MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

OPTN/SRTR 2016 Annual Data Report: Intestine.

Despite improvements in medical and surgical treatment of intestinal failure, intestine transplant continues to play an important role. In 2016, a total of 147 intestine transplants were performed, 80 intestine-without-liver and 67 intestine-liver. Over the past decade, the age distribution of candidates waitlisted for intestine and intestine-liver transplant shifted from primarily pediatric to increasing proportions of adults. In 2016, 58.2% of candidates on the intestine list at any time during the year were aged younger than 18 years, with a decrease over time in those aged younger than 6 years and an increase in those aged 6-17 years. Adults accounted for 41.9% of candidates on the list at any time during the year, with a stable proportion of those aged 18-34 years and a decrease in those aged 35 years or older. By age, pretransplant mortality rate was highest for adult candidates at 11.7 per 100 waitlist years and lowest for children aged younger than 6 years at 2.2 per 100 waitlist years. For intestine transplants with or without a liver in 2009-2011, 1- and 5-year graft survival was 72.0% and 54.1%, respectively, for recipients aged younger than 18 years, and 70.5% and 44.1%, respectively, for recipients aged 18 years or older.

Measuring and monitoring equity in access to deceased donor kidney transplantation.

The Organ Procurement and Transplantation Network monitors progress toward strategic goals such as increasing the number of transplants and improving waitlisted patient, living donor, and transplant recipient outcomes. However, a methodology for assessing system performance in providing equity in access to transplants was lacking. We present a novel approach for quantifying the degree of disparity in access to deceased donor kidney transplants among waitlisted patients and determine which factors are most associated with disparities. A Poisson rate regression model was built for each of 29 quarterly, period-prevalent cohorts (January 1, 2010-March 31, 2017; 5 years pre-kidney allocation system [KAS], 2 years post-KAS) of active kidney waiting list registrations. Inequity was quantified as the outlier-robust standard deviation (SDw ) of predicted transplant rates (log scale) among registrations, after "discounting" for intentional, policy-induced disparities (eg, pediatric priority) by holding such factors constant. The overall SDw declined by 40% after KAS implementation, suggesting substantially increased equity. Risk-adjusted, factor-specific disparities were measured with the SDw after holding all other factors constant. Disparities associated with calculated panel-reactive antibodies decreased sharply. Donor service area was the factor most associated with access disparities post-KAS. This methodology will help the transplant community evaluate tradeoffs between equity and utility-centric goals when considering new policies and help monitor equity in access as policies change.

OPTN/SRTR 2016 Annual Data Report: Liver.

Data on adult liver transplants performed in the US in 2016 are no-table for (1) the largest total number of transplants performed (7841); (2) the shortest median waiting time in recent history (11.3 months); (3) continued reduction in waitlist registrations and transplants for hepatitis C-related indications; (4) increasing numbers of patients whose clinical profiles are consistent with non-alcoholic fatty liver disease; and (5) equilibration of transplant rates in patients with and without hepatocellular carcinoma. Despite the increase in the number of available organs, waitlist mortality remained an important concern. Graft survival rates continued to improve. In 2016, 723 new active candidates were added to the pediatric liver transplant waiting list, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) was stable, 408 active and 169 inactive. The number of pediatric living donor liver transplants decreased from a peak of 79 in 2015 to 62 in 2016, with most from donors closely related to the recipients. Graft survival continued to improve over the past decade among recipients of deceased donor and living donor livers.

Late subannular aortic root rupture following transcatheter aortic valve implantation presenting as ST elevation myocardial infarction.

Transcatheter aortic valve implantation (TAVI) has transformed the treatment of severe aortic stenosis. Here, we present a case of late aortic root rupture presenting as ST-elevation myocardial infarction five weeks following successful TAVI. Aortic root rupture is a rare complication of TAVI, which occurs in ∼1% of procedures and usually arises during or soon after the procedure and is associated with high mortality (∼50%). Early recognition of late-presenting complications related to TAVI, including aortic root rupture, is essential for specialists and nonspecialists. © 2016 Wiley Periodicals, Inc.

OPTN/SRTR 2015 Annual Data Report: Intestine.

Intestine and intestine-liver transplant remains important in the treatment of intestinal failure, despite decreased morbidity associated with parenteral nutrition. In 2015, 196 new patients were added to the intestine transplant waiting list, with equal numbers waiting for intestine and intestine-liver transplant. Among prevalent patients on the list at the end of 2015, 63.3% were waiting for an intestine transplant and 36.7% were waiting for an intestine-liver transplant. The pretransplant mortality rate decreased dramatically over time for all age groups. Pretransplant mortality was notably higher for intestine-liver than for intestine transplant candidates (respectively, 19.9 vs. 2.8 deaths per 100 waitlist years in 2014-2015). By age, pretransplant mortality was highest for adult candidates, at 19.6 per 100 waitlist years, and lowest for children aged younger than 6 years, at 3.6 per 100 waitlist years. Pretransplant mortality by etiology was highest for candidates with non-congenital types of short-gut syndrome. Numbers of intestine transplants without a liver increased from a low of 51 in 2013 to 70 in 2015. Intestine-liver transplants increased from a low of 44 in 2012 to 71 in 2015. Short-gut syndrome (congenital and non-congenital) was the main cause of disease leading to intestine and to intestine-liver transplant. Patient survival was lowest for adult intestine-liver recipients and highest for pediatric intestine recipients.

OPTN/SRTR 2015 Annual Data Report: Liver.

Several notable developments in adult liver transplantation in the US occurred in 2015. The year saw the largest number of liver transplants to date, leading to reductions in median waiting time, in waitlist mortality for all model for end-stage liver disease categories, and in the number of candidates on the waiting list at the end of the year. Numbers of additions to the waiting list and of liver transplants performed in patients with hepatitis C virus infection decreased for the first time in recent years. However, other diagnoses, such as non-alcoholic fatty liver disease and alcoholic cirrhosis, became more prevalent. Despite large numbers of severely ill patients undergoing liver transplant, graft survival rates continued to improve. The number of new active candidates added to the pediatric liver transplant waiting list in 2015 was 689, down from a peak of 826 in 2005. The number of prevalent pediatric candidates (on the list on December 31 of the given year) continued to decline, to 373 active and 195 inactive candidates. The number of pediatric liver transplants peaked at 613 in 2008 and was 580 in 2015. The number of living donor pediatric liver transplants increased to its highest level, 79, in 2015; most were from donors closely related to the recipients. Pediatric graft survival rates continued to improve.

Intestine.

Intestine and intestine-liver transplant plays an important role in the treatment of intestinal failure, despite decreased morbidity associated with parenteral nutrition. In 2014, 210 new patients were added to the intestine transplant waiting list. Among prevalent patients on the list at the end of 2014, 65% were waiting for an intestine transplant and 35% were waiting for an intestine-liver transplant. The pretransplant mortality rate decreased dramatically over time for all age groups. Pretransplant mortality was highest for adult candidates, at 22.1 per 100 waitlist years compared with less than 3 per 100 waitlist years for pediatric candidates, and notably higher for candidates for intestine-liver transplant than for candidates for intestine transplant without a liver. Numbers of intestine transplants without a liver increased from a low of 51 in 2013 to 67 in 2014. Intestine-liver transplants increased from a low of 44 in 2012 to 72 in 2014. Short-gut syndrome (congenital and other) was the main cause of disease leading to both intestine and intestine-liver transplant. Graft survival improved over the past decade. Patient survival was lowest for adult intestine-liver recipients and highest for pediatric intestine recipients.

Liver.

The median waiting time for patients with MELD ≥ 35 decreased from 18 days in 2012 to 9 days in 2014, after implementation of the Share 35 policy in June 2013. Similarly, mortality among candidates listed with MELD ≥ 35 decreased from 366 per 100 waitlist years in 2012 to 315 in 2014. The number of new active candidates added to the pediatric liver transplant waiting list in 2014 was 655, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) continued to decline, 401 active and 173 inactive. The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and was 478 in 2014. The number of living donor liver pediatric transplants was 52 in 2014; most were from donors closely related to the recipients. Graft survival continued to improve among pediatric recipients of deceased donor and living donor livers.

The role of rotational thromboelastometry in assessment of haemostasis during pregnancy in women with factor XI deficiency.

INTRODUCTION: Women with factor XI (FXI) deficiency are at an increased risk of bleeding complications at delivery. Obstetric management is complicated by a lack of correlation between FXI level and bleeding risk. AIM: The aims of this study were to assess the difference in rotational thromboelastometry (ROTEM® ) in parturient women with FXI deficiency compared to parturient and non-parturient controls and to evaluate the usefulness of ROTEM® in assessing bleeding risk at delivery in women with FXI deficiency. METHODS: ROTEM® was performed on 60 women: 27 with FXI deficiency, 20 age-matched parturient controls and 12 non-parturient controls. Pregnancy outcomes and haemostatic cover was reviewed in 57 deliveries of women with FXI deficiency. RESULTS: Women with FXI deficiency had a longer clotting time (CT) and clot formation time (CFT) (P < 0.001), reduced alpha angle (P < 0.001) but no difference in MCF (P = 0.054) compared to parturient controls. Compared to non-parturient controls, they had a longer CT (P < 0.001), but shorter CFT (P < 0.001), increased alpha angle (P < 0.001) and increased MCF (P = 0.005). ROTEM® was an additional helpful parameter in managing parturient women with FXI deficiency, reducing the need for factor administration. CONCLUSION: ROTEM® demonstrated hypercoagulable changes during pregnancy in women with FXI deficiency. However, they took longer to clot compared to parturient controls, but had increased clot consolidation and clot strength compared to non-parturient controls. ROTEM® is an additional test that is helpful to assess bleeding risk and provision of appropriate haemostatic cover at delivery.

OPTN/SRTR 2013 Annual Data Report: intestine.

Despite improvements in medical and surgical treatment of intestinal failure over the past decade, intestine transplant continues to play an important role. Of 171 new patients added to the intestine transplant waiting list in 2013, 49% were listed for intestine-liver transplant and 51% for intestine transplant alone or with an organ other than liver. The pretransplant mortality rate decreased dramatically over time for all age groups, from 30.3 per 100 waitlist years in 2002-2003 to 6.9 for patients listed in 2012-2013. The number of intestine transplants decreased from 91 in 2009 to 51 in 2013; intestine-liver transplants decreased from 135 in 2007 to a low of 44 in 2012, but increased slightly to 58 in 2013. Ages of intestine and intestineliver transplant recipients have changed substantially; the number of adult recipients was double the number of pediatric recipients in 2013. Graft survival improved over the past decade. Graft failure in the first 90 days posttransplant occurred in 14.1% of intestine recipients and in 11.2% of intestine-liver recipients in 2013. The number of recipients alive with a functioning intestine graft has steadily increased since 2002, to 1012 in 2013; almost half were pediatric intestine-liver transplant recipients.

OPTN/SRTR 2013 Annual Data Report: liver.

During 2013, 10,479 adult candidates were added to the liver transplant waiting list, compared with 10,185 in 2012; 5921 liver transplants were performed, and 211 of the transplanted organs were from living donors. As of December 31, 2013, 15,027 candidates were registered on the waiting list, including 12,407 in active status. The most significant change in allocation policy affecting liver waitlist trends in 2013 was the Share 35 policy, whereby organs from an entire region are available to candidates with model for end-stage liver disease scores of 35 or higher. Median waiting time for such candidates decreased dramatically, from 14.0 months in 2012 to 1.4 months in 2013, but the effect on waitlist mortality is unknown. The number of new active pediatric candidates added to the liver transplant waiting list increased to 693 in 2013. Transplant rates were highest for candidates aged younger than 1 year (275.6 per 100 waitlist years) and lowest for candidates aged 11 to 17 years (97.0 per 100 waitlist years). Five-year graft survival was 71.7% for recipients aged younger than 1 year, 74.9% for ages 1 to 5 years, 78.9% ages 6 to 10 years, and 77.4% for ages 11 to 17 years.

OPTN/SRTR 2012 Annual Data Report: intestine.

Advances in the medical and surgical treatments of intestinal failure have led to a decrease in the number of transplants over the past decade. In 2012, 152 candidates were added to the intestinal transplant waiting list, a new low. Of these, 64 were listed for intestine-liver transplant and 88 for intestinal transplant alone or with an organ other than liver. Historically, the most common organ transplanted with the intestine was the liver; this practice decreased substantially from a peak of 52.9% in 2007 to 30.0% in 2012. Short-gut syndrome, which encompasses a large group of diagnoses, is the most common etiology of intestinal failure. The pretransplant mortality rate decreased dramatically over time for all age groups, from 51.0 per 100 wait-list years in 1998-1999 to 6.7 for patients listed in 2010-2012. Numbers of intestinal and intestine-liver transplants steadily decreased from 198 in 2007 to 106 in 2012. By age, intestinal transplant recipients have changed substantially; the number of adult recipients now approximately equals the number of pediatric recipients. Graft survival has improved over the past decade. Graft failure in the first 90 days after transplant occurred in 15.7% of 2011-2012 intestinal transplant recipients, compared with 21% in 2001-2002.

OPTN/SRTR 2012 Annual Data Report: liver.

Liver transplant in the us remains a successful life-saving procedure for patients with irreversible liver disease. In 2012, 6256 adult liver transplants were performed, and more than 65,000 people were living with a transplanted liver. The number of adults who registered on the liver transplant waiting list decreased for the first time since 2002; 10,143 candidates were added, compared with 10,359 in 2011. However, the median waiting time for active wait-listed adult candidates increased, as did the number of candidates removed from the list because they were too sick to undergo transplant. The overall deceased donor transplant rate decreased to 42.3 per 100 patient-years, and varied geographically from 18.9 to 228.0 per 100 patient-years. Graft survival continues to improve, especially for donation after circulatory death livers. The number of new active pediatric candidates added to the waiting list also decreased. Almost 75% of pediatric candidates listed in 2009 underwent transplant within 3 years; the 2012 rate of deceased donor transplants among active pediatric wait-listed candidates was 136 per 100 patient-years. Graft survival for deceased donor pediatric transplants was 92.8% at 30 days. Medicare paid for some or all of the care for more than 30% of liver transplants in 2010.

Effects of a dietary antioxidant blend and vitamin E on growth performance, oxidative status, and meat quality in broiler chickens fed a diet high in oxidants.

The aim of the study was to determine the effects of a dietary antioxidant blend (AB) and vitamin E on performance, oxidative status, and meat quality. Cobb 500 male broilers (n = 1,200, d 0) were randomly distributed into 6 treatments with 10 replicate pens. Treatments included 1) HO: high oxidant diet, vitamin E at 10 IU/kg, 3% oxidized soybean oil, 3% polyunsaturated fatty acid (PUFA) source; 2) VE: the HO diet with vitamin E at 200 IU/kg; 3) AOX: the HO diet with AB at 135 mg/kg; 4) VE+AOX: the HO diet with vitamin E at 200 IU/kg and AB at 135 mg/kg; 5) SC: standard control; and 6) PC: positive control, the SC diet with AB at 135 mg/kg. From d 0 through d 21, high oxidant diet treatment birds had greater BW, ADG, and ADFI than the SC birds; the AOX birds had better G:F on d 10 and 42, and from d 0 to 42 than SC birds (P < 0.05). The plasma TBA reactive substance level was lower in the AOX birds than the VE treatment birds in all phases (P < 0.05). High oxidant diet treatment birds had greater α-1-acid glycoprotein levels on d 10 than SC and PC birds (P < 0.05). The AOX, PC, and SC birds had a greater level of uric acid than the HO and VE+AOX birds on d 10. Superoxide dismutase expression in the liver was less with the HO treatment compared with the SC treatment on d 7 (P < 0.05). The vitamin E concentration in the breast muscle was greatest in the VE birds, whereas vitamin A concentration was greater in the PC birds compared with the SC birds on d 21 (P < 0.05). Compared with VE and AOX, the HO treatment had greater drip loss (P < 0.05). In conclusion, dietary addition of AOX was effective in improving growth, moderately restored the whole body antioxidant capability, and reduced drip loss.

Effects of a dietary antioxidant blend and vitamin E on fatty acid profile, liver function, and inflammatory response in broiler chickens fed a diet high in oxidants.

The aim of the current study was to determine the effects of a dietary antioxidant blend and vitamin E on fatty acid profile, inflammatory response, and liver function. Cobb 500 male broilers (n = 1,200, d 0) were randomly distributed into 6 treatments with 10 replicate floor pens. Treatments included (1) a high-oxidant diet, with vitamin E at 10 IU/kg, 3% oxidized oil, 3% polyunsaturated fatty acids (PUFA) source (HO); (2) the HO diet with vitamin E at 200 IU/kg (VE); (3) the HO diet with an antioxidant blend at 135 mg/kg (AOX); (4) the HO diet with both vitamin E at 200 IU/kg and an antioxidant blend at 135 mg/kg (VE+AOX); (5) standard control (SC); and (6) a positive control, which was the SC diet with an antioxidant blend at 135 mg/kg. The concentrations of 20:4, 20:5, 22:5, 22:6, and all the n-3 fatty acids were greater in the abdominal fat of HO, VE, AOX, and VE+AOX birds than SC and positive control birds on d 21 and 42 (P < 0.001). Compared with HO treatment, AOX and VE+AOX preserved the deposition of PUFA better (P < 0.001). The HO birds had greater concentrations of aspartate aminotransferase on d 21 and 42, and γ-glutamyl transferase on d 21, whereas AOX and VE+AOX chickens had restored γ-glutamyl transferase concentration (P < 0.01). The inflammation scores of abdominal fat of AOX and VE+AOX birds were lower than the HO on d 21 (P < 0.001). Compared with SC, the VE and VE+AOX birds exhibited greater vacuole scores on d 21 and 42 (P < 0.01). The lower vacuoles score in SC was associated with a greater expression of peroxisome proliferator activated receptor -γ and -α (P < 0.05). The expression of inflammatory genes in the liver did not differ among treatments. In conclusion, the AOX and AOX+VE diets were effective in preserving PUFA in the abdominal fat, moderately improved liver function, and reduced inflammation in fat.

The Impact of Virtual Reality on Anxiety and Pain During US-Guided Breast Biopsies: A Randomized Controlled Clinical Trial.

OBJECTIVE: To investigate the efficacy of immersive virtual reality (VR) in combination with standard local anesthetic for mitigating anxiety and pain during US-guided breast biopsies compared to local anesthetic alone. METHODS: Patients scheduled for US-guided biopsy were invited to participate. Eligible patients were females 18 years of age or older. Patients were randomized to VR or control group at a 1:1 ratio. Patients in the VR group underwent biopsy with the addition of a VR experience and patients in the control group underwent usual biopsy. Patient-perceived levels of anxiety and pain were collected before and after biopsy via the State-Trait Anxiety Inventory (STAI) and Visual Analog Scale (VAS). Physiological data were captured during biopsy using a clinically validated wristband. Differences in anxiety, pain, and physiologic data were compared between the VR and control group. RESULTS: Sixty patients were enrolled. After excluding 2 patients with VR device malfunction, there were 29 patients in the VR and 29 patients in the control group for analysis. The VR group had reduced anxiety compared to the control group based on postintervention STAI (P <.001) and VAS (P = .036). The VR group did not have lower pain based on postintervention VAS (P = .555). Physiological measures showed higher RR intervals and decreased skin conductance levels, which are associated with lower anxiety levels in the VR group. CONCLUSION: Use of VR in addition to standard local anesthetic for US-guided breast biopsies was associated with reduced patient anxiety. Virtual reality may be a useful tool to improve the patient biopsy experience.

OPTN/SRTR 2011 Annual Data Report: liver.

The current liver allocation system, introduced in 2002, decreased the importance of waiting time for allocation priorities; the number of active wait-listed candidates and median waiting times were immediately reduced. However, the total number of adult wait-listed candidates has increased since 2002, and median waiting time has increased since 2006. Pretransplant mortality rates have been stable, but the number of candidates withdrawn from the list as being too sick to undergo transplant nearly doubled between 2009 and 2011. Deceased donation rates have remained stable, with an increasing proportion of expanded criteria donors. Living donation has decreased over the past 10 years. Transplant outcomes remain robust, with continuously improving graft survival rates for deceased donor, living donor, and donation after circulatory death livers. Numbers of new and prevalent pediatric candidates on the waiting list have decreased. Pediatric pretransplant mortality has decreased, most dramatically for candidates aged less than 1 year. The transplant rate has increased since 2002, and is highest in candidates aged less than 1 year. Graft survival continues to improve for pediatric recipients of deceased donor and living donor livers. Incidence of acute rejections increases with time after transplant. Posttransplant lymphoproliferative disorder remains an important concern in pediatric recipients.

OPTN/SRTR 2011 Annual Data Report: intestine.

Since 2006, the number of new intestinal transplant candidates listed each year has declined, likely reflecting increased medical and surgical treatment for intestinal failure. Historically, intestinal transplant occurred primarily in the pediatric population; in 2011, 41% of prevalent candidates on the waiting list were aged 18 years or older. The most common etiology of intestinal failure remains short-gut syndrome, which encompasses several diagnoses. The proportion of candidates with high medical urgency status decreased and time on the waiting list increased in 2011. The overall rate of transplant decreased from a peak of 92.7 transplants per 100 wait-list years in 2005 to 49.2 in 2011. The number of intestines recovered and transplanted per donor has decreased since 2007, possibly due to fewer listed patients. Almost 50% of deceased donor intestines were transplanted with another organ in 2011. Historically, the most common organ transplanted with the intestine was the liver, but in 2011 it was the pancreas. Graft survival has continued to improve over the past decade, and the number of recipients alive with a functioning intestinal graft has steadily increased since 1998. Hospitalization is common, occurring in 84.8% of recipients by 6 months posttransplant and in almost all by 4 years.

Expression and properties of hyperpolarization-activated current in rat dorsal root ganglion neurons with known sensory function.

The hyperpolarization-activated current (I(h)) has been implicated in nociception/pain, but its expression levels in nociceptors remained unknown. We recorded I(h) magnitude and properties by voltage clamp from dorsal root ganglion (DRG) neurons in vivo, after classifying them as nociceptive or low-threshold-mechanoreceptors (LTMs) and as having C-, Aδ- or Aα/ß-conduction velocities (CVs). For both nociceptors andLTMs, I(h) amplitude and I(h) density (at -100 mV) were significantly positively correlated with CV.Median I(h) magnitudes and I(h) density in neuronal subgroupswere respectively:muscle spindle afferents(MSAs):-4.6 nA,-33 pA pF(-1); cutaneous Aα/ß LTMs: -2.2 nA, -20 pA pF(-1); Aß-nociceptors: -2.6 nA, -21 pA pF(-1); both Aδ-LTMs and nociceptors: -1.3 nA, ∼-14 pA pF(-1); C-LTMs: -0.4 nA, -7.6 pA pF(-1); and C-nociceptors: -0.26 nA, -5 pApF(-1). I(h) activation slow time constants (slow τ values) were strongly correlated with fast τ values; both were shortest in MSAs. Most neurons had τ values consistent with HCN1-related I(h); others had τ values closer to HCN1+HCN2 channels, or HCN2 in the presence of cAMP. In contrast, median half-activation voltages (V(0.5)) of -80 to -86 mV for neuronal subgroups suggest contributions of HCN2 to I(h). τ values were unrelated to CV but were inversely correlated with I(h) and I(h) density for all non-MSA LTMs, and for Aδ-nociceptors. From activation curves ∼2-7% of I(h)would be activated at normal membrane potentials. The high I(h) may be important for excitability of A-nociceptors (responsible for sharp/pricking-type pain) and Aα/ß-LTMs (tactile sensations and proprioception). Underlying HCN expression in these subgroups therefore needs to be determined. Altered high I(h) may be important for excitability of A-nociceptors (responsible for sharp/pricking-type pain) and Aα/ß-LTMs (tactile sensations and proprioception). Underlying HCN expression in these subgroups therefore needs to be determined. Altered Ih expression and/or properties (e.g. in chronic/pathological pain states) may influence both nociceptor and LTM excitability.expression and/or properties (e.g. in chronic/pathological pain states) may influence both nociceptor and LTM excitability.