticoagulated (group 1), prophylactically anticoagulated (group 2), or not therapeutically anticoagulated (group 3). The collected data included anticoagulant and antiplatelet medications (type, form and duration of administration, dosage) at the time of retrieval. Phone interviews and chart review was performed for the international normalized ratio (INR), activated partial thromboplastin time, platelet count, infusion of blood products, and retrieval-related hemorrhagic complications. RESULTS: Group 1 included 65 attempted filter retrievals in 61 therapeutically anticoagulated patients by measured INR or dosing when receiving low-molecular-weight heparin (LMWH). Four retrievals were not successful. In patients receiving oral anticoagulation, the median INR was 2.35 (range, 2 to 8). Group 2 comprised 23 successful filter retrievals in 22 patients receiving a prophylactic dose of LMWH. Group 3 included 27 attempted filter retrievals in 27 patients not receiving therapeutic anticoagulation. Six retrievals were not successful. Five patients were receiving oral anticoagulation with a subtherapeutic INR (median, 1.49; range, 1.16 to 1.69). No anticoagulation medication was administered in 22 patients. In none of the groups were hemorrhagic complications related to the retrieval procedures identified. CONCLUSIONS: These results suggest that retrieval of vena cava filters in anticoagulated patients is safe. Interruption or reversal of anticoagulation for the retrieval of vena cava filters is not indicated.

Exposure dating of Late Glacial and pre-LGM moraines in the Cordon de Doña Rosa, Northern/Central Chile (~ 31°S)

Despite the important role of the Central Andes (15–30° S) for climate reconstruction, knowledge about the Quaternary glaciation is very limited due to the scarcity of organic material for radiocarbon dating. We applied 10Be surface exposure dating (SED) on 22 boulders from moraines in the Cordon de Doña Rosa, Northern/Central Chile (~31° S). The results show that several glacial advances in the southern Central Andes occurred during the Late Glacial between ~14.7±1.5 and 11.6±1.2 ka. A much more extensive glaciation is dated to ~32±3 ka, predating the temperature minimum of the global LGM (Last Glacial Maximum: ~20 ka). Reviewing these results in the paleoclimatic context, we conclude that the Late Glacial advances were most likely caused by an intensification of the tropical circulation and a corresponding increase in summer precipitation. High-latitude temperatures minima, e.g. the Younger Dryas (YD) and the Antarctic Cold Reversal (ACR) may have triggered individual advances, but current systematic exposure age uncertainties limit precise correlations. The absence of LGM moraines indicates that moisture advection was too limited to allow significant glacial advances at ~20 ka. The tropical circulation was less intensive despite the maximum in austral summer insolation. Winter precipitation was apparently also insufficient, although pollen and marine studies indicate a northward shift of the westerlies at that time. The dominant pre-LGM glacial advances in Northern/Central Chile at ~32 ka required lower temperatures and increased precipitation than today. We conclude that the westerlies were more intense and/or shifted equatorward, possibly due to increased snow and ice cover at higher southern latitudes coinciding with a minimum of insolation.

Different anticoagulation strategies in off-pump coronary artery bypass operations: a European survey

In order to determine anticoagulation strategies in OPCAB a questionnaire survey among 750 European cardio-thoracic surgeons was performed. Questions addressed volume of OPCAB procedures performed, intra- and perioperative heparinization and antiplatelet therapy, as well as perioperative management. A total of 325 (43.7%) questionnaires were returned and validated. Perioperative protocols for administration of antiplatelets differed among the respondent surgeons. Perioperative prophylaxis of thrombosis (low or high molecular weight heparin) is performed by 78%. Intraoperative heparin dosage range between 70 U/kg to 500 U/kg, 60% of respondents prefer a low-dose regimen (< or = 150 U/kg). Correspondingly, the lowest activated clotting time (ACT) during surgery is accepted to be 200 s by 24%, 250 s by 18% and 300 s by 26% of surgeons. Protamine is used by 91% of respondents, while 52% perform a 1:1 reversal. A cell-saver and antifibrinolytics are used by 70% and 40%, respectively. Interestingly, 56% of respondents think bleeding in OPCAB patients is not reduced when compared to on-pump CABG. In addition, 34% of respondents believe there is an increased risk of early graft occlusion following OPCAB. This survey demonstrates widely different intra- and perioperative anticoagulation strategies for OPCAB procedures among European surgeons.

Neer Award 2007: Reversion of structural muscle changes caused by chronic rotator cuff tears using continuous musculotendinous traction. An experimental study in sheep

HYPOTHESIS: Chronic rotator cuff tears are associated with irreversible architectural muscle changes and a high rate of repair failure. The changes observed in man and their irreversibility with a single stage repair can be reproduced in sheep. It was the purpose of this experiment to test the hypothesis that slow, continuous elongation of a retracted musculotendinous unit allows reversal of the currently irreversible structural muscle changes. MATERIALS AND METHODS: The infraspinatus tendon of 12 sheep was released using a greater tuberosity osteotomy and allowed to retract for 4 months. Then, a new device was mounted on the scapular spine and used to extend the infraspinatus muscuculotendinous unit transcutaneously by 1 mm per day. Thereafter, the tendon was repaired back to the greater tuberosity. We assessed the muscular architecture using magnetic resonance imaging, macroscopic dissection, histology, and electron microscopy. Fatty infiltration (in Hounsfield units 1/4 HU) and muscular cross-sectional area (in % of the control side) were monitored with computed tomography at tendon release, initiation of elongation, repair, and at sacrifice. RESULTS: Sixteen weeks after tendon release, the mean tendon retraction was 29 +/- 6 mm (14% of original length, P = .008). In 8 sheep, elongation was achieved as planned (group I), but in 4, the elongation failed technically (group II). The mean traction time was 24 +/- 6 days with a mean traction distance of 19 +/- 4 mm. At sacrifice, the mean pennation angle in the infraspinatus of group I was not different from the control side (29.8 degrees +/-7.5 degrees vs. 30 degrees +/-6 degrees , P = .575). In group II, the pennation angle had increased from 30 degrees +/-6 degrees to 55 degrees +/-14 degrees (P = .035). There was no fatty infiltration at the time of tendon release. After retraction, there was a significant increase in fatty infiltration of the infraspinatus muscle and a decrease of its cross-sectional area to 57% of the contralateral side (P = .0001). During traction, the degree of fatty infiltration remained unchanged (36 HU to 38 HU, P = .381), and atrophy improved to a muscle square area of 78% of the contralateral side (P = .0001) in group I. In group II, an increase of fatty infiltration was measured from 36 HU to 28 HU; however, this increase was not significant (P = .144). Atrophy did not change in group II (57-55%, P = .946). At sacrifice, the remaining muscle mass was 64% in group I and 46% in group II (P = .019). DISCUSSION: Our preliminary results document, that continuous elongation of a retracted, fatty infiltrated and atrophied musculotendinous unit is technically feasible. CONCLUSION: In the sheep, continuous elongation can lead to restoration of normal muscle architecture, to partial reversal of muscle atrophy, and to arrest of the progression of fatty infiltration. LEVEL OF EVIDENCE: Basic science level 2; Prospective comparative therapeutic study.

North-south palaeohydrological contrasts in the central Mediterranean during the Holocene: tentative synthesis and working hypotheses

On the basis of a multi-proxy approach and a strategy combining lacustrine and marine records along a north–south transect, data collected in the central Mediterranean within the framework of a collaborative project have led to reconstruction of high-resolution and well-dated palaeohydrological records and to assessment of their spatial and temporal coherency. Contrasting patterns of palaeohydrological changes have been evidenced in the central Mediterranean: south (north) of around 40° N of latitude, the middle part of the Holocene was characterised by lake-level maxima (minima), during an interval dated to ca. 10 300–4500 cal BP to the south and 9000–4500 cal BP to the north. Available data suggest that these contrasting palaeohydrological patterns operated throughout the Holocene, both on millennial and centennial scales. Regarding precipitation seasonality, maximum humidity in the central Mediterranean during the middle part of the Holocene was characterised by humid winters and dry summers north of ca. 40° N, and humid winters and summers south of ca. 40° N. This may explain an apparent conflict between palaeoclimatic records depending on the proxies used for reconstruction as well as the synchronous expansion of tree species taxa with contrasting climatic requirements. In addition, south of ca. 40° N, the first millennium of the Holocene was characterised by very dry climatic conditions not only in the eastern, but also in the central- and the western Mediterranean zones as reflected by low lake levels and delayed reforestation. These results suggest that, in addition to the influence of the Nile discharge reinforced by the African monsoon, the deposition of Sapropel 1 has been favoured (1) by an increase in winter precipitation in the northern Mediterranean borderlands, and (2) by an increase in winter and summer precipitation in the southern Mediterranean area. The climate reversal following the Holocene climate optimum appears to have been punctuated by two major climate changes around 7500 and 4500 cal BP. In the central Mediterranean, the Holocene palaeohydrological changes developed in response to a combination of orbital, ice-sheet and solar forcing factors. The maximum humidity interval in the south-central Mediterranean started ca. 10 300 cal BP, in correlation with the decline (1) of the possible blocking effects of the North Atlantic anticyclone linked to maximum insolation, and/or (2) of the influence of the remnant ice sheets and fresh water forcing in the North Atlantic Ocean. In the north-central Mediterranean, the lake-level minimum interval began only around 9000 cal BP when the Fennoscandian ice sheet disappeared and a prevailing positive NAO-(North Atlantic Oscillation) type circulation developed in the North Atlantic area. The major palaeohydrological oscillation around 4500–4000 cal BP may be a non-linear response to the gradual decrease in insolation, with additional key seasonal and interhemispheric changes. On a centennial scale, the successive climatic events which punctuated the entire Holocene in the central Mediterranean coincided with cooling events associated with deglacial outbursts in the North Atlantic area and decreases in solar activity during the interval 11 700–7000 cal BP, and to a possible combination of NAO-type circulation and solar forcing since ca. 7000 cal BP onwards. Thus, regarding the centennial-scale climatic oscillations, the Mediterranean Basin appears to have been strongly linked to the North Atlantic area and affected by solar activity over the entire Holocene. In addition to model experiments, a better understanding of forcing factors and past atmospheric circulation patterns behind the Holocene palaeohydrological changes in the Mediterranean area will require further investigation to establish additional high-resolution and well-dated records in selected locations around the Mediterranean Basin and in adjacent regions. Special attention should be paid to greater precision in the reconstruction, on millennial and centennial timescales, of changes in the latitudinal location of the limit between the northern and southern palaeohydrological Mediterranean sectors, depending on (1) the intensity and/or characteristics of climatic periods/oscillations (e.g. Holocene thermal maximum versus Neoglacial, as well as, for instance, the 8.2 ka event versus the 4 ka event or the Little Ice Age); and (2) on varying geographical conditions from the western to the eastern Mediterranean areas (longitudinal gradients). Finally, on the basis of projects using strategically located study sites, there is a need to explore possible influences of other general atmospheric circulation patterns than NAO, such as the East Atlantic–West Russian or North Sea–Caspian patterns, in explaining the apparent complexity of palaeoclimatic (palaeohydrological) Holocene records from the Mediterranean area.

Snow variability in the Swiss Alps 1864-2009

We present a climate analysis of nine unique Swiss Alpine new snow series that have been newly digitized. The stations cover different altitudes (450–1860 m asl) and all time series cover more than 100 years (one from 1864 to 2009). In addition, data from 71 stations for the last 50–80 years for new snow and snow depth are analysed to get a more complete picture of the Swiss Alpine snow variability. Important snow climate indicators such as new snow sums (NSS), maximum new snow (MAXNS) and days with snowfall (DWSF) are calculated and variability and trends analysed. Series of days with snow pack (DWSP) ≥ 1 cm are reconstructed with useful quality for six stations using the daily new snow, local temperature and precipitation data. Our results reveal large decadal variability with phases of low and high values for NSS, DWSF and DWSP. For most stations NSS, DWSF and DWSP show the lowest values recorded and unprecedented negative trends in the late 1980s and 1990s. For MAXNS, however, no clear trends and smaller decadal variability are found but very large MAXNS values (>60 cm) are missing since the year 2000. The fraction of NSS and DWSP in different seasons (autumn, winter and spring) has changed only slightly over the ∼150 year record. Some decreases most likely attributable to temperature changes in the last 50 years are found for spring, especially for NSS at low stations. Both the NSS and DWSP snow indicators show a trend reversal in most recent years (since 2000), especially at low and medium altitudes. This is consistent with the recent ‘plateauing’ (i.e. slight relative decrease) of mean winter temperature in Switzerland and illustrates how important decadal variability is in understanding the trends in key snow indicators.

Pulmonary venous flow velocity patterns in 404 individuals without cardiovascular disease

OBJECTIVE To determine the pulmonary venous flow velocity (PVFV) values in a large normal population. DESIGN Prospective study in consecutive individuals. SETTING University hospital. METHODS Among 404 normal individuals, the flow velocity pattern in the right upper pulmonary vein was recorded in 315 subjects using transthoracic echocardiography, and in both upper pulmonary veins in 100 subjects using transoesophageal echocardiography. Subjects were divided into five age groups. The PVFV values were compared between transthoracic and transoesophageal echocardiography within the age groups, and intraindividually between the right and left upper pulmonary veins in transoesophageal echocardiography. RESULTS Normal PVFV values for the right upper pulmonary vein in transthoracic and transoesophageal echocardiography are presented. The duration of flow reversal at atrial contraction was overestimated using transthoracic echocardiography (mean (SD): 96 (21) ms in transoesophageal echocardiography, 120 (28) ms in transthoracic echocardiography, p < 0.0001). Systolic to diastolic peak flow velocity ratio (S:D) increased earlier with advancing age with transoesophageal echocardiography than with transthoracic echocardiography. Similar results were found for the corresponding time-velocity integrals. Data from the left and right upper pulmonary veins differed with respect to onset and deceleration of flow velocities, but not for flow durations or peak velocities. CONCLUSIONS Normal PVFV values generally show a wide range. The data presented will be of value in assessing left ventricular diastolic function and mitral regurgitation using the PVFV pattern.

Climatic variability during the last interglacial inferred from geochemical proxies in the Lake El'gygytgyn sediment record

The Last Interglacial Period (LIP) is often regarded as a good analogue for potential climatic conditions under predicted global warming scenarios. Despite this, there is still debate over the nature, duration and frequency of climatic changes during this period. One particularly contentious issue has been the apparent evidence of climatic instability identified in many marine cores but seemingly lacking from many terrestrial archives, especially within the Arctic, a key region for global climate change research. In this paper, geochemical records from Lake El'gygytgyn, north-eastern Russia, are used to infer past climatic changes during the LIP from within the high Arctic. With a sampling resolution of ~20–~90 years, these records offer the potential for detailed, high-resolution palaeoclimate reconstruction. This study shows that the LIP commenced in central Chukotka ~129 thousand years ago (ka), with the warmest climatic conditions occurring between ~128 and 127 ka before being interrupted by a short-lived cold reversal. Mild climatic conditions then persisted until ~122 ka when a marked reduction in the sedimentation rate suggests a decrease in precipitation. A further climatic deterioration at ~118 ka marks the return to glacial conditions. This study highlights the value of incorporating several geochemical proxies when inferring past climatic conditions, thus providing the potential to identify signals related to environmental change within the catchment. We also demonstrate the importance of considering how changes in sedimentation rate influence proxy records, in order to develop robust palaeoenvironmental reconstructions.