[Early rehabilitation in Baden-Wurttemberg--a study of all Baden-Wurrtemberg early rehabilitation centers]. / Frührehabilitation in Baden-Württemberg--Eine Untersuchung aller Frührehabilitationseinrichtungen Baden-Württembergs.

Over a period of 12 months, all persons among the 10.4 million inhabitants of the state of Baden-Württemberg were included in the study who had suffered severe brain damage and were treated in special early rehab units, comprising 147 beds for adults and 43 for children. With 830 patients admitted, the incidence of severe brain damage was 7.98/100.000 in adults and 1.11/100.000 in children. 50 to 70 year old patients were over-represented, those older than 70 years were underrepresented due to geriatric rehab facilities for the latter. Male patients dominated, while female were somewhat younger. 54% of the patients were admitted from the hospital which had performed primary care, with an average stay of 67 days. Average early rehab duration was 53 days (arithmetic average; median 40 days, some patients required up to one year). 32.8% of the patients had suffered traumatic brain damage (ICD 851, 852, 854) and 40.9% non-traumatic brain affection (ICD 430, 431, 433-438, 310, 348), including 12.2% CVA (ICD 433-438), 8.5% subarachnoid and 12.3% intracerebral hemorrhage. Severity as indexed by the early rehab Barthel index improved from an initial average of -119 to -34 at discharge. 80% of the patients showed an overall improvement (71% of them by up to 200 points and 46% by up to 100 points).

Cranial rhythmic impulse related to the Traube-Hering-Mayer oscillation: comparing laser-Doppler flowmetry and palpation.

The primary respiratory mechanism (PRM) as manifested by the cranial rhythmic impulse (CRI), a fundamental concept to cranial osteopathy, and the Traube-Hering-Mayer (THM) oscillation bear a striking resemblance to one another. Because of this, the authors developed a protocol to simultaneously measure both phenomena. Statistical comparisons demonstrated that the CRI is palpably concomitant with the low-frequency fluctuations of the THM oscillation as measured with the Transonic Systems BLF 21 Perfusion Monitor laser-Doppler flowmeter. This opens new potential explanations for the basic theoretical concepts of the physiologic mechanism of the PRM/CRI and cranial therapy. Comparison of the PRM/CRI with current understanding of the physiology of the THM oscillation is therefore warranted. Additionally, the recognition that these phenomena can be simultaneously monitored and recorded creates a new opportunity for further research into what is distinctive about the science and practice of osteopathic medicine.

A hazard of home oxygen therapy.

Although it is generally safe, there are morbidities associated with home oxygen use. Experience in our burn unit led to an analysis of burn complications from this therapy. A retrospective review of records during a 12-year period identified 23 patients with burns associated with home oxygen use. Average age of the patients was 70 years, with chronic obstructive pulmonary disease the most prevalent indication for use. Concomitant cigarette smoking was the most common inciting mechanism of the burns (70%). Average burn size was 3.9% of total body surface area. Eleven patients presented in the first 10 years of the study period, whereas 12 presented in the last 2 years. We have seen a rise in injuries with the use of home oxygen. The absolute number of injuries sustained is unknown, because many are likely unreported. To decrease the morbidity and costs associated with these injuries, the need for continuing safety education is apparent.

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.

Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.

Drug-like properties and the causes of poor solubility and poor permeability.

There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.

Geldanamycin provides posttreatment protection against glutamate-induced oxidative toxicity in a mouse hippocampal cell line.

The benzoquinoid ansamycin geldanamycin interferes with many cell signaling pathways and is currently being evaluated as an anticancer agent. The main intracellular target of geldanamycin is the 90-kDa heat shock protein, hsp90. In this report we demonstrate that geldanamycin is effective at preventing glutamate-induced oxidative toxicity in the HT22 mouse hippocampal cell line, even if given 4 h after glutamate treatment. Geldanamycin prevents glutamate-induced internucleosomal DNA cleavage in the HT22 cells but does not reverse the depletion of glutathione levels brought about by glutamate treatment. Both anabolic and catabolic effects are generated by geldanamycin treatment of HT22 cells, as evidenced by the induction of hsp70 expression and degradation of c-Raf-1 protein, respectively. Thus, geldanamycin may provide an effective strategy for manipulating signaling pathways in neuronal cells that use hsp90 as they proceed through a programmed cell death pathway in response to oxidative stress.

Normoxic ventilation during resuscitation and outcome from asphyxial cardiac arrest in rats.

The formation of reactive oxygen species during reperfusion is one trigger for neuronal injury after global cerebral ischemia. Because formation of reactive oxygen species requires delivery of molecular oxygen to ischemic tissue, restricting inspired oxygen during reperfusion may decrease neurological damage. This study examined whether ventilation with room air rather than pure oxygen during resuscitation would improve neurological recovery after cardiac arrest in rats. Adult, male rats were subjected to 8 min of asphyxia resulting in cardiac arrest. During resuscitation, rats were ventilated either with hyperoxia (FiO2 = 1.0) or normoxia (FiO2 = 0.21, room air). Neurobehavioral deficits were scored daily for 72 h after resuscitation, after which brains were collected for histology. Normoxia decreased arterial oxygen content. Other physiological parameters and mortality did not differ between groups. All surviving rats exhibited behavioral and histological signs of brain damage. Neurological deficit scores did not differ between normoxia and hyperoxia conditions at any time point. The number of ischemic neurons in the hippocampus also did not differ between groups. These data indicate neither benefit nor detriment of reducing inspired oxygen concentration during resuscitation from asphyxial cardiac arrest in rats.

Vertebrobasilar distribution stroke mimicking transtentorial herniation.

Strokes in the vertebrobasilar arterial distribution may result in a variety of physical findings and can be challenging to diagnose. We report a case of a 60-year-old woman with infarction of the left midbrain, right pons, and bilateral thalami with physical findings resembling transtentorial herniation.

Quantitative structure-activity relationships among macrolide antibacterial agents: in vitro and in vivo potency against Pasteurella multocida.

Quantitative structure-activity relationships have been found among macrolide antibacterial agents in their potencies against the bacterial pathogen Pasteurella multocida both in vitro and in mouse infections. To obtain these relationships we measured, among other things, the pK(a)'s and log P's of 15 known macrolides of diverse structures. Among these compounds, in vitro potency [log(1/MIC)] is a function of log P, log D, and CMR (R = 0.86). In vivo potency is a function of the higher pK(a), the HPLC chromatographic capacity factor log k', log(1/MIC) and pNF (R = 0.93). pNF is defined as the negative logarithm of the fraction of neutral drug molecules present in aqueous solution at pH 7.4. The same physical properties were determined for 14 macrolides not used in developing the original QSAR models. Using the in vivo model, we calculated the mouse protection potency ranges for these new compounds. Ten estimates agreed with those observed, three were lower by a half-order of magnitude, and one was calculated to be active in the range of 15-50 mg/kg, but in fact was not active at 50 mg/kg, the highest level tested. When these new compounds were combined with the original 15, and the QSAR's updated, the new equations for the in vitro and in vivo potencies were essentially the same as those originally found. Hence, the physical properties indicated above are major determinants of macrolide antibacterial potencies.

Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis.

OBJECTIVE: To assess the efficacy of 0.75% metronidazole vaginal gel, formulated at pH 4.0, for the treatment of bacterial vaginosis in a double-blind, placebo-controlled crossover trial. METHODS: Fifty-three women with bacterial vaginosis (clue cells of at least 20% plus vaginal pH of at least 4.7, amine odor, or homogeneous discharge) were enrolled. Women with concomitant infection by Candida, Trichomonas, Chlamydia trachomatis, or Neisseria gonorrhoeae were excluded. Five grams of metronidazole gel or placebo was inserted intravaginally twice daily for 5 days. Response to therapy was evaluated at 4-16 days and 1 month after treatment. RESULTS: Twenty-six of the 30 women (87%) who received metronidazole were free of bacterial vaginosis 9-21 days after enrollment, compared with only four (17%) of 23 placebo-treated women (P < .001). Women who were cured were followed prospectively. Those who had persistent bacterial vaginosis were crossed over to metronidazole gel in an open trial; bacterial vaginosis was eradicated in 21 of 23 (91%) of these women at the 2-week follow-up. Recurrent bacterial vaginosis developed within 1 month in four (15%) of 26 women who were initially cured after receiving metronidazole gel. Response to therapy was accompanied by a decrease in vaginal Bacteroides, Gardnerella vaginalis, and Mycoplasma hominis. CONCLUSIONS: Treatment with intravaginal metronidazole gel resulted in a clinical cure in 87% (placebo-controlled trial) to 91% (crossover trial) of women with bacterial vaginosis. The recurrence rate of 15% at 1 month after treatment is similar to that reported with oral metronidazole.

[Glutaric acidemia/glutaric aciduria I as differential chorea minor diagnosis]. / Die Glutarazidämie/Glutarazidurie I als Differentialdiagnose der Chorea minor.

Glutaracidemia/glutaraciduria type I is an acute or subacute neuropathic disorder of infancy or early childhood. The following symptoms characterize the clinical course: macrocephalus present at birth, cerebral atrophy revealed by CT or MRI scans, most striking in the frontal and temporal lobes, choreoathetosis and dystonia as neurological handicaps. The deficiency of glutaryl-CoA-dehydrogenase leads to glutaracidemia and glutaraciduria. It is reported on a three year old girl. The glutaraciduria is an important differential diagnosis to chorea minor.

Hydantoin bioisosteres. In vivo active spiro hydroxy acetic acid aldose reductase inhibitors.

The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40. These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity. In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity. In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution. Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity. The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23. ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.

[Vocational preparation and education of adolescent patients with epilepsy]. / Berufsvorbereitung und Ausbildung bei jugendlichen Anfallskranken.

Often young epileptics cannot begin a regular apprenticeship immediately after leaving school. Many cases show some somatic and psychointellectual retardation and delayed social development and maturation. Impairment of learning and concentration due to drug-side effects aggravates gaps in basic knowledge which result from frequent school absences due to epileptic illness. Attendance of a vocational training scheme for one year ensures that educational and social deficiencies can be reduced and the practice of daily work can be obtained. The epileptologist should pay particular attention to good compliance. The large variety of psycho-social and behavioural problems can be improved by event-orientated group psychotherapy. A vocational testing period can follow. Time and type of seizures have to be respected in vocational counselling. The vocational training centre for handicapped adolescents offers a comprehensive education by vocational instructors, epileptologists and psychologists.

The frequency of unrecognized type 2 herpes simplex virus infection among women. Implications for the control of genital herpes.

To evaluate the prevalence of symptomatic versus asymptomatic or unrecognized type 2 herpes simplex virus (HSV-2) infection, the authors performed physical examination, viral cultures, and type-specific serologic assays in 776 randomly selected women attending an STD clinic and 636 female university students. Forty-six percent of women attending the STD clinic compared with 8.8% of the university students had serologic evidence of HSV-2 infection. Clinical or historical evidence of genital herpes was present in only 34% of the HSV-2 seropositive women attending the STD clinic and in 29% of the HSV-2 seropositive women attending the university clinic. Among women attending the STD clinic, the prevalence of recognized genital infection was more common among those with HSV-2 antibodies only versus those with HSV-1 and -2 antibodies (odds ratio = 2.39; 95% confidence interval = 1.30-4.37), suggesting that HSV-1 infection reduces the likelihood of recognizing HSV-2 infection. In view of the high proportion of seropositive individuals with unrecognized HSV-2 infection in both high and low prevalence HSV-2 seropositive populations, newly developed HSV type-specific serologic methods should be evaluated for detecting carriers of HSV-2 infection and counseling these individuals about strategies for avoiding sexual and perinatal transmission of HSV-2.

A unified approach to systematic isosteric substitution for acidic groups and application to NMDA antagonists related to 2-amino-7-phosphonoheptanoate.

A systematic approach to the replacement of acidic groups with potential bioisosteres is described. The strategy involves simple nucleophilic displacement of a common alkyl halide precursor with a variety of mercaptoazoles and related molecules. The mercaptoazoles and their oxidized derivatives (sulfinyl- and sulfonylazoles) represent a series of possible surrogates for acidic groups which span a pKa range from about 4.5-11.5. This simple strategy was extended to include 2-hydroxy- or 2-aminothiophenyl groups which function as relatively nonacidic isosteres for a phosphonic acid. By replacing the phosphonic acid of 2-amino-7-phosphonoheptanoate (AP-7) with these groups, we have synthesized novel N-methyl-d-aspartate (NMDA) antagonists.

Prevalence of genital papillomavirus infection among women attending a college student health clinic or a sexually transmitted disease clinic.

We examined 454 women randomly selected from a Sexually Transmitted Disease (STD) Clinic and 545 consecutive college women undergoing annual examination. Patients were examined for visible genital warts, koilocytes, and human papillomavirus (HPV) antigen on cervical smears and for cervical HPV DNA types 6, 11, 16, 18, and 31. Genital warts were found in 11% of STD Clinic patients and 2% of students (P less than .001). Among those women without genital warts, HPV DNA or antigen was detected in cervical specimens from 10.6% of STD Clinic patients and 11.4% of students (P = .73), with HPV type 16, 18, or 31 being 9.8 times more frequent than cervical HPV 6 or 11 among students and 5.8 times more frequent among STD Clinic patients. Dysplasia was present in 53% of those with HPV type 6 or 11 and in 41% of those with HPV type 16, 18, or 31 DNA.