Why are the high altitude inhabitants like the Tibetans shorter and lighter?

High altitude inhabitants (HAI) are generally smaller than low altitude inhabitants (LAI). This anthropological observation has recently been confirmed in the Tibetan refugees who have settled in India since 1950s. Those settled at lower altitudes (970 m) are taller and muscular than compatriots settled at higher altitudes (3500 m). While lower socioeconomic status is implicated in growth retardation at higher altitudes, the smaller stature in adults in well-off communities says otherwise. Hypobaric hypoxia (HH) is the main challenge at high altitudes, which the long established HAI have overcome via biological adaptations, including larger chests, raised blood hemoglobin, and producing more nitric oxide (NO), which deliver similar levels of oxygen to tissues, as LAI. The Tibetans produce 10-fold more NO than LAI. NO is a potent inhibitor of steroidogenesis. Therefore I hypothesize that the short stature and lower musculature in HAI results from steroid deficiency precipitated by NO, which HAI produce to cope with HH.     

7-tert-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one, a classic polymodal inhibitor of transient receptor potential vanilloid type 1 with a reduced liability for hyperthermia, is analgesic and ameliorates visceral hypersensitivity

The therapeutic potential of transient receptor potential vanilloid type 1 (TRPV1) antagonists for chronic pain has been recognized for more than a decade. However, preclinical and clinical data revealed that acute pharmacological blockade of TRPV1 perturbs thermoregulation, resulting in hyperthermia, which is a major hurdle for the clinical development of these drugs. Here, we describe the properties of 7-tert-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (BCTP), a TRPV1 antagonist with excellent analgesic properties that does not induce significant hyperthermia in rodents at doses providing maximal analgesia. BCTP is a classic polymodal inhibitor of TRPV1, blocking activation of the human channel by capsaicin and low pH with IC(50) values of 65.4 and 26.4 nM, respectively. Similar activity was observed with rat TRPV1, and the inhibition by BCTP was competitive and reversible. BCTP also blocked heat-induced activation of TRPV1. In rats, the inhibition of capsaicin-induced mechanical hyperalgesia was observed with a D(50) value of 2 mg/kg p.o. BCTP also reversed visceral hypersensitivity and somatic inflammatory pain, and using a model of neuropathic pain in TRPV1 null mice we confirmed that its analgesic properties were solely through the inhibition of TRPV1. We were surprised to find that BCTP administered orally induced only a maximal 0.6°C increase in core body temperature at the highest tested doses (30 and 100 mg/kg), contrasting markedly with N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide (AMG517), a clinically tested TRPV1 antagonist, which induced marked hyperthermia (>1°C) at doses eliciting submaximal reversal of capsaicin-induced hyperalgesia. The combined data indicate that TRPV1 antagonists with a classic polymodal inhibition profile can be identified where the analgesic action is separated from the effects on body temperature.     

Involving the patient to ask about hospital hand hygiene: a National Patient Safety Agency feasibility study

Healthcare-associated infections (HAIs) affect at least 300,000 patients annually in the UK and represent a significant, yet largely preventable, burden to healthcare systems. Hand hygiene by healthcare workers (HCWs) is the leading prevention measure, but compliance with good practice is generally low. The UK National Patient Safety Agency surveyed the public, inpatients, and HCWs, particularly frontline clinical staff and infection control nurses, in five acute care hospitals to determine whether they agreed that a greater level of involvement and engagement with patients would contribute to increased compliance with hand hygiene and reduce HAIs. Fifty-seven percent (302/530) of the public were unlikely to question doctors on the cleanliness of their hands as they assumed that they had already cleaned them. Forty-three percent (90/210) of inpatients considered that HCWs should know to clean their hands and trusted them to do so, and 20% (42/210) would not want HCWs to think that they were questioning their professional ability to do their job correctly. Most HCWs surveyed (178/254, 71%) said that HAI could be reduced to a greater or lesser degree if patients asked HCWs if they had cleaned their hands before touching them. Inviting patients to remind HCWs about hand hygiene through the provision of individual alcohol-based hand-rub containers and actively supporting an 'It's OK to ask' attitude were perceived as the most useful interventions by both patients and HCWs. However, further work is required to refute the myth among HCWs that patient involvement undermines the doctor- or HCW-patient relationship.     

Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport

Background Prokineticin 2 (PROK2) is an inflammatory cytokine‐like molecule expressed predominantly by macrophages and neutrophils infiltrating sites of tissue damage. Given the established role of prokineticin signaling on gastrointestinal function, we have explored Prok2 gene expression in inflammatory conditions of the gastrointestinal tract and assessed the possible consequences on gut physiology. Methods Prokineticin expression was examined in normal and colitic tissues using qPCR and immunohistochemistry. Functional responses to PROK2 were studied using calcium imaging and a novel antagonist, Compound 3, used to determine the role of PROK2 and prokineticin receptors in inflammatory visceral pain and ion transport. Key Results Prok2 gene expression was up‐regulated in biopsy samples from ulcerative colitis patients, and similar elevations were observed in rodent models of inflammatory colitis. Prokineticin receptor 1 (PKR1) was localized to the enteric neurons and extrinsic sensory neurons, whereas Pkr2 expression was restricted to sensory ganglia. In rats, PROK2‐increased intracellular calcium levels in cultured enteric and dorsal root ganglia neurons, which was blocked by Compound 3. Moreover, PROK2 acting at prokineticin receptors stimulated intrinsic neuronally mediated ion transport in rat ileal mucosa. In vivo, Compound 3 reversed intracolonic mustard oil‐induced referred allodynia and TNBS‐induced visceral hypersensitivity, but not non‐inflammatory, stress‐induced visceral pain. Conclusions & Inferences Elevated Prok2 levels, as a consequence of gastrointestinal tract inflammation, induce visceral pain via prokineticin receptors. This observation, together with the finding that PROK2 can modulate intestinal ion transport, raises the possibility that inhibitors of PROK2 signaling may have clinical utility in gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease.     

Generalized q-sampling imaging fiber tractography reveals displacement and infiltration of fiber tracts in low-grade gliomas

Purpose

Low-grade gliomas (LGGs) are slow growing brain tumors that often cause displacement and/or infiltration of the surrounding white matter pathways. Differentiation between infiltration and displacement of fiber tracts remains a challenge. Currently, there is no reliable noninvasive imaging method capable of revealing such white matter alteration patterns. We employed quantitative anisotropy (QA) derived from generalized q-sampling imaging (GQI) to identify patterns of fiber tract alterations by LGGs.

Methods

Sixteen patients with a neuropathological diagnosis of LGG (WHO grade II) were enrolled. Peritumoral fiber tracts underwent qualitative and quantitative evaluation. Contralateral hemisphere counterparts were used for comparison. Tracts were qualitatively classified as unaffected, displaced, infiltrated or displaced, and infiltrated at once. The average QA of whole tract (W), peritumoral tract segment (S), and their ratio (S/W) were obtained and compared to the healthy side for quantitative evaluation.

Results

Qualitative analysis revealed 9 (13.8%) unaffected, 24 (36.9%) displaced, 13 (20%) infiltrated, and 19 (29.2%) tracts with a combination of displacement and infiltration. There were no disrupted tracts. There was a significant increase in S/W ratio among displaced tracts in the pre-operative scans in comparison with the contralateral side. QA values of peritumoral tract segments (S) were significantly lower in infiltrated tracts.

Conclusion

WHO grade II LGGs might displace, infiltrate, or cause a combination of displacement and infiltration of WM tracts. QA derived from GQI provides valuable information that helps to differentiate infiltration from displacement. Anisotropy changes correlate with qualitative alterations, which may serve as a potential biomarker of fiber tract integrity.

     

Increased binding of fibrinogen to glycoprotein IIIa-proline33 (HPA-1b, PlA2, Zwb) positive platelets in patients with cardiovascular disease.

AIMS: The GPIIb-IIIa complex on the platelet membrane plays an important part in thrombosis as it is the receptor for fibrinogen. The gene for platelet membrane glyco-protein IIIa has multiple alleles one of which, the GPIIIa-Proline33 (HPA-1b, PlA2, Zwb) allele has been reported in some, but not all studies, to be associated with an increased risk of myocardial infarction. We investigated whether the presence of the Pro33 form of GPIIIa on the platelet membrane is associated with increased fibrinogen binding. METHODS AND RESULTS: Blood samples from 70 patients (54 male) with stable angina of whom 22 (18 male) had a history of previous myocardial infarction, were analysed for the GPIIIa-Leu-Pro33 polymorphism at the genomic level, and for whole blood flow cytometric measurement of platelet fibrinogen binding. The GPIIIa-Pro33 form was present in 20 (28.6%) patients (1 homozygous) representing an allele frequency of 0.85 and 0.15 (GPIIIa-Leu33:Pro33). The incidence of myocardial infarction was higher (40.0%) in patients positive for GPIIIa-Pro33 than in those without (32.0%) but this was not significant (P=0.58). Fibrinogen binding to ADP-stimulated platelets was significantly higher in the GPIIIa-Pro33 positive group at all ADP concentrations (<0.0001; two way ANOVA). There was no association between fibrinogen binding and the level of expression of the GPIIb-IIIa complex, platelet volume or platelet count. Fibrinogen binding in response to thrombin stimulation was not different between the groups (P>0.05). CONCLUSIONS: The increased tendency of platelets from patients with the Pro33 form of GPIIIa may predispose patients with this allele to a higher risk of acute thrombotic events, and argues for selective use of therapeutic agents that inhibit ADP-mediated platelet activation in occlusive vascular disease states.