A 3-year follow-up after anterior colporrhaphy compared with collagen-coated transvaginal mesh for anterior vaginal wall prolapse: a randomised controlled trial.

OBJECTIVE: To compare the 1-year (previously published) and 3-year objective and subjective cure rates, and complications, related to the use of a collagen-coated transvaginal mesh for anterior vaginal wall prolapse against a conventional anterior repair. DESIGN: Randomised controlled study. SETTING: Six departments of obstetrics and gynaecology in Norway, Sweden, Finland, and Denmark. POPULATION: A total of 138 women, of 55 years of age or older, admitted for stage ≥2 anterior vaginal wall prolapse. METHODS: The women scheduled for primary anterior vaginal wall prolapse surgery were randomised between conventional anterior colporrhaphy and surgery with a collagen-coated prolene mesh. All patients were evaluated using the Pelvic Organ Prolapse Quantification (POP-Q) assessment before and after surgery. Symptoms related to pelvic organ prolapse were evaluated using the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Pelvic Floor Distress Inventory (PFDI-20). MAIN OUTCOME MEASURES: Objective cure, defined as POP-Q stage <2 prolapse at the 1- and 3-year follow-ups. Furthermore, mesh exposure and dyspareunia were also recorded. RESULTS: In total, 138 patients (70 from the mesh group versus 68 from the conventional anterior colporrhaphy group) out of 160 (86.3%) participated in the 3-year follow-up. POP-Q revealed an objective anatomic cure for 88.1 and 91.4%, respectively, in the mesh group at the 1- and 3-year follow-ups, compared with 39.9 and 41.2% in the colporrhaphy group. No difference between the groups was observed regarding PFIQ-7, PFDI-20, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) scores. The number of mesh exposures did not change during the study period and all exposures were minor. CONCLUSION: Our study demonstrates that although the objective outcome was superior in the mesh group, the use of mesh had no impact on the subjective outcome. TWEETABLE ABSTRACT: POP-Q deteriorates after anterior prolapse surgery but remains stable in women with mesh implantation.

Relationship between the Pelvic Organ Prolapse Quantification system (POP-Q), the Pelvic Floor Impact Questionnaire (PFIQ-7), and the Pelvic Floor Distress Inventory (PFDI-20) before and after anterior vaginal wall prolapse surgery.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate the degree of correlation between the Pelvic Organ Quantification system (POP-Q) measurements and symptom questionnaire scores before and after surgery. This was a part of a randomized controlled study comparing conventional colporrhaphy with mesh repair surgery. METHODS: The correlation between POP-Q measurements and Pelvic Floor Impact Questionnaire (PFIQ-7) and Pelvic Floor Distress Inventory (PFDI-20) scores was investigated in 164 women 55 years or older scheduled for primary anterior vaginal wall prolapse surgery at baseline and the correlation between the change in point Ba and scores following surgery. Statistical analyses used McNemar's and Wilcoxon signed-rank tests, Spearman's rank-order correlation, and multiple linear regression. RESULTS: Surgery significantly improved POP-Q, PFIQ-7, and PFDI-20 scores, including subscales. We observed weak correlations between POP-Q and PFIQ-7, including subscales (r 0.173-0.324, p < 0.05), and PFDI-20, including the Pelvic Organ Prolapse Distress Inventory (POPDI) subscale (r 0.180-0.211, p < 0.05). Regression analysis demonstrated a significant relationship between point Ba and PFIQ-7 (p = 0.001) and PFDI-20 (p = 0.04), respectively. Furthermore, we observed a significant relationship between the change in point Ba (following surgery) and change in scores; point Ba following surgery was significantly correlated with symptoms of bulging (r = 0.303, p < 0.01) and bladder-emptying problems (r = 0.213, p < 0.01). CONCLUSIONS: The weak correlation between POP-Q and urogenital symptoms based on questionnaire scores suggests that neither scoring system is optimal.

Anterior colporrhaphy compared with collagen-coated transvaginal mesh for anterior vaginal wall prolapse: a randomised controlled trial.

OBJECTIVE: To investigate the anatomical cure rate and complications related to collagen-coated mesh for cystocele, compared with a conventional anterior colporrhaphy. DESIGN: A randomised controlled study. SETTING: Six departments of obstetrics and gynaecology in Norway, Sweden, Finland, and Denmark. POPULATION: Women aged 55 years or older, referred for surgery with a prolapse of the anterior vaginal wall of stage 2 or higher. METHODS: Women scheduled for primary cystocoele surgery were randomised to either anterior colporrhaphy or a collagen-coated Prolene mesh. Power analysis indicated that 130 patients had to be randomised. All patients were evaluated using the Pelvic Organ Prolapse-Quantification (POP-Q) measurement. Quality of life, symptoms, and sexual function were evaluated using the Pelvic Floor Impact Questionnaire, the Pelvic Floor Distress Inventory, and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire. MAIN OUTCOME MEASURES: The primary outcome was objective cure, defined as prolapse below POP-Q stage 2 at the 12-months follow-up. Secondary outcomes were quality of life, symptoms, and presence (or not) of complications. RESULTS: In total, 161 women were randomised to either anterior colporrhaphy or mesh (participant ages 64.9 ± 6.4 years versus 64.7 ± 6.6 years, respectively; mean ± SD). The objective cure rate was 39.8% (95% CI 28.6-50.9%) in the anterior colporrhaphy group, compared with 88.1% (95% CI 80.7-95.6%) in the mesh group (P < 0.001). Vaginal mesh exposure occurred in ten women (13.3%) and dyspareunia occurred in two women (2.7%, not significant) in the mesh group at the 12-months follow-up. Questionnaires revealed no difference between the groups. CONCLUSIONS: Our study demonstrates a significantly improved objective cure rate associated with a high exposure rate among women with mesh surgery as opposed to conventional surgery.

Hypertension in developing economies: a review of population-based studies carried out from 1980 to 1998.

AIM: Hypertension is an established major risk factor underlying the epidemic of coronary and cardiovascular diseases in most developed countries, and it has been shown to be a public health problem in many developing countries since the 1970s. This review was carried out to illustrate the current situation with regard to blood pressure levels and the prevalence and management of hypertension in developing countries. METHODS: A search for papers published in medical journals from 1991 to 1998 was performed using the MEDLINE database. A total of 40 articles were selected according to previously defined criteria. RESULTS: Hypertension is a public health problem for most of the developing countries reviewed, and it is frequently associated with low levels of awareness, treatment and control. A positive association between the gross national product per capita and the prevalence of hypertension in developing countries is also evident. CONCLUSIONS: Differences in methodology between national surveys make international comparisons difficult. Nevertheless, low-cost hypertension control programmes in developing countries are needed, along with development of the primary prevention of hypertension.

Dynamic response of cochlear blood flow to occlusion of anterior inferior cerebellar artery in guinea pigs.

In this study we investigated the autoregulation and hemodynamics of cochlear blood flow (CBF) as measured by laser-Doppler flowmetry. When the anterior inferior cerebellar artery was clamped, CBF decreased approximately 40% (not to "biological zero"), followed by a gradual increase. When the clamp was released, CBF quickly increased to as much as 167% of the baseline level and then slowly returned to baseline. We assume that the dynamic CBF response to anterior inferior cerebellar artery clamping reflects primarily a combination of passive elastic properties of the cochlear vessels and active autoregulatory mechanisms. The decrease portion of the negative phase and the increase portion of the positive phase reflect mainly passive behavior, static compliance, and resistance of vessels, whereas the slow exponential negative and positive changes indicate an active response of vessels: an autoregulatory mechanism based on compensatory vascular dilation and constriction. Our preliminary data show a very strong CBF autoregulatory response to a change in intravascular pressure. Sympathetic stimulation can enhance this autoregulation, and CO2 inhalation promotes compensatory dilation and inhibits compensatory vascular constriction.

The tonic sympathetic input to the cochlear vasculature in guinea pig.

Vascular tones is an essential component in maintaining steady regional blood flow and dynamic responsiveness of a vascular bed. Sympathetic innervation can contribute to vascular tone. Although certain studies have reported evoked changes in cochlear blood flow (CBF) with activation of the sympathetic fibers to the cochlear vasculature, other studies have failed to show evidence of sympathetic contribution to CBF regulation when the cervical sympathetic fibers were unilaterally sectioned. We hypothesized that the bilateral 'sympathectomy of the stellate ganglia' would remove sufficient sympathetic input to the cochlea to yield a change in CBF resting level. To test this hypothesis a new technique was used to expose the stellate ganglia (SG) bilaterally and induce a chemical sympathectomy. We observed that unilateral SG blockade with 2 microliters of 4 mM lidocaine hydrochloride on either side produced a 5-10% increase in CBF, which recovered to baseline during the following 2 min. A subsequent blockade of the contralateral SG produced a rapid 25-35% increase, which then recovered partially during the following 3-4 min, remaining 5-15% above the baseline over a 20 min measurement period. Superior cervical ganglion transection did not affect CBF. Our results provide evidence for the existence of a tonic sympathetic component in the control of vascular tone in guinea pig cochlea. This neural effect is derived bilaterally from SG. This result is consistent with previous anatomical studies showing the bilateral innervation of the cochlea by the SG sympathetic fibers and with previous physiological studies on the bilaterality of evoked changes in CBF due to electric stimulation of SG.

Stellate ganglion drives sympathetic regulation of cochlear blood flow.

The functional properties of the sympathetic fibers innervating the cochlea are not well understood. Adrenergic fibers supplying lateral wall structures of the cochlea have been observed terminating on radiating arterioles and collecting venules. Adrenergic fibers also terminate as 'free' endings in the spiral osseous lamina. Stimulation or transection of sympathetic fibers originating from superior cervical chain and supplying the cochlea have yielded mixed results concerning many aspects of cochlea physiology. In order to clarify the origin of sympathetic fibers and their role in control of cochlear blood flow (CBF), we examined the effect of electrical stimulation of the stellate ganglion (ESS) and transection of postganglionic fibers from the stellate on CBF measured by laser Doppler flowmetry and on systemic blood pressure (BP) in the guinea pig. ESS produced a 20-35% increase in BP and 10-15% decrease in CBF. The decrease in CBF presumably reflects the net result of increased perfusion pressure, local autoregulatory mechanisms, and a direct sympathetic-induced vasoconstriction. Section of the immediate postganglionic sympathetic trunk had little or no effect on the ESS-related change in BP; however, it eliminated the CBF reduction. Intravenously infused beta 1-blocker diminished the BP increase due to ESS, while the electrically-evoked reduction in CBF remained. Local application of an alpha-blocker on the round window blocked ESS evoked CBF reductions without altering the BP increase. These data confirm the functional role of sympathetic projections from the stellate ganglion in CBF regulation in guinea pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Substance P increases cochlear blood flow without changing cochlear electrophysiology in rats.

Carotid artery infusions of substance P yielded reductions in systemic blood pressure and elevations in cochlear blood flow (CoBF), measured via laser Doppler flowmeter, with no alterations in cochlear action potentials or cochlear microphonics in Wistar-Kyoto rats. Additionally, direct micro-infusions of substance P into the anterior inferior cerebellar artery, which contributes to the local vascular perfusion of the cochlea, yielded elevations in CoBF with no changes in systemic blood pressure. Pretreatment with a specific substance P receptor antagonist, ([D-Pro2,D-Trp7,9]SP) via the carotid artery or the anterior inferior cerebellar artery, diminished subsequent substance P-induced vascular responses. These results suggest that endogenous substance P, like other vasoactive peptides, may interact with a substance P-specific receptor population in the cochlea and may therefore participate in the ongoing regulation of CoBF. These findings also support the premise that vasodilatory hormones, along with vasoconstrictive agents, may be involved in the autoregulation of CoBF.

Betahistine increases vestibular blood flow.

Betahistine is used for treatment of several vestibular disorders. Despite the accepted use of this histamine-like substance, its mechanism of action is not well understood. The purpose of this study was to assess the possibility that one of the activities of betahistine is increasing blood flow in the peripheral vestibular end organs. Using a novel surgical approach, we identified the posterior semicircular canal ampulla of guinea pigs and placed a laser Doppler probe in position to obtain blood flow measurements from the posterior semicircular canal ampulla. Blood pressure, heart rate, and vestibular blood flow were continuously recorded. Concentration-response curves were obtained for betahistine (2.5, 5, 7.5, and 10 mg/kg) and control-vehicle (0.15 mol/L NaCl) infusions. A separate group of subjects was pretreated with the competitive selective H3 agonist, thioperimide maleate, before betahistine treatment. Increases in vestibular blood flow and decreases in blood pressure were observed in response to betahistine infusions. Pretreatment with thioperamide maleate abolished these changes at low doses of betahistine and attenuated the responses at higher doses of betahistine. These results show that betahistine administration induces increases in vestibular blood flow. These findings support the potential use of betahistine for treatment of vestibular disorders, which may be caused by compromised circulation.

Hearing of dentists in the long run: a 15-year follow-up study.

Pure tone audiograms from 68 dentists with a minimum of 10 yr in dental practice were taken in 1973 and a follow-up was carried out in 1988. The aim was to study whether the dental occupation carried a risk for hearing handicap or not. Allowance for age and sex was made by using the presbyacusis values of SPOOR as the reference. At the speech range of frequencies dentists did not differ from the reference. At higher frequencies of 4, 6, and 8 kHz dentists tended to have higher hearing thresholds than expected. At 6 kHz, both male and female dentists had highly significantly greater hearing thresholds than expected by the corresponding references in both the studies. This difference remained essentially similar over the follow-up period, indicating that dental drill noise was insufficient to cause continuous loss of hearing. While mild NIHL was very common and tended to appear earlier in male than in female dentists, there was in the long run no continuous loss of hearing in either sex other than that attributable to the natural development of presbyacusis.

Sudden deafness: a comparison of anticoagulant therapy and carbogen inhalation therapy.

Sudden deafness (SD) is a sudden or rapidly progressive, partial or complete, typically unilateral sensorineural hearing impairment that has no known specific etiologic factor. This study was designed to compare, in a group of 168 consecutive patients with SD, the effect of anticoagulant therapy and carbogen inhalation therapy. Special attention was paid to the shape of the audiogram relative to the clinical outcome and the treatment modality. We found that the configuration of the audiogram of SD patients is prognostic of the outcome, and that patients with a low-frequency-sloping hearing impairment have a better prognosis compared to the patients with a high-sloping loss. Anticoagulant treatment was most effective in low-sloping hearing losses, while carbogen inhalation may be more effective for patients with high-sloping hearing losses.

Hydrops-induced changes in cochlear blood flow.

Laser Doppler flowmetry was used to assess cochlear blood flow (CBF) in the hydropic ear in four experiments. 1) The increase in CBF elicited by local electrical stimulation of the cochlea in the hydropic ear was compared to that observed in normal controls. The magnitude of the evoked CBF change was reduced by approximately 30% in the hydropic ear compared to the normal ear. 2) The reduction in CBF evoked by direct electrical stimulation of the superior cervical ganglion was reduced by approximately one third in the hydropic ear compared to a normal ear. 3) Rhythmic (flux motion or vasomotion) variations in CBF, observed in association with lower blood pressure and thought to extend the autoregulatory range in an organ system, were reduced or eliminated in the hydropic ear. 4) The autoregulatory response to a decreased perfusion pressure, produced by decreased cardiac output, was clearly reduced relative to control in the hydropic ear. These findings represent the first report of significant CBF changes with hydrops. They are consistent with reports of increased sensitivity of the hydropic ear to trauma and stress and may be relevant considerations in the treatment of hydrops in humans.

Effects of stellate ganglion stimulation on bilateral cochlear blood flow.

The effect of intraneural electrical stimulation of the stellate ganglion (SG) on bilateral cochlear blood flow (CBF) was investigated with laser-Doppler flowmetry. The SG of 15 anesthetized guinea pigs was exposed by a novel surgical approach and stimulated with a specially designed intraneural bipolar platinum-iridium electrode. Bilateral CBF was continuously monitored. Stimulation of 0.25 mA caused a detectable increase of the systemic blood pressure (BP) and a bilateral decrease of the cochlear vascular conductance (R, defined as the ratio CBF/BP). A stimulus of 0.5 mA elicited a statistically significant ipsilateral CBF (CBFi) decrease of 3.6% +/- 5.1% from the baseline and a contralateral CBF (CBFc) decrease of 3.1% +/- 5.5%. That no statistical difference was found between CBFi and CBFc indicates that a unilateral sympathetic stimulation of the SG can cause equal bilateral responses. These responses were accompanied by a significantly increased BP (8.7% +/- 5.2% of baseline) and consequently a greatly decreased R (12.2% +/- 6.5%) of the ipsilateral cochlea. Bilateral sections of the cervical sympathetic trunk below the level of the superior cervical ganglion did not alter the evoked changes in CBF, BP, and R. It is concluded that SG stimulation can decrease the conductivity of the cochlear vessels or the supplying vessels of the cochlea. Additionally, the SG nerve fibers that cause these effects do not pass through the superior cervical ganglion.

Radiological parameters of the bony nasopharynx and the adenotonsillar size compared with sleep apnea episodes in children.

The role of enlarged adenoids and tonsils in recurrent respiratory infections and upper airway obstruction has become well-established earlier. In this study we investigated the relationship between the X-ray properties of the nasopharynx and the sleep quality by using a new sleep registration method: The Static Charge Sensitive Bed (SCSB). The estimation of the bony nasopharyngeal dimensions, the measurement of adenotonsillar volume and the sleep recordings were performed as adenoidectomy, tonsillectomy or adenotonsillectomy in hospitalized children. A surprisingly high frequency of sleep apnea episodes was found in sleep recordings of about 8 h. No correlations could be established between the X-ray anatomical estimates and sleep apnea episodes.

A critical look at the treatment of maxillary sinusitis with long-term draining tubes.

Long-term draining tubes (LTD) have become a common treatment in complicated and prolonged forms of maxillary sinus empyema. Since not all patients show good recovery with this treatment we used sinus-manometry, mathematical calculations, and scanning electron microscopy (SEM) to critically analyze 6 cases with a prolonged history of the disease. Five out of the 6 patients recovered quickly after removal of the LTDs, normally performed sinus punctures, and an appropriate antibacterial treatment. One patient underwent functional endoscopic sinus surgery. Two of the 6 patients had uncommon bacterial cultures (Pseudomonas mirabilis, Klebsiella oxytoga) in their sinus secreta. Two of the removed LTDs were examined with SEM. The porous polyethylene was shown to have absorbed bacterial plague which, besides narrowing the lumen, can cause recurrent infections. In 5 other patients, the draining pressure (DP) was 0.9 +/- 0.16(M +/- SD) kg/cm2, as measured during irrigation with a No. 2 Lichtwitz needle (1.8 mm, i.d). Mathematical calculation using the Hagen-Boisseouille equation indicated that with our LTDs (0.7 mm, i.d.) the DP needs to be 40 times greater than the DP when using an ordinary Lichtwitz needle to get equal flushing capacity. We recommend i) LTD treatment of maxillary sinus empyema be closely followed up ii) that, in prolonged cases, the LTDs should be removed and the sinuses repeatedly irrigated with an ordinary needle or antrostomy, and iii) that a more suitable tubing material and insertion system (to allow a larger radius of the tube) be developed.

A follow-up study of patients suffering from sudden sensorineural hearing loss.

Sudden sensorineural hearing loss (S-SNHL) is a common problem with a high recovery rate. However, little is known of the long-term prognosis of affected patients. The purpose of this follow-up study was to evaluate the long-term hearing results of S-SNHL patients. The sample consisted of 168 patients with S-SNHL treated with carbogen inhalation and/or anticoagulant therapy during the period 1982-89. A questionnaire was sent to these patients, and audiological investigations were carried out in a selection of these patients in 1997. Comparison of the different treatment methods showed that the difference observed in improvement of hearing was statistically significant between the carbogen inhalation and anticoagulant treatment groups. The hearing improvement achieved was stable for, on average, 8 years of follow-up. During the follow-up period, Ménière's disease was diagnosed in only 1 of the 116 patients who answered the questionnaire and no cases of acoustic neurinoma were diagnosed, indicating that establishment of a careful patient history and clinical and audiological investigations are sufficient for the diagnosis of S-SNHL. In general, the hearing improvement achieved in S-SNHL patients is stable during long-term follow-up.

Blood flow-independent accumulation of cisplatin in the guinea pig cochlea.

Considerable interindividual variability in the ototoxic effect of cisplatin has become the unpredictable dose-limiting factor in its use as curative as well as palliative therapy. The drug accumulates in highly vascular areas in the cochlea, causing dose-related hair cell loss. The purpose of this study was to assess blood flow-dependent aspects of cisplatin absorption in the cochlea in order to better understand factors that may influence cisplatin-induced ototoxicity. The effect of reduced cochlear blood flow on the ototoxic action of cisplatin was studied in guinea pigs. Before cisplatin administration the cochlear vasculature in each animal was unilaterally pre-constricted, by the application of 2% epinephrine to the round window. A 20-30% reduction in cochlear blood flow, assessed by laser Doppler flowmetry, was maintained before and after intravenous infusion of 0.1% cisplatin. Cisplatin infusion affected cochlear blood flow but not vessel conductivity. The cochlear blood flow decrease, maintained by local epinephrine application to the round window during cisplatin infusion, did not alter the cisplatin-induced hearing loss. In addition, the concentration of free cisplatin in scala tympani perilymph did not differ between epinephrine-treated and non-treated ears. Our results indicate that cisplatin transport into the cochlea is not an energy-dependent process in the lateral wall vasculature.

The mechanism and site of action of lidocaine hydrochloride in guinea pig inner ear.

Lidocaine was applied to the round window (RW) in order to localize its site of action in the cochlea. Cochlear microphonic (CM), summating potential (SP), and compound action potential (CAP) input/output functions were measured to a 16 kHz tone burst to assess the functional changes of the cochlea. In separate experiments, the effect of lidocaine on the whole cell current of isolated outer hair cells (OHC) was studied. A dose of 2 microliters of 40 mM lidocaine in saline solution, when applied to the RW, caused a small change in all measured variables, indicating a passage of the drug through the RW membrane to sites of action. However, 160 mM of lidocaine further decreased CM, SP, and CAP by a total of 40% from the control. A partial recovery occurred for CM during the 30 min follow-up period. CAP and SP continued to decline. In isolated OHCs, lidocaine decreased the whole cell current in a dose-dependent fashion. The KD for lidocaine effect on OHCs was 7 mM. Our in vivo results indicate that lidocaine affects OHCs and reduces CM, causing a subsequent reduction in SP and CAP. The increased effect of lidocaine on CAP and SP, while CM is recovering, suggests an additional specific effect of lidocaine on the cochlear nerve and/or on inner hair cells. Considering that lidocaine alters OHC current (in isolated hair cells) and that lidocaine does not affect endocochlear potential [Laurikainen et al. Acta Otolaryngol (Stockh) 1991: 112: 800-9], the observed CM changes are most likely due to an in vivo effect on OHCs. Thus, the early effect of lidocaine on the cochlea appears to be due to a significant change in organ of Corti function, rather than to direct anesthesia of the cochlear nerve. Later, an independent effect of the drug may occur on neural tissues in the inner ear.

Experimental basis for lidocaine therapy in cochlear disorders.

In order to further our basic understanding of the effects of lidocaine hydrochloride in the inner ear, cochlear potentials and blood flow (CBF) were assessed after intravenous (i.v.), anterior inferior cerebellar artery (AICA), and local round window (RW) lidocaine administrations in guinea pigs and rats. Lidocaine RW applications produced a dose dependent decrease in compound action potentials (CAP) and cochlear microphonics (CM). The sensitivity changes were more pronounced at high frequencies. These findings suggest that lidocaine has specific pharmacological action in the inner ear other than simple anesthesia of the auditory nerve. The basal turn endocochlear potentials (EP) were not altered by topical lidocaine, implicating altered organ of Corti function following local application of lidocaine. RW applications of lidocaine had no effect on CBF or systemic blood pressure (BP). I.v. infusions caused substantial reductions in BP. In the case of systemic infusions the percent changes in CBF were equal to and accountable by the BP changes. The microinfusions (50 mg/ml, 100 nl/min) through AICA produced a 30%, long lasting increase in CBF. However, neither systemic lidocaine nor AICA infusions had an effect on CAP or CM. These findings indicate that systemically given lidocaine may not cross the blood-cochlear barrier and that the cochlear electrophysiological effects due to lidocaine when given locally are partly mediated by direct influence on cochlear hair cell function; they also suggest that lidocaine-induced interference with active ion transport in the lateral wall or an influence on CBF are not contributing factors.