Biomedical subjects

J Harris

Publications and source records attributed to J Harris.

At least 37 records · Page 2Linked to original sources

PubMed2004

Determination of the T cell epitopes of the lipocalin allergen, Rat n 1.

BACKGROUND: Laboratory animal allergy (LAA) is an important cause of occupational sensitization and asthma. Rats are a frequent cause of LAA and the major rat allergen, Rat n 1, is a member of the lipocalin protein family, which includes several other animal allergens such as the cow allergen, Bos d 2. To date, Bos d 2 is the only mammalian lipocalin allergen to have been studied in detail. OBJECTIVE: We undertook a cross-sectional study of a large population of individuals exposed to laboratory rats to determine the proliferative responses of peripheral blood mononuclear cells (PBMCs) to the major rat allergen, Rat n 1. METHODS: Eighty-three cases (defined by a positive skin prick test (SPT) > or =3 mm and/or a positive RAST > or =2% binding) and 274 referents without specific IgE to rats were tested for their proliferative responses of PBMCs to rat allergen. Cytokine release to rat urinary protein was examined in 28 sensitized and 42 non-sensitized exposed individuals. RESULTS: Proliferation to rat urinary protein was weak in all individuals. Four regions within Rat n 1 were identified as containing potential immunodominant T cell epitopes and three of these co-localized within the conserved regions of the lipocalin molecule. All four regions within Rat n 1 overlapped considerably with the characterized epitopes of the lipocalin allergen, Bos d 2. IL-5 and ratios of IL-5/IFN-gamma were significantly increased in cases. CONCLUSION: The response to Rat n 1 is remarkably similar to the cow lipocalin allergen Bos d 2. T cell epitopes within lipocalins appear to co-localize with the conserved regions of the molecule. LAA is characterized by an increased production of IL-5. Investigation of other lipocalin allergens will provide further information about the allergenicity of this group of proteins.

Allergens↗

PubMed2004

Association of HLA-DQ5 and HLA-DR1 with sensitization to organic acid anhydrides.

BACKGROUND: Organic acid anhydrides are low molecular weight industrial chemicals, able to cause rhinoconjunctivitis and asthma associated with specific IgE against hapten-carrier protein conjugate. Only a proportion of exposed workers develop IgE-associated allergy to acid anhydrides. OBJECTIVE: We determined whether genetic susceptibility, in particular, HLA Class II alleles may be a risk factor. METHODS: We undertook HLA typing in 52 cases who had confirmed specific IgE and in 73 referents matched on site, age and duration of acid anhydride exposure identified in cross-sectional studies of workers exposed to hexahydrophthalic (HHPA), methylhexahydrophthalic (MHHPA) and methyltetrahydrophthalic (MTHPA) anhydrides. RESULTS: The linked alleles DQ5 (odds ratio [OR]=4.3; 95% confidence interval [95% CI]=1.7, 11) and DR1 (OR 3.0; 95% CI 1.2, 11) were more prevalent in cases than in referents. Within DQ5, DQB1(*)0501 was particularly frequent (OR 3.0; 95% CI 1.2, 7.4). CONCLUSION: DQB1(*)05 gene confers susceptibility to develop specific IgE antibodies against HHPA, MHHPA and a non-significant trend with MTHPA. DQB1(*)0501 is protective for other low molecular chemical sensitizers (isocyanates and plicatic acid) which may indicate varying affinities for the corresponding specific class II molecules.

Adult↗

PubMed2004

Concentrations and determinants of NO2 in homes of Ashford, UK and Barcelona and Menorca, Spain.

UNLABELLED: This study examined indoor nitrogen dioxide (NO2) concentrations in Ashford, Kent (UK), Menorca Island and Barcelona city (Spain) and the contribution of their most important indoor determinants (e.g. gas combustion appliances and cigarette smoking). The homes examined (n = 1421) were those from infants recruited for the Asthma Multicentre Infants Cohort Study, which aimed to assess, using a standard protocol, the effects of pre- and post-natal environmental exposures in the inception of atopy and asthma. Indoor NO2 was measured using passive filter badges placed on a living room wall of the homes for between 7 and 15 days. Homes in the three centers had significantly different concentrations of indoor NO2, with those in Barcelona showing the highest levels (median NO2 levels: 5.79, 6.06 and 23.87 p.p.b. in Ashford, Menorca and Barcelona, respectively). Multiple regression analysis showed that the principal indoor determinants of NO2 concentrations in the three cohorts were the heating/cooking fuel used in the house (gas fire increased average NO2 concentrations by 1.27-fold and gas cooker by 2.13 times), parental cigarette smoking and season of measurement. Those variables significantly related to indoor NO(2) accounted for 23, 14 and 39% of the variation in indoor NO2 concentration in Ashford, Barcelona and Menorca, respectively. In all the cohorts combined, 52% of the variation could be explained in this way. Although outdoor NO2 was not measured concurrently, its additional contribution was estimated. In conclusion, despite differences in indoor NO2 mean concentrations probably reflecting different outdoor NO2 level, home factors affecting indoor NO2 values and their specific contributions were constant across the three cohorts. PRACTICAL IMPLICATIONS: This study found that principal determinants associated to indoor NO2 in three different sites of Europe: Ashford (UK), Barcelona and Menorca (Spain) were the energy source present in the home and cigarette smoking, despite these areas presented different climates, levels of outdoor contamination, housing characteristics and ventilation behavior. It is suggested that interventions in homes of these three centers will need to address principally cigarette smoking and gas combustion appliances. These latter factors require institutional intervention, while cigarette smoking mainly require personal changes.

Adult↗

PubMed2004

Glutamate and tachykinin receptors in central sensitization of withdrawal reflexes in the decerebrated rabbit.

This study assessed the involvement of NMDA and group I metabotropic glutamate receptors, and tachykinin NK1 and NK3 receptors, in central sensitization of withdrawal reflexes in the decerebrated rabbit. Reflexes evoked in the ankle flexor tibialis anterior and the knee flexor semitendinosus by electrical stimulation at the base of the toes were enhanced for 29-63 min after application of 20% mustard oil to the tips of the toes. Selective antagonists of mGlu1, mGlu5, NMDA and NR2B-subunit-containing NMDA glutamate receptors, as well as NK1, and NK3 receptors, and a non-selective blocker of all tachykinin receptors, were assessed for their effects on the magnitude and duration of the increase in reflexes induced by mustard oil. Dizocilpine, an antagonist of all NMDA receptors (1 mg intrathecal) abolished facilitation of tibialis anterior reflexes and significantly reduced the magnitude and duration of increase of the semitendinosus response. The NR2B-subtype selective antagonist CP-101,606 decreased the magnitude of facilitation of both reflexes but had no effect on duration of enhancement. Selective antagonists for the mGlu1 (CPCCOEt, 1-3 mg intrathecal), mGlu5 (MPEP, 0.2-1 mg intrathecal), NK1 (L-733,060, 0.3 mg intrathecal) or NK3 (SR 142,801, 1 mg kg(-1) i.v.) receptors had no effect on the amplitude or duration of sensitization. However, the non-selective tachykinin receptor blocker ZD-6021 (0.3 mg intrathecal) reduced the amplitude but not the duration of sensitization in the flexor reflexes. Combination of ZD-6021 with CP-101,606 (doses as above) decreased both aspects of the sensitization response. Dizocilpine reduced reflexes evoked from the heel per se, and dizocilpine, CP-101,606 and ZD-6021 reduced arterial blood pressure. Otherwise the drugs used had no effects on baseline variables. The present data confirm the importance of NMDA receptors as a critical part of the process of central sensitization, provide no evidence for a role of metabotropic glutamate receptors, and show that simultaneous blockade of all tachykinin receptors is required to reveal their role in hyperalgesia. The data further indicate that a combined pharmacological approach offers a potential way forward for the development of new antihyperalgesic agents.

Animals↗

PubMed2004

The introduction of solids in relation to asthma and eczema.

BACKGROUND: Despite scarce scientific evidence, current feeding guidelines recommend delayed introduction of solids for the prevention of asthma and allergy. AIMS: To explore whether late introduction of solids is protective against the development of asthma, eczema, and atopy. METHODS: A total of 642 children were recruited before birth and followed to the age of 5(1/2) years. Main outcome measures were: doctor's diagnosis of eczema ever, atopy according to skin prick test results against inhalant allergens, preschool wheezing, transient wheezing, all defined at age 5-5(1/2) years. Introduction of solids as main exposure measure was assessed retrospectively at age 1 year. RESULTS: There was no evidence for a protective effect of late introduction of solids for the development of preschool wheezing, transient wheezing, atopy, or eczema. On the contrary, there was a statistically significant increased risk of eczema in relation to late introduction of egg (aOR 1.6, 95% CI 1.1 to 2.4) and milk (aOR 1.7, 95% CI 1.1 to 2.5). Late introduction of egg was furthermore associated with a non-significant increased risk of preschool wheezing (aOR 1.5, 95% CI 0.92 to 2.4). There was no statistical evidence of feeding practices playing a different role in the development of asthma and eczema after stratification for parental asthma and atopy status. CONCLUSIONS: Results do not support the recommendations given by present feeding guidelines stating that a delayed introduction of solids is protective against the development of asthma and allergy.

Age Factors↗

PubMed2004

Association study of Notch 4 polymorphisms with Alzheimer's disease.

BACKGROUND: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer's disease. OBJECTIVE: To investigate the potential impact of two polymorphisms within this gene on the risk of developing Alzheimer's disease. METHODS: Genotyping of promoter and 5'-UTR polymorphisms was done in Scottish, English, and French populations. The potential functionality of the 5'-UTR polymorphism was assessed by testing its impact on A beta load in Alzheimer brains and also by undertaking electrophoretic mobility shift assays and transfection experiments. RESULTS: No association of the Notch4 polymorphisms alone with the disease was observed in any of the populations. However, an interaction of the 5'-UTR C/T polymorphism with the epsilon 4 allele of the APOE gene was detected in United Kingdom populations but not in the French. No relation between the 5'-UTR polymorphism and A beta loads was detected overall or in the presence or absence of the epsilon 4 allele. No DNA protein specific binding was found with proteins from neuroblastoma, glioma, or astrocytoma cells, and no allele dependent transcriptional activity was detected. CONCLUSIONS: No association between two NOTCH4 polymorphisms alone and Alzheimer's disease was observed in the three populations, but there was evidence of an increased risk associated with the 5'-UTR CC genotype in epsilon 4 bearers in the United Kingdom. As no functionality for this polymorphism could be determined, it is likely that the interaction is spurious or results from a linkage disequilibrium of this 5'-UTR polymorphism with another marker elsewhere in the 6p21.3 locus.

5' Untranslated Regions↗

PubMed2004

Mortality in a cohort of vermiculite miners exposed to fibrous amphibole in Libby, Montana.

BACKGROUND: Fibrous tremolite is a widespread amphibole asbestiform mineral, airborne fibres of which constitute an environmental hazard in Libby, Montana, northern California, and elsewhere. AIMS: To determine excess risk from lung cancer, mesothelioma, and all-cause mortality in a cohort of men exposed to tremolite, but no other form of asbestos. METHODS: Mortality by certified cause and various measures of exposure to tremolite and related amphibole fibres was assessed in a cohort of 406 vermiculite mineworkers in Libby, Montana, employed before 1963 and followed until 1999. RESULTS: Total deaths were: lung cancer 44 (SMR 2.40), non-malignant respiratory disease (NMRD) 51 (SMR 3.09), all causes 285 (SMR 1.27); included among the total were 12 deaths ascribed to mesothelioma (4.21% of all deaths). Adjusted linear increments in relative risks (per 100 f/ml.y), estimated by Poisson regression, were: lung cancer (0.36, 95% CI 0.03 to 1.20), NMRD (0.38, 95% CI 0.12 to 0.96), and all deaths (0.14, 95% CI 0.05 to 0.26). CONCLUSIONS: The all-cause linear model would imply a 14% increase in mortality for mine workers exposed occupationally to 100 f/ml.y or about 3.2% for a general population exposed for 50 years to an ambient concentration of 0.1 f/ml. Amphibole fibres, tremolite in particular, are likely to be disproportionately responsible for cancer mortality in persons exposed to commercial chrysotile, but to what extent cannot be readily assessed.

Aluminum Silicates↗

PubMed2004

Measurement properties of the Frenchay Activities Index among individuals with a lower limb amputation.

OBJECTIVE: To assess the reliability and validity of the original and a modified version of the Frenchay Activities Index (FAI) among individuals with a lower limb amputation. DESIGN: Two week test-retest design. SETTING: South Western Ontario Amputee Program, London, Ontario, Canada. SUBJECTS: Consecutive sample of 84 individuals, primarily men (78.6%), mean age 56.5 years with a unilateral transtibial (71.4%) or transfemoral amputation related to traumatic (59.5%) or vascular causes. INTERVENTIONS: All subjects completed a questionnaire containing the FAI and other scales, the 2-minute walk and timed up and go tests during a regularly scheduled clinic visit. Fifty-five subjects completed a second FAI which was mailed to them two weeks later. Twenty-nine others completed the second FAI upon return for testing related to another project. MAIN MEASURES: FAI, Activity-specific Balance Confidence Scale, Prosthetic Evaluation Questionnaire-Mobility Scale, 2-minute walk, timed up and go and walking device aid use. RESULTS: Relative reliability for the FAI (intraclass correlation coefficient (ICC) = 0.79) and FAI-18 (ICC = 0.78) was acceptable, however bias between measurements was detected. Hypothesized relationships (p < 0.001) between both FAI versions and the Activity-specific Balance Confidence Scale, Prosthetic Evaluation Questionnaire-Mobility Scale, 2-minute walk and timed up and go test were observed. Significant group differences were observed for amputation cause, mobility device use, age and years as an amputee. Neither version distinguished between amputee level or gender groups. CONCLUSIONS: The original and modified FAI are valid and reliable tools for unilateral amputees. Reliability is adequate to detect group but not individual level differences. Additional FAI-18 items did not substantially improve the ability to detect between-amputation-group differences.

Activities of Daily Living↗

PubMed2004

Early prescriptions of antibiotics and the risk of allergic disease in adults: a cohort study.

BACKGROUND: It is frequently asserted that antibiotic prescriptions in childhood are associated with the development of allergic disease, especially asthma. A study was undertaken to establish the direction of this relationship. METHODS: A retrospective cohort study of 746 adults was performed in three general practices. Antibiotic prescriptions in the first 5 years of life, collected from contemporary medical records, were related to self-reports of asthma and hay fever and the results of skin prick testing with common aeroallergens. RESULTS: There was no relationship between early antibiotic prescription and atopy, either for all antibiotic use (OR 1.01) or for antibiotics prescribed at different ages. The significant associations between prescriptions at ages 4 and 5 and hay fever (OR 1.23 and 1.16, respectively) were explained by coexisting asthma. Relationships between antibiotic use and asthma (allergic or otherwise) were statistically significant and strengthened with increasing age of prescription, but were largely confined to antibiotics prescribed for lower respiratory symptoms. CONCLUSIONS: The reported associations between childhood antibiotic use and asthma are most plausibly explained by "reverse causation"--the tendency for prescriptions to be written for the early manifestations of pre-existing asthma.

Adult↗

PubMed2003

Risk of action tremor in relatives of tremor-dominant and postural instability gait disorder PD.

BACKGROUND: Action tremor may be more prevalent in relatives of patients with Parkinson's disease (PD) than in relatives of control subjects. This tremor could represent mild PD or essential tremor. An estimate of the risk of this condition in families of patients with PD is important when studying the genetics of PD. OBJECTIVE: S: To determine the risk of action tremor in first-degree relatives of probands with tremor-dominant PD (TD-PD) and postural instability gait disorder PD (PIGD-PD) compared with first-degree relatives of control probands. METHODS: PD and control probands participated in a familial aggregation study of PD. The presence of action tremor in their relatives was ascertained from reports of one or more informants. Relatives who met diagnostic criteria for PD were excluded. Cox proportional hazards models adjusting for gender, education, race, and vital status (dead vs alive) of the relatives were used to assess the relative risk (RR) of action tremor in first-degree relatives of PD probands vs first-degree relatives of control probands. RESULTS: There were 487 PD probands, 409 control probands, and 5,563 relatives. The risk of action tremor was higher in the relatives of TD-PD probands than in the relatives of control probands (RR = 2.14; 95% CI = 1.53 to 2.98) but not in the relatives of PIGD-PD probands compared with the relatives of control probands (RR = 1.81; 95% CI = 0.66 to 5.02). CONCLUSION: The risk of action tremor was increased in the relatives of PD probands, particularly when they had TD-PD. Whether the tremor in these relatives represents essential tremor or an isolated manifestation of PD requires further investigation.

Comorbidity↗

PubMed2003

Accuracy of family history data on Parkinson's disease.

BACKGROUND: Genetic studies of PD frequently rely on family history interviews (FHI), yet the accuracy of data obtained in this way is unclear. OBJECTIVE: To assess the interinformant reliability and validity of family history information on PD in first-degree relatives of PD cases and controls. METHODS: A structured FHI was administered to nondemented PD cases and controls and to a second informant (self-report, sibling or child of the subject) for each relative. Interinformant agreement was assessed on four algorithm-derived diagnostic categories of PD: definite, definite or probable, definite, probable or possible ("conservative diagnosis"); or definite, probable, possible, or uncertain ("liberal diagnosis"). The sensitivity and specificity of each diagnostic category were assessed, using as the gold standard diagnoses based on either in-person examination or medical record review. RESULTS: Five hundred thirty-six families containing 2,225 first-degree relatives were included in the interinformant reliability study. Agreement between informants was excellent for definite or probable PD for all three pairwise comparisons: proband vs self-report (kappa = 0.92), proband vs sibling of subject (kappa = 0.80), and proband vs child of subject (kappa = 0.87). Agreement was also good to excellent for the conservative diagnosis (kappa = 0.66, 0.49, and 0.79). In the validity analysis (141 individuals in 96 families), the conservative diagnosis provided the best combination of sensitivity (95.5%) and specificity (96.2%) for the proband's family history report. No difference was apparent across categories defined by case or control status, relationship to the proband, or gender or age at onset of the proband. However, specificity was lower for deceased relatives than for living relatives. CONCLUSION: The FHI can be used to obtain reliable and valid family history information on PD in first-degree relatives when a conservative diagnostic algorithm is applied.

Algorithms↗

PubMed2003

Optical detection of hot-electron spin injection into GaAs from a magnetic tunnel transistor source.

Injection of spin-polarized hot-electron current from a magnetic tunnel transistor into GaAs is demonstrated by the observation of polarized light emission from a GaAs/In(0.2)Ga(0.8)As multiple quantum well light-emitting diode. Electroluminescence from the quantum wells shows a polarization of approximately 10% after subtraction of a linear background polarization. The polarization shows a strong dependence on the bias voltage across the diode, which may originate from changes in the electron spin relaxation rate in the quantum wells under varying bias conditions.

Journal Article↗

PubMed2003

Parkin-proven disease: common founders but divergent phenotypes.

OBJECTIVE: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Delta40) to search for evidence of a common founder. METHOD: Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed. RESULTS: All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean +/- SD 29.3 +/- 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex3Delta40 carriers with one normal parkin allele. Haplotype analysis revealed both Ex3Delta40 and Ex7 924 C-->T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 C-->T (R275W) and Ex3Delta40 mutations, their clinical presentation and mode of inheritance were variable. CONCLUSION: Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism.

Adult↗

PubMed2003

Effects of arginine-vasopressin (AVP) on long-term potentiation in intact anesthetized rats.

We studied the effects of the neuropeptide arginine-vasopressin (AVP) on the long-term potentiation (LTP) paradigm in the dentate gyrus (DG) of urethane intact anesthetized rats. Intracerebroventricular injection of 1 microg of the hormone in 1 microl of physiological solution 3 min before tetanization, produced a significant increase in both components of the perforant path-evoked potentials (EP) in the DG. The effects were already evident 1 min after tetanization. Amplitude of the EPs increased continuously for the 2h of recording time, reaching values 100% above baseline, reference levels. In contrast, in previous in vitro studies, enhancement of LTP with AVP appeared only after 15 min of exposure of the hippocampal slice to the hormone, increased EPSPs were no higher than 50% from baseline, reached a plateau at 40 min decreasing slowly thereafter. Not only quantitative but also qualitative differences can be observed between in vitro and in vivo intact preparations in response to identical hormones. This study emphasizes the importance of hormone neurotransmitter interactions in determining electrophysiological characteristics of response to AVP.

Action Potentials↗

PubMed2003

Reality monitoring and visual hallucinations in Parkinson's disease.

Between 8 and 40% of Parkinson disease (PD) patients will have visual hallucinations (VHs) during the course of their illness. Although cognitive impairment has been identified as a risk factor for hallucinations, more specific neuropsychological deficits underlying such phenomena have not been established. Research in psychopathology has converged to suggest that hallucinations are associated with confusion between internal representations of events and real events (i.e. impaired-source monitoring). We evaluated three groups: 17 Parkinson's patients with visual hallucinations, 20 Parkinson's patients without hallucinations and 20 age-matched controls, using tests of visual imagery, visual perception and memory, including tests of source monitoring and recollective experience. The study revealed that Parkinson's patients with hallucinations appear to have intact visual imagery processes and spatial perception. However, there were impairments in object perception and recognition memory, and poor recollection of the encoding episode in comparison to both non-hallucinating Parkinson's patients and healthy controls. Errors were especially likely to occur when encoding and retrieval cues were in different modalities. The findings raise the possibility that visual hallucinations in Parkinson's patients could stem from a combination of faulty perceptual processing of environmental stimuli, and less detailed recollection of experience combined with intact image generation.

Aged↗

PubMed2003

Tetrodotoxin block of A-fibre conduction and its effect on reflex responses evoked by electrical stimulation of the sural nerve in the decerebrated rabbit.

In the present study, we have investigated the viability of using tetrodotoxin (TTX) to induce selective blockade of myelinated fibre conduction in rabbit sural nerve, and explored some aspects of reflexes evoked by non-myelinated sural nerve afferents before and after application of TTX. In rabbits decerebrated under halothane-nitrous oxide anaesthesia, application of 30 nM TTX to the desheathed sural nerve completely blocked Abeta and Adelta waves of the compound action potential evoked by electrical stimulation of the nerve at 95 times threshold. The amplitude of C-fibre volleys evoked by these stimuli was reduced to a mean of 60 % of pre-treatment values. Reflexes evoked in medial gastrocnemius motoneurones by sural nerve stimulation showed corresponding changes after TTX treatment, with activation latency increasing from 5-7 ms in the control state to > 100 ms after TTX application. Temporal summation (wind up) in long latency reflexes (> 100 ms) was significantly enhanced after application of TTX. These data show that low concentrations of TTX can selectively block conduction in rabbit sural nerve A-fibres, providing a method for studying the central actions of non-myelinated C-fibres in isolation.

Animals↗

PubMed2003

In praise of unprincipled ethics.

In this paper a plea is made for an unprincipled approach to biomedical ethics, unprincipled of course just in the sense that the four principles are neither the start nor the end of the process of ethical reflection. While the four principles constitute a useful "checklist" approach to bioethics for those new to the field, and possibly for ethics committees without substantial ethical expertise approaching new problems, it is an approach which if followed by the bioethics community as a whole would, the author believes, lead to sterility and uniformity of approach of a quite mindbogglingly boring kind. Moreover, much of bioethics is not concerned with identifying the principles or values appropriate to a particular issue, but rather involves analysing the arguments that are so often already in play and which present themselves as offering solutions in one direction or another. Here, as I try to show in discussion of these four scenarios, the principles allow massive scope in interpretation and are, frankly, not wonderful as a means of detecting errors and inconsistencies in argument.

Bioethical Issues↗

PubMed2003

Incidence and prevalence of head lice in a district health authority area.

There are very few recent studies of the incidence and prevalence of head lice in the UK. A population-based questionnaire survey was carried out in a district health authority area. Two hundred and four of 235 primary schools (87%) agreed to participate. A total of 21,556 of 43,889 (49%) questionnaires were returned by parents. Overall 438 children had head lice at the time of the survey, giving a prevalence of 2.03%; 8,059 had had lice at some time in the last year giving an annual incidence of 37.4%.

Age Distribution↗