The gut microbiome and depression: a review.

BACKGROUND: Recent explorations into the gut microbiome of humans and animals reveal implications in chronic physical and mental health disorders. Relatively little is known regarding the relationship of gut microbiome and depression. In the current review, we reviewed existing scientific data related to the gut microbiome and healthy patients versus patients with depression. Additionally, scientific literature containing the utility of microbiome interventions to improve depression symptoms was reviewed. METHODS: A PubMed and Clinical Key literature search combined the key terms 'gut,' 'microbiome,' 'bacteria,' and 'depression' to identify studies investigating these relationships. RESULTS: 76 relevant articles were identified. Human and animal studies reviewed examined marked alterations in the dominant bacterial phyla in the gut of individuals with depression, the connection between leaky gut and neuroinflammation in depression, brain regulatory centers impacted by changes in the gut microbiome, and the benefits of the addition of a probiotic/prebiotic for gut and mental health. CONCLUSIONS: The current review confirmed the suspected direct communication between the gut microbiome, brain functioning, and depression. Additionally, studies suggest antibiotics disrupt the gut microbiome. There are important implications for psychiatrists in providing opportunities for intervention and enhancement of current treatments for individuals with depression.

Characteristics and Clinical Outcomes of Individuals at High Risk for Pancreatic Cancer: A Descriptive Analysis from a Comprehensive Cancer Center.

Pancreatic cancer (PC), a leading cause of cancer-related deaths in the United States, is typically diagnosed at an advanced stage. To improve survival, there is an unmet need to detect pre-malignant lesions and early invasive disease. Prime populations to study for early detection efforts include cohorts of high risk individuals (HRI): those with increased risk to develop pre-malignant pancreatic cysts and PC because of a familial or hereditary predisposition to the disease and those in the general population of sporadic cases who are incidentally found to harbor a pre-malignant pancreatic cyst. The objective of this study was to describe the characteristics and clinical outcomes of cohorts of HRI identified at Moffitt Cancer Center. We set out to determine the uptake of screening, the prevalence and characteristics of solid and cystic pancreatic lesions detected via screening or as incidental findings, and the age at which lesions were detected. Of a total of 329 HRI, roughly one-third were found to have pancreatic lesions, most of which constituted pre-malignant cysts known as intraductal papillary mucinous neoplasms. Individuals with the highest genetic risk for PC were found to have smaller cysts at a much earlier age than sporadic cases with incidental findings; however, many individuals at high genetic risk did not have abdominal imaging reports on file. We also identified a subset of HRI at moderate genetic risk for PC that were found to have cystic and solid pancreatic lesions as part of a diagnostic work-up rather than a screening protocol. These findings suggest the pancreatic research community should consider expanding criteria for who should be offered screening. We also emphasize the importance of continuity of care between cancer genetics and gastrointestinal oncology clinics so that HRI are made aware of the opportunities related to genetic counseling, genetic testing, and screening.

Proton Conductivity in Phosphoric Acid: The Role of Quantum Effects.

Phosphoric acid has one of the highest intrinsic proton conductivities of any known liquids, and the mechanism of this exceptional conductivity remains a puzzle. Our detailed experimental studies discovered a strong isotope effect in the conductivity of phosphoric acids caused by (i) a strong isotope shift of the glass transition temperature and (ii) a significant reduction of the energy barrier by zero-point quantum fluctuations. These results suggest that the high conductivity in phosphoric acids is caused by a very efficient proton transfer mechanism, which is strongly assisted by quantum effects.

Correlation between temperature variations of static and dynamic properties in glass-forming liquids.

Detailed analysis of the static structure factor S(Q) in several glass-forming liquids reveals that the temperature variations of the width of the main diffraction peak ΔQ(T) correlate with the fragility of these liquids. This observation suggests a direct connection between rather subtle structural changes and sharp slowing down of structural relaxation in glass-forming liquids. We show that this observation can be rationalized using the Adam-Gibbs approach, through a connection between temperature variations of structural correlation length, l_{c}∼2π/ΔQ, and the size of cooperatively rearranging regions.

Influence of cold-water immersion on indices of muscle damage following prolonged intermittent shuttle running.

The aim of this study was to assess the effects of cold-water immersion (cryotherapy) on indices of muscle damage following a bout of prolonged intermittent exercise. Twenty males (mean age 22.3 years, s = 3.3; height 1.80 m, s = 0.05; body mass 83.7 kg, s = 11.9) completed a 90-min intermittent shuttle run previously shown to result in marked muscle damage and soreness. After exercise, participants were randomly assigned to either 10 min cold-water immersion (mean 10 degrees C, s = 0.5) or a non-immersion control group. Ratings of perceived soreness, changes in muscular function and efflux of intracellular proteins were monitored before exercise, during treatment, and at regular intervals up to 7 days post-exercise. Exercise resulted in severe muscle soreness, temporary muscular dysfunction, and elevated serum markers of muscle damage, all peaking within 48 h after exercise. Cryotherapy administered immediately after exercise reduced muscle soreness at 1, 24, and 48 h (P < 0.05). Decrements in isometric maximal voluntary contraction of the knee flexors were reduced after cryotherapy treatment at 24 (mean 12%, s(x) = 4) and 48 h (mean 3%, s(x) = 3) compared with the control group (mean 21%, s(x) = 5 and mean 14%, s(x) = 5 respectively; P < 0.05). Exercise-induced increases in serum myoglobin concentration and creatine kinase activity peaked at 1 and 24 h, respectively (P < 0.05). Cryotherapy had no effect on the creatine kinase response, but reduced myoglobin 1 h after exercise (P < 0.05). The results suggest that cold-water immersion immediately after prolonged intermittent shuttle running reduces some indices of exercise-induced muscle damage.

Renal effects of amlodipine in normotensive renal transplant recipients.

Renal effects of amlodipine in normotensive renal transplant recipients. The use of cyclosporin A (CsA) has improved the success of renal transplantation, but is associated with hypertension and significant renal toxicity. Previous reports suggest that calcium channel blockers may be useful in opposing the adverse effects of CsA. We have evaluated the effects of amlodipine (5 mg, once daily for 8 weeks) on renal function in 27 normotensive renal transplant recipients with stable renal function, in a double-blind, placebo-controlled, multicentre, cross over study. Amlodipine significantly reduced serum creatinine concentration relative to placebo (mean+/-SD: 168+/-65 vs 177+/-66 micromol/l; P=0.002) and there was a strong trend towards an increase in effective renal plasma flow on amlodipine relative to placebo (238+/-92 vs 217+/-87 ml/min; P=0.055). Glomerular filtration rate and lithium clearance were unaffected. Trough CsA blood concentration was unaffected. Amlodipine was well tolerated, with a low incidence of adverse events, and did not affect blood pressure or heart rate. In conclusion, amlodipine reduced serum creatinine in normotensive renal transplant recipients after only 8 weeks treatment, and was well tolerated in concomitant administration with CsA.

Reduced dose OKT3 prophylaxis in sensitised kidney recipients.

Prophylactic use of the monoclonal antibody OKT3 has been studied for the prevention of rejection in sensitised renal transplant recipients. Patients receiving a full dose (FD) regimen were compared to a subsequent consecutive group of patients receiving a reduced dose (RD) regimen. The characteristics of the two groups were not significantly different with regard to age, HLA mismatch and panel-reactive antibody (PRA) status. The number of days that OKT3 was given was 12.9 +/- 1.8 for the FD regimen and 11.3 +/- 2.8 for the RD regimen. The total dose of OKT3 given was 64.4 +/- 9 mg (FD) and 38.3 +/- 8.5 mg (RD). Patient survival at 12 months was 8/8 for FD and 17/17 for RD. Graft survival at 12 months was 7/8 for FD and 17/17 for RD. Creatinine at 24 months was 185 +/- 68 and 201 +/- 81 mumol/l for FD and RD, respectively. A reduced dose regimen of OKT3 produced excellent and comparable results to the standard recommended full-dose regimen. The cost per patient was reduced 40% from 5676 pounds for FD to 3344 pounds for RD.

Pharmacokinetics and immunodynamics of chimeric IL-2 receptor monoclonal antibody SDZ CHI 621 in renal allograft recipients.

SDZ CHI 621 is a murine-human chimeric monoclonal antibody (mAb) to the interleukin-2 (IL-2) receptor (CD25) intended for prophylactic immunosuppression against acute rejection in the first several weeks following kidney transplantation. A multicentre, prospective, dose-finding study was conducted in 37 primary, mismatched cadaver kidney transplant patients to assess its tolerability, pharmacokinetics and immunodynamics. Successive cohorts of patients were stratified to receive total doses of 20, 30, 40 or 60 mg (n = 4, 4, 14, 15, respectively) administered as 15- or 20-mg intravenous infusions with the first dose given preoperatively and subsequent doses within the first 10 days posttransplant. Daily mAb serum concentrations were analysed by a radioimmunoassay method and the percentage of peripheral T-lymphocytes expressing CD25 from serial blood samples was determined by FACScan. Intravenous administrations were well tolerated. mAb concentration profiles exhibited a biphasic decline with an initial t1/2 of 14.4 +/- 14.2 h, terminal t1/2 of 13.4 +/- 6.0 days, distribution volume (Vss) of 6.9 +/- 3.31 and clearance of 17.4 +/- 7.8 ml/h. The concentration-effect (mAb-CD25) relationship indicated that mAb concentrations exceeding a threshold of about 0.7 microgram/ml corresponded to complete suppression of CD25 (< or = 3% CD25+ T-cells). The threshold mAb concentration was exceeded at all dose levels, whereas the duration above the threshold (and thus of CD25 suppression) rose with increasing dose: 20 mg, 20 +/- 7 days; 30 mg, 32 +/- 6 days; 40 mg, 37 +/- 10 days; and 60 mg, 53 +/- 17 days. As mAb concentrations declined below the threshold following the last dose, CD25 expression returned to baseline (18-44% CD25+ T-cells) within a few days.

Prolonged action of a chimeric interleukin-2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation.

A high affinity chimeric CD25 mAb (chRFT5: SDZ CHI 621) blocking interleukin-2 binding to the interleukin-2 receptor alpha-chain was evaluated in a phase I/II study in human renal cadaveric transplantation. The chRFT5 was well tolerated with no immediate adverse effects during 6 spaced infusions (from before transplantation to day 24) in 24 patients escalating from 2.5- to 25-mg dosages. The chRFT5 had a long terminal half-life with a mean of 13.1 days. There was good correlation between the detection of chRFT5 in the serum by radioimmunoassay, the coating and suppression of CD25 on T cells, and antibody activity in patient serum samples. The chRFT5 activity persisted in vivo for up to 120 days. No antibody response to the chRFT5 was detected in any of the patients, even though two patients who required treatment with antithymocyte globulin or OKT3 developed xenogeneic antiglobulin responses while chRFT5 was still present in vivo. There was a 33% incidence of rejection and the first rejection episode always occurred during chRFT5 therapy. Patients who did not reject during therapy did not reject during the first year following transplantation. Equal numbers of patients received dual and triple immunosuppressive therapy together with chRFT5. Posttransplant lymphoproliferative disorder developed in 2 patients, both on triple therapy, at 9 months after transplantation. The disorder did not develop in any patient receiving dual therapy, and no further cases have been observed to a minimum of 2 years' follow-up. No other viral, fungal, or bacterial infectious complications were prevalent in patients treated with chRFT5.

Transplanting patients with abnormal lower urinary tracts.

Since 1977, 23 patients with bladder or bladder outlet dysfunction leading to renal failure have received 28 kidney transplants in our institution. Three patients were provided with an ileal conduit, but the remainder were transplanted using their own bladder following urodynamic assessment and bladder reconstruction. Graft and patient survival were good when compared to a group of patients with normal lower urinary tracts, actuarial graft survival at 5 years being 70% for both groups and patient survival being 82% and 90%, respectively. Patients who develop renal failure from detrusor/sphincter dysfunction can be transplanted successfully once the cause of the renal failure has been identified and corrected.

Pancreatic transplantation as a small programme.

Seventeen pancreatic transplantations were performed in 17 patients with diabetic renal failure over a 6-year period. Ten patients received a simultaneous kidney transplant, the other seven having undergone previous successful renal transplantation. The actuarial pancreatic survival rate at 12 months was 63 per cent and the patient survival rate 92 per cent. The kidney transplant 12-month survival rate (86 per cent) did not differ significantly from that in a group of 22 diabetic patients receiving kidney transplants alone during the same period. Patients with a successful pancreatic transplantation had an increase in quality of life but most developed one or more complications; sometimes these required prolonged hospitalization. Pancreatic transplantation should be restricted to patients with diabetic renal failure who are particularly unstable or exhibit progressive diabetic complications. A small programme can be successful in directing what is an expensive procedure towards patients who are most likely to benefit.

Is there an optimal time for the first cyclosporin dose in renal transplantation?

It is customary for patients undergoing kidney transplantation to receive their first dose of cyclosporin either just before or during the transplant operation. This ensures the early establishment of good levels of immunosuppression but might depress early graft function and contribute towards the development of acute tubular necrosis. In a controlled clinical trial, we have studied the effects of withholding cyclosporin for 12 h in patients undergoing cadaveric renal transplantation. Consecutive adult recipients of a cadaveric renal transplant were randomised to receive their first dose of cyclosporin (10 mg/kg p.o.) 6 h prior to transplant surgery or 12 h afterwards. All patients received azathioprine (1.5 mg/kg i.v.) and methylprednisolone (0.5 g i.v.) in addition during surgery. From the 2nd day onwards both groups were treated with an identical triple immunosuppressive regimen. The 27 patients who received their first dose of cyclosporin post-operatively had significantly better immediate and subsequent function than did the 26 patients who received their cyclosporin at the time of surgery. The delayed dosing was associated with improved graft survival and no increase in the frequency of rejection episodes. This regimen is recommended for all patients receiving triple therapy.