Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells.

Ataxia telangiectasia (A-T) is a highly pleiotropic disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, immunodeficiency, hypersensitivity to radiotherapy and elevated risk of malignancies. Leukemia and lymphoma, along with lung failure, are the main causes of morbidity and mortality in A-T patients. At present, no effective therapy for A-T exists. One promising therapeutic approach is bone marrow transplantation (BMT) that is already used as a curative therapy for other genomic instability syndromes. We used an established clinically relevant non-myeloablative host-conditioning regimen and transplanted green fluorescent protein (GFP)-expressing ataxia telangiectasia mutated (ATM)-competent bone marrow-derived cells (BMDCs) into Atm-deficient mice. GFP expression allowed tracking of the potential migration of the cells into the tissues of recipient animals. Donor BMDCs migrated into the bone marrow, blood, thymus, spleen and lung tissue of Atm-deficient mice showing an ATM-competent phenotype. BMT inhibited thymic lymphomas, normalized T-lymphocyte populations, improved weight gain and rearing activity of Atm-deficient mice. In contrast, no GFP(+) cells were found in the cerebellum or cerebrum, and we detected decreased size index in MRI imaging of the cerebellum in 8-month-old transplanted Atm-deficient mice in comparison to wild-type mice. The repopulation with ATM-competent BMDCs is associated with a prolonged lifespan and significantly improved the phenotype of Atm-deficient mice.

Effectiveness of COVID-19 Vaccines against SARS-CoV-2 Infection among Persons Attending the RT-PCR center at a Medical College Hospital in Telangana: A Case- Control Study.

Background: In January 2021, India's drug regulator issued restricted emergency approval for COVISHIELD and COVAXIN, which were manufactured in India. In mid-January 2021, in India, there were 10.5 million confirmed cases and 0.15 million deaths. The objectives were to evaluate vaccine effectiveness (VE) of coronavirus disease 2019 (COVID-19) vaccines made in India against severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) infection. Materials and Methods: A test-negative case-control study was conducted from May 2021 to December 2021 for a duration of 8 months among people attending a reverse transcriptase polymerase chain reaction (RT-PCR) center at a medical college hospital for RT-PCR test for SARS-CoV-2. The baseline characteristics and RT-PCR report were collected from the RT-PCR center. The exposure to COVID-19 vaccines was enquired via phone call or was checked with data available with the health authorities. Results: After applying inclusion and exclusion criteria and case and control definitions, a total of 380 participants (95 cases and 285 controls) were included. The adjusted VE of two doses of COVISHIED vaccine against symptomatic SARS-CoV-2 infection was 52.2% (41.7 to 62.1), and that of a single dose was 40.88% (31.26 to 51.29). The adjusted VE of two doses of COVAXIN vaccine against SARS-CoV-2 infection was 39% (29.40 to 49.27). The overall VE was 48.20% (37.90 to 58.22) for two doses of any vaccines. Conclusions: Vaccines made in India were nearly 50% effective. Further new studies should be conducted as new variants of SARS-CoV-2 are emerging. We do not know the VE against the variants, and whether booster doses are required or not is not yet established.

A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA.

Lipid mediators derived from omega (n)-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) play key roles in bronchoconstriction, airway inflammation, and resolution processes in asthma. This study compared the effects of dietary supplementation with either a combination of LCPUFAs or eicosapentaenoic acid (EPA) alone to investigate whether the combination has superior beneficial effects on the outcome of asthmatic mice. Mice were sensitized with house dust mite (HDM) extract, and subsequently supplemented with either a combination of LCPUFAs or EPA alone in a recall asthma model. After the final HDM and LCPUFA administration, airway hyperresponsiveness (AHR), bronchoalveolar lavages, and lung histochemistry were examined. Lipid mediator profiles were determined by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). The LCPUFA combination reduced AHR, eosinophilic inflammation, and inflammatory cytokines (IL-5, IFN-γ, and IL-6) in asthmatic mice, whereas EPA enhanced inflammation. The combination of LCPUFAs was more potent in downregulating EPA-derived LTB5 and LTC5 and in supporting DHA-derived RvD1 and RvD4 (2.22-fold and 2.58-fold higher levels) than EPA alone. Ex vivo experiments showed that LTB5 contributes to granulocytes' migration and M1-polarization in monocytes. Consequently, the LCPUFA combination ameliorated airway inflammation by inhibiting adverse effects of EPA and promoting pro-resolving effects supporting the lipid mediator-dependent resolution program.

Safety and immunogenicity of a cluster specific immunotherapy in children with bronchial asthma and mite allergy.

BACKGROUND: Cluster specific immunotherapy (SIT) is a modern form of allergen immunotherapy allowing safe administration of high allergen doses in a short time interval compared to classic SIT. In the current study, we investigated the safety profile and immunological effect of cluster SIT in children with allergic asthma due to house dust mite allergy. METHODS: A total of 34 children (6-18 years) with allergic asthma were assigned to cluster (n = 22) or classic SIT (n = 12). To achieve a maintenance dose of allergen extract, cluster patients received 14 injections of house dust mite allergen within 6 weeks, whereas the classic SIT group received 14 injections within 14 weeks. Safety was monitored by recording adverse events. Immunogenicity was measured by specific IgG(Mite) and IgG4(Mite), by antibody-blocking properties on basophil activation, and by the T cell subset transcription factors Foxp3, T-bet, and GATA-3. RESULTS: There were no significant differences in local and systemic side effects between the two groups. In the cluster group, serum levels of specific IgG(Mite) (p < 0.001) and specific IgG4(Mite) (p < 0.001) significantly increased after 8 weeks, while it took 12 weeks in the classic SIT group. These data were confirmed by blocking CD63 expression as well as release of cysteinyl leukotrienes after in vitro basophil stimulation. No differences in transcription factor expression were found in the two groups. CONCLUSION: Cluster SIT is safe in children. Additionally, our data demonstrated an even more rapid induction of specific immune tolerance. Cluster SIT is an attractive alternative to conventional up-dosing schedules with fewer consultations for the patients.

Angiotensin II-induced hypertension in the rat. Effects on the plasma concentration, renal excretion, and tissue release of prostaglandins.

We examined in rats the effects of intraperitoneal angiotensin II (AII) infusion for 12 d on urinary excretion, plasma concentration, and in vitro release of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a PGI2 metabolite. AII at 200 ng/min increased systolic blood pressure (SBP) progressively from 125 +/- 3 to 170 +/- 9 mmHg (P less than 0.01) and elevated fluid intake and urine volume. Urinary 6-keto-PGF1 alpha excretion increased from 38 +/- 6 to 55 +/- 5 and 51 +/- 7 ng/d (P less than 0.05) on days 8 and 11, respectively, of AII infusion, but urinary PGE2 excretion did not change. Relative to a control value of 129 +/- 12 pg/ml in vehicle-infused (V) rats, arterial plasma 6-keto-PGF1 alpha concentration increased by 133% (P less than 0.01) with AII infusion. Aortic rings from AII-infused rats released more 6-keto-PGF1 alpha (68 +/- 7 ng/mg) during 15-min incubation in Krebs solution than did rings from V rats (40 +/- 3 ng/mg); release of PGE2, which was less than 1% of that of 6-keto-PGF1 alpha, was also increased. Slices of inner renal medulla from AII-infused rats released more 6-keto-PGF1 alpha (14 +/- 1 ng/mg) during incubation than did slices from V rats (8 +/- 1 ng/mg, P less than 0.05), but PGE2 release was not altered. In contrast, AII infusion did not alter release of 6-keto-PGF1 alpha or PGE2 from inferior vena cava segments or from renal cortex slices. Infusion of AII at 125 ng/min also increased SBP, plasma 6-keto-PGF1 alpha concentration, and in vitro release of 6-keto-PGF1 alpha from rings of aorta and renal inner medulla slices; at 75 ng/min AII had no effect. SBP on AII infusion day 11 correlated positively with both 6-keto-PGF1 alpha plasma concentration (r = 0.54) and net aortic ring release (r = 0.70) when data from all rats were combined. We conclude that augmentation of PGI2 production is a feature of AII-induced hypertension. The enhancement of PGI2 production may be an expression of nonspecific alteration in vascular structure and metabolic functions during AII-induced hypertension, as well as the result of a specific effect of the peptide on the arachidonate-prostaglandin system.

Micropuncture study of diuretic effects on sodium and calcium reabsorption in the dog nephron.

A close relationship has been observed between the clearance rates of sodium and calcium under a variety of diuretic conditions. The thiazide diuretics act differently in dissociating the renal tubular reabsorption of sodium and calcium. This phenomenon has been further investigated using recollection micropuncture and clearance techniques in a group of 14 dogs subjected to three consecutive experimental phases: expansion to 3% of body weight (BWt) with Ringer's solution, chlorothiazide infusion at 20 mg/kg/h, and furosemide in a prime of 10 mg/kg/ and a 10 mg/kg/h infusion. Diuretic losses were balanced with infusion of equal volumes of Ringer's solution throughout the experiment. Chlorothiazide increased the fractional excretion (FE) of sodium almost threefold while FE(Ca) was not significantly altered. Furosemide increased FE(Na) and FE(Ca) to an approximately equal, and more marked, degree. This dissociation of sodium and calcium reabsorption after chlorothiazide was also evident in the superficial distal tubule, where (tubule fluid/plasma sodium) (TF/P(Na)) increased from 0.32 to 0.49 (P < 0.01) and TF/(ultrafiltrate)UF(Ca) was unchanged (0.35-0.31). Furosemide markedly reduced the transtubular concentration gradient for both sodium (0.86) and calcium (0.94). TF/P(Inul in) decreased progressively from 3.79 to 2.78 to 2.33 in three phases. In the late proximal tubule, chlorothiazide induced a fall of TF/P(Inul in) from 1.57 to 1.44 (P < 0.01), but the ratio TF/UF(Ca): TF/P(Na) was unchanged. Furosemide had no significant proximal effect. It is concluded that acute administration of chlorothiazide reduces sodium reabsorption in the distal hephron, presumably the cortical diluting segment, without affecting calcium reabsorption.

C-reactive protein induced activation of MAP-K and RANTES in human renal distal tubular epithelial cells in vitro.

AIMS: C-reactive protein (CRP) is a component of the acute-phase reaction to inflammation, severe tissue injury, and infection. Investigations have shown that CRP concentration is highly increased in the urine during acute renal graft dysfunction and, therefore, may affect tubular cell metabolism. Nevertheless, no data about the effects of CRP on human renal tubular epithelial cells are available. METHODS: Human renal distal tubular cells (DTC) were isolated immunomagnetically and cultured. Cells were stimulated with affinity chromatography pure native CRP from human ascites (10 - 0.001 microg/ml). Phosphorylation of MAP-K was assessed by Westernblot analysis. Release of RANTES and interleukin-6 was evaluated with an enzyme immunoassay. Cytotoxic effects of CRP were determined by a commercially available Live/Dead assay and MTT assay. Effects on cell proliferation were analyzed by a fluorimetric assay. RESULTS: Westernblot analysis clearly showed that CRP activates the MAP-K pathway of DTC. CRP upregulated RANTES expression of DTC in a significant and dose-dependent manner. CRP (10 microg/ml) induced a 12.3-fold upregulation, CRP 1 or 0.1 microg/ml induced a 6.3-/2.8-fold RANTES upregulation, respectively. Interleukin-6 synthesis was not influenced. Cytotoxic, proliferative or apoptotic effects were not observed at the concentrations used. CONCLUSIONS: We demonstrated an activating effect of CRP on DTC in vitro. In vivo, this effect of CRP might be part of the immune activation cascade during episodes of renal graft rejection or bacterial infections.

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice.

Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a co-conditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host-conditioning regimen together with TBI (0.2-2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose-dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of γ-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atm-deficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model.

Estradiol is responsible for reduced renal prostaglandin dehydrogenase activity in female rats.

The contribution of sex steroids to sex-related differences in renal prostaglandin dehydrogenase activity and urinary prostaglandin excretion was examined in 7-8-week-old male and female rats subjected to sham-operation or gonadectomy at 3 weeks of age. Rats were injected subcutaneously twice over a 6-day interval with vehicle (peanut oil, 0.5 mg/kg) or with depot forms of testosterone (10 mg/kg), estradiol (0.1 mg/kg), progesterone (5 mg/kg), or with estradiol and progesterone combined (0.1 and 5 mg/kg). After the second injection, 24-h urine samples were collected for prostaglandin measurement by radioimmunoassay; the rats were killed, and renal and pulmonary prostaglandin dehydrogenase activities were determined by radiochemical assay. Renal prostaglandin dehydrogenase activity was 10-times higher in intact male rats than in intact females. Gonadectomy increased renal prostaglandin dehydrogenase activity 4-fold in females, but had no effect in males; estradiol, alone or combined with progesterone, markedly suppressed renal prostaglandin dehydrogenase activity in both sexes, while testosterone or progesterone alone had no effect. Pulmonary prostaglandin dehydrogenase did not differ between the sexes and was unaffected by gonadectomy or sex-steroid treatment. Intact female sham-operated rats excreted 70-100% more prostaglandin E2, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in urine than did males; gonadectomy abolished the difference in urinary prostaglandin E2 excretion. Estradiol decreased urinary prostaglandin E2 in females but not in males; treatment with other sex steroids did not alter urinary prostaglandin excretion.

Vasopressin release in male and female rats: effects of gonadectomy and treatment with gonadal steroid hormones.

We have found, in normal Wistar rats 10-11 weeks old, that the plasma vasopressin concentration (PADH) and the 24-h urinary excretion of vasopressin (UADHV) were higher in males than in females (P less than 0.01). In rats that were gonadectomized when they were 3 weeks old and studied when they were 10-11 weeks old, PADH and UADHV were reduced in males (P less than 0.01) and increased in females (P less than 0.01 for UADHV; PADH not significant) compared to those in intact males and females, respectively. Treatment of castrated male rats with testosterone tended to increase PADH, but estradiol, progesterone, or a combination of estradiol and progesterone were without effect; UADHV was increased by testosterone (P less than 0.01) and lowered by estradiol plus progesterone (P less than 0.01). In ovariectomized rats, PADH was unaffected by either testosterone or estradiol, but was decreased by progesterone alone (P less than 0.05) or in combination with estradiol (P less than 0.05). In these ovariectomized rats, UADHV was unaffected by testosterone and was decreased by estradiol and progesterone individually or in combination (P less than 0.01). These findings suggest that the gonadal steroid hormones can act either centrally to affect ADH release or peripherally to affect ADH metabolism. Compared to intact male rats, the lower PADH in intact female rats was accompanied by lower urine osmolality and greater urine volume, but further study will be required to appreciate fully the physiological significance of the differing PADH in males and females.

Plasma concentrations, renal excretion, and tissue release of prostaglandins in the rat with dexamethasone-induced hypertension.

This study was designed to investigate whether the hypertension produced by dexamethasone in the rat is associated with a deficit in circulating and renal prostaglandin E2 (PGE2) and PGI2, PGs that are presumed to contribute to antihypertensive mechanisms. The administration of dexamethasone (2.5 mg kg-1 week-1, sc) increased systolic blood pressure by 41 +/- 6 mm Hg (P less than 0.05) after 14 days of treatment, associated with elevations of urine volume and fluid intake and loss of body weight. The glucocorticoid, however, had no effect on the plasma concentration, urinary excretion, or vascular and renal tissue release of immunoreactive 6-keto-PGF1 alpha, a PGI2 metabolite. In contrast, dexamethasone increased (P less than 0.05) the plasma PGE2 concentration by 157% and PGE2 urinary excretion by 134% after 14 days of treatment. However, the basal release of immunoreactive PGE2 as well as the angiotension II-induced release of radiolabeled arachidonic acid and PGs from renal medulla slices incubated in Krebs solution were diminished in rats receiving dexamethasone. The steroid also reduced to about 60% (P less than 0.05) of the control value the activity in renal homogenates of 15-hydroxyprostaglandin dehydrogenase (PGDH), a major PG-catabolizing enzyme, without affecting the activity of the enzyme in the lung. Hence, the increased plasma concentration and renal excretion of PGE2 caused by dexamethasone in the face of reduced renomedullary production of the PG is presumably related to diminished degradation in the kidney and perhaps in other extrapulmonary tissues. Altogether, this study demonstrates that the hypertension induced by dexamethasone in the rat is not associated with a deficit in circulating and renal PGE2 and PGI2.

Biphasic effect of dexamethasone on urinary prostaglandins in rats: relation to alterations in renal medulla triglycerides and prostaglandin metabolism.

This study was designed to characterize the time course of the effects of dexamethasone (2.5 mg kg-1 week-1, sc) on the renal arachidonate-prostaglandin (PG) system and to define the effect of the steroid on the interstitial cells of the renal inner medulla (RIC). The RIC are rich in triglycerides, which, due to their high content of arachidonic acid, may be a source of arachidonate for PG synthesis during conditions of phospholipase inhibition. After 1 day of dexamethasone treatment, the urinary excretion of PGE2 and PGF2 alpha was reduced to about 50% of the control value (P less than 0.05), and angiotensin II-induced release of arachidonic acid and PGs from renal medulla slices was blunted (P less than 0.05). In contrast, dexamethasone treatment did not affect ionophore A23187-induced release of PGs and arachidonic acid from renal medulla slices. By day 3 of dexamethasone treatment, urinary excretion of PGE2 and PGF2 alpha had returned to control levels, and by days 5 and 14 the excretion rates of both were clearly increased (P less than 0.05). The rise in urinary PG excretion was accompanied by a reduction of renal 15-hydroxyprostaglandin dehydrogenase activity, augmentation of renal medulla microsomal PG synthetase activity, and diminution of renal medulla triglycerides, the latter associated with a reduction in the number of RIC and of RIC osmiophilic granules. This study demonstrates that the effects of dexamethasone on urinary PG are biphasic; this may reflect the changing balance between the opposing actions of the steroid on renal PG-synthesizing and catabolizing enzymes and the inhibitory effect on the synthesis of renal PG that is linked to activation of specific renal lipases by endogenous factors such as angiotensin II.

Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone.

The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene have been shown to protect against bone loss in ovariectomized rats. However, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in vitro screens to select for compounds that are mechanistically distinct from tamoxifen and raloxifene in an effort to define the properties of an ER modulator required for bone protection. Using this approach, we identified a novel high affinity ER antagonist, GW5638, which when assayed in vitro functions as an ER antagonist, inhibiting the agonist activity of estrogen, tamoxifen, and raloxifene and reversing the "inverse agonist" activity of the pure antiestrogen ICI182,780. Thus, GW5638 appears to function as an antagonist in these in vitro systems, although in a manner distinct from other known ER modulators. Predictably, therefore, GW5638 alone displays minimal uterotropic activity in ovariectomized rats, but will inhibit the agonist activity of estradiol in this environment. Unexpectedly, however, this compound functions as a full ER agonist in bone and the cardiovascular system. These data suggest that the mechanism by which ER operates in different cells is not identical, and that classical agonist activity is not required for the bone protective activity of ER modulators.

Vasopressor hyperresponsiveness in New Zealand genetically hypertensive rats.

The relationship of blood pressure (BP) to vascular hyperresponsiveness to norepinephrine (NE) in New Zealand genetically hypertensive (NZGH) rats was studied with an isolated, perfused hindquarters preparation. Four separate studies were conducted, and the findings were as follows. 1) Compared with New Zealand normotensive rats (NZNR), NZGH rats by 3 weeks of age clearly showed hyperresponsiveness, although the BP difference had not yet fully developed. 2) Bilateral renal denervation of NZGH at 3 weeks of age delayed the development of hypertension for 4 weeks, but did not lessen the vascular hyperresponsiveness. 3) In one-kidney, one clip renal hypertensive NZNR, vascular responsiveness was increased but remained less than that of age-matched NZGH. 4) In an F2 generation of NZGH-NZNR cross-bred rats, the average adult systolic BP was 163 mm Hg, similar to that of the NZGH parent strain; however, vascular responsiveness was reduced to an intermediate level, lower than that of NZGH but higher than that of NZNR. It is concluded that the vascular hyperresponsiveness of NZGH rats to NE is a primary characteristic that can be largely dissociated from elevated BP.

Renal prostaglandin excretion and metabolism in male and female New Zealand normotensive and genetically hypertensive rats.

Reduced renal 15-hydroxyprostaglandin dehydrogenase (PGDH) activity has been proposed as a cause, subsequent to elevation of intrarenal prostaglandin (PG) E2 levels, of the development or maintenance of high blood pressure (BP) in the New Zealand genetically hypertensive (NZGH) rat. To test this hypothesis, PGDH activity in homogenates of kidneys and lungs and in urine concentration and excretion of PGE2 were determined in male and female NZGH and normotensive control (NZNR) rats. Lung PGDH activities of the four groups were similar. Renal PGDH activity was 50% lower for the male NZGH than for the male NZNR, but for the female rats no difference in renal PGDH activity was found between NZGH and NZNR. In addition, there was a large sex-related difference in renal PGDH activities, values for the female rats being only 5% to 10% of the values for males. Urine PGE2 concentration and excretion were two to five times greater for the female rats than for the males, but did not differ between male NZGH and male NZNR. From these observations, it appears that neither renal PGDH activity nor urine PGE2 levels is associated with hypertension in the New Zealand genetically hypertensive strain of rats.

Platelet activating factor vasoconstriction of dog kidney. Inhibition by alprazolam.

Systemic administration of platelet activating factor (PAF; acetyl glyceryl ether phosphorylcholine) reduces renal blood flow, but the mechanism responsible for that effect has not been defined. To address that problem, we determined the effects on renal blood flow of PAF administered directly into the renal artery in pentobarbital (30 mg/kg)-anesthetized dogs. Bolus injections of PAF (0.2-0.8 microgram) caused transient renal vasoconstriction, reducing renal blood flow by 20 to 60% without altering systemic blood pressure; lyso-PAF (1 microgram) had no effect. The effects of PAF on renal blood flow were not altered by alpha-adrenergic blockade (phentolamine, 3 mg/kg) or by angiotensin II receptor blockade ([Sar1,Ala8]angiotensin II, 6 micrograms/kg/min), but they were increased in magnitude and duration by meclofenamate (5 mg/kg), a cyclooxygenase inhibitor. Methysergide (3 mg/kg), a serotonin antagonist, slightly reduced PAF effects, but a specific blocker of vascular serotonin receptors did not. Renal venous plasma platelet density was not altered by infusion of PAF into the renal artery at a dose (1-2 micrograms/min) that caused a sustained 20% renal blood flow decrease. Alprazolam, a benzodiazepine that competitively inhibited PAF-induced aggregation in canine platelet-rich plasma, also inhibited the renal vasoconstrictor action of PAF (0.8 mg/min, into the renal artery) but did not alter renal vasoconstrictor effects of norepinephrine or angiotensin II.

Renal denervation at weaning retards development of hypertension in New Zealand genetically hypertensive rats.

The development of hypertension was studied in 3 to 13-week old New Zealand genetically hypertensive (NZGH) rats subjected to bilateral renal denervation (D) or sham operations (S) at 4 weeks of age. Denervation retarded the development of hypertension and delayed the establishment of stable hypertension; blood pressure of D-NZGH rats was 15-40 mm Hg lower than that of S-NZGH rats from 3 to 7 weeks after surgery, but was similar in the two groups thereafter. D-rat renal catecholamine content was reduced to 17% of control at 1 week after surgery; by the fourth week post surgery, renal catecholamine content had risen to 40% of control, and blood pressure of the D-group had begun to rise, suggesting that spontaneous renal reinnervation prevented the antihypertensive effect of renal denervation from being a permanent one. During the period when blood pressure of the S-rats was greater than that of the D-rats, urinary sodium excretion of the two groups was not significantly different, suggesting that over this interval the relationship between blood pressure and urinary sodium excretion shifted to the right along the pressure axis in the S-rats but not in the renal denervated rats. Throughout the 60-day period of observation, urinary excretion of prostaglandin E2 and kallikrein did not differ between the renal-denervated and sham-operated rats.

Behavioral response to induced conflict in families with a hypertensive father.

To clarify the possible environmental mediation of familial aggregation of blood pressure (BP), we examined whether the behavior of family members differed between families with a hypertensive (n = 16) or a normotensive (n = 15) father. Three-member families consisting of a father, mother, and a boy or girl aged 8-13 years were videotaped as they interacted under standard conditions calling for disagreement or conflict. Their BPs were recorded before and after interactions. The videotaped material was reliably coded into behavioral categories by independent observers. The aggregate of all three members of families with hypertensive fathers, as well as normotensive mothers and the children in these families, showed significantly more negative nonverbal behavior than their counterparts in families with normotensive fathers.

Induction of RANTES, HLA-DR, and intercellular adhesion molecule-1 on highly purified distal tubular cells from human kidney.

BACKGROUND: Expression of proinflammatory molecules by tubular epithelial cells plays an important role in renal allograft rejection and inflammatory kidney diseases. Different studies from patients with acute rejection point to the involvement of distal tubular segments. At present no in vitro system for the human distal tubule is established. METHODS: Human distal tubular cells were isolated immunomagnetically. Cultured cells were stimulated with cytokines (interferon-gamma, tumor necrosis factor-alpha, interleukin-1beta, or a cytokine mix). Secretion of RANTES (regulated upon activation, normal T-cell expressed and secreted) was evaluated with an enzyme-linked immunoassay. Expression of HLA-DR and intercellular adhesion molecule (ICAM)-1 was assessed by flow cytometric analysis and immunofluorescence studies. RESULTS: Our data clearly indicate that distal tubular cells express RANTES, HLA-DR, and ICAM-1 in response to a mixture of specific cytokines. Dexamethasone inhibited the induced expression of RANTES and HLA-DR significantly, but not that of ICAM-1. CONCLUSIONS: We demonstrate an appropriate in vitro system for the human distal tubule. The present study proves the involvement of the distal tubular segment during inflammatory kidney diseases.

Determinants of hypercapnia in occlusive sleep apnea syndrome.

To assess the relative contributions of age, gender, obesity, pulmonary function, and the severity of sleep-induced respiratory abnormalities to the development of alveolar hypoventilation in patients with occlusive sleep apnea syndrome, prospective data from III patients with occlusive sleep apnea were analyzed by stepwise logistic and multiple regression techniques. The significant variables in a logistic regression model predicting the presence of hypercapnia were daytime arterial oxygen pressure (PaO2; p less than 0.0001) and gender (p less than 0.04), the latter reflecting the higher number of hypercapnic women in our patient population. Multiple regression analysis performed in the hypercapnic group to study the determinants of the severity of elevation of arterial carbon dioxide tension (PaCO2) revealed significant contribution from the PaO2, the apnea-plus-hypopnea index (AHI), and the percent predicted forced vital capacity (r2 = 0.56; p less than 0.0001), whereas in the normocapnic patients, PaCO2 related to PaO2 only. These results suggest that daytime hypoxemia, mechanical impairment of the respiratory system due to obesity or obstructive airway disease (or both), and the severity of sleep-induced respiratory abnormalities as assessed by AHI contribute to the severity of carbon dioxide retention in patients with occlusive sleep apnea in a multifactorial fashion.